Review ArticleNanotechnology in Cancer Drug Delivery and SelectiveTargeting
Kumar Bishwajit Sutradhar and Md Lutful Amin
Department of Pharmacy Stamford University Bangladesh 51 Siddeswari Road Dhaka 1217 Bangladesh
Correspondence should be addressed to Kumar Bishwajit Sutradhar kumarbishwajitpharmgmailcom
Received 24 September 2013 Accepted 28 October 2013 Published 16 January 2014
Academic Editors C Alexiou H Duan and I H El-Sayed
Copyright copy 2014 K B Sutradhar and Md L Amin This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited
Nanoparticles are rapidly being developed and trialed to overcome several limitations of traditional drug delivery systems andare coming up as a distinct therapeutics for cancer treatment Conventional chemotherapeutics possess some serious side effectsincluding damage of the immune system and other organs with rapidly proliferating cells due to nonspecific targeting lack ofsolubility and inability to enter the core of the tumors resulting in impaired treatment with reduced dose and with low survival rateNanotechnology has provided the opportunity to get direct access of the cancerous cells selectively with increased drug localizationand cellular uptake Nanoparticles can be programmed for recognizing the cancerous cells and giving selective and accurate drugdelivery avoiding interaction with the healthy cells This review focuses on cell recognizing ability of nanoparticles by variousstrategies having unique identifying properties that distinguish them from previous anticancer therapies It also discusses specificdrug delivery by nanoparticles inside the cells illustratingmany successful researches and how nanoparticles remove the side effectsof conventional therapies with tailored cancer treatment
1 Introduction
Cancer is one of the most serious fatal diseases in todayrsquosworld that kills millions of people every year It is one of themajor health concerns of the 21st century which does nothave any boundary and can affect any organ of people fromany place [1] Cancer the uncontrolled proliferation of cellswhere apoptosis is greatly disappeared requires very complexprocess of treatment Because of complexity in genetic andphenotypic levels it shows clinical diversity and therapeuticresistance A variety of approaches are being practiced forthe treatment of cancer each of which has some significantlimitations and side effects [2] Cancer treatment includessurgical removal chemotherapy radiation and hormonetherapy Chemotherapy a very common treatment deliversanticancer drugs systemically to patients forquenching theuncontrolled proliferation of cancerous cells [3] Unfortu-nately due to nonspecific targeting by anticancer agentsmany side effects occur and poor drug delivery of thoseagents cannot bring out the desired outcome in most of thecases Cancer drug development involves a very complex
procedure which is associated with advanced polymer chem-istry and electronic engineering The main challenge ofcancer therapeutics is to differentiate the cancerous cellsand the normal body cells That is why the main objectivebecomes engineering the drug in such a way as it can identifythe cancer cells to diminish their growth and proliferationConventional chemotherapy fails to target the cancerouscells selectively without interacting with the normal bodycells Thus they cause serious side effects including organdamage resulting in impaired treatment with lower dose andultimately low survival rates [4]
Nanotechnology is the science that usually deals with thesize range from a few nanometers (nm) to several hundrednm depending on their intended use [5] It has been the areaof interest over the last decade for developing precise drugdelivery systems as it offers numerous benefits to overcomethe limitations of conventional formulations [6 7] It is verypromising both in cancer diagnosis and treatment since it canenter the tissues at molecular level Cancer nanotechnology isbeing enthusiastically evaluated and implemented in cancertreatment indicating a major advance in detection diagnosis
Hindawi Publishing CorporationISRN NanotechnologyVolume 2014 Article ID 939378 12 pageshttpdxdoiorg1011552014939378
2 ISRN Nanotechnology
and treatment of the disease Various researches are beingcarried out in order to discover more accurate nanotechnol-ogy based cancer treatment minimizing the side effects of theconventional ones [5] Nanoparticles are now being designedto assist therapeutic agents to pass through biologic barriersto mediate molecular interactions and to identify molecularchanges They have larger surface area with modifiable opti-cal electronicmagnetic and biologic properties compared tomacroparticles Current nanotechnology based drug deliverysystems for cancer treatment which are alreadymarketed andunder research and evaluation include liposomes polymericmicelles dendrimers nanospheres nanocapsules and nan-otubes [8 9] Nanotechnology based formulations that havealready been marketed are DOXIL (liposomal doxorubicin)and Abraxane (albumin bound paclitaxel) [10]
2 Limitations of Conventional Chemotherapy
Conventional chemotherapeutic agents work by destroyingrapidly dividing cells which is the main property of neo-plastic cells This is why chemotherapy also damages normalhealthy cells that divide rapidly such as cells in the bonemarrow macrophages digestive tract and hair follicles [2]The main drawback of conventional chemotherapy is thatit cannot give selective action only to the cancerous cellsThis results in common side effects of most chemotherapeu-tic agents which include myelosuppression (decreased pro-duction of white blood cells causing immunosuppression)mucositis (inflammation of the lining of the digestive tract)alopecia (hair loss) organ dysfunction and even anemia orthrombocytopeniaThese side effects sometimes impose dosereduction treatment delay or discontinuance of the giventherapy [11 12] In case of solid tumors cell division maybe effectively ceased near the center making chemother-apeutic agents insensitive to chemotherapy Furthermorechemotherapeutic agents often cannot penetrate and reachthe core of solid tumors failing to kill the cancerous cells [13]
Traditional chemotherapeutic agents often get washedout from the circulation being engulfed by macrophagesThus they remain in the circulation for a very short timeand cannot interact with the cancerous cells making thechemotherapy completely ineffective The poor solubilityof the drugs is also a major problem in conventionalchemotherapy making them unable to penetrate the biolog-ical membranes [4] Another problem is associated with P-glycoprotein a multidrug resistance protein that is overex-pressed on the surface of the cancerous cells which preventsdrug accumulation inside the tumor acting as the effluxpump and often mediates the development of resistanceto anticancer drugs Thus the administered drugs remainunsuccessful or cannot bring the desired output [14ndash17]
3 Nanotechnology in Cancer Targeting
Nanotechnology has made a great revolution in selectivecancer targeting Nanoparticles can be designed throughvarious modifications such as changing their size shapechemical and physical properties and so forth to program
them for targeting the desired cells They can target theneoplastic cells either through active or passive targeting
31 Active Targeting In case of active targeting nanoparticlescontaining the chemotherapeutic agents are designed insuch a way as they directly interact with the defected cellsActive targeting is based on molecular recognition Hencethe surface of the nanoparticles is modified to target thecancerous cells Usually targeting agents are attachedwith thesurface of nanoparticles for molecular recognition Designednanoparticles target the cancerous cells either by ligand-receptor interaction or antibody-antigen recognition [18ndash20]Nanotechnology based targeted delivery system has threemain components (i) an apoptosis-inducing agent (anti-cancer drug) (ii) a targeting moiety-penetration enhancerand (iii) a carrier A variety of substances are used to constructa nanoparticle Commonly used materials include ceramicpolymers lipids and metals [21] Natural and syntheticpolymers and lipids are typically used as drug delivery vectors[22ndash24] Particles containing chemotherapeutic agents areengulfed by phagocytes and rapidly cleared by the retic-uloendothelial system (RES) A variety of strategies weredeveloped to sustain the nanoparticles in blood stream oneof which is the alteration of the polymeric composition of thecarrier Nanoparticles are coated with hydrophilic polymersto avoid wash out and remain in the bloodstream for a longerperiod of time that can sufficiently target cancerous cellsHydrophilic polymer coating on the nanoparticle surfacerepels plasma proteins and escapes from being opsonized andcleared This is described as a ldquocloudrdquo effect [25ndash28] Com-monly used hydrophilic polymers include polyethylene glycol(PEG) poloxamines poloxamers polysaccharides and soforth [29 30] Cancerous cells have some unique propertiesthat differentiate them from the healthy cells at molecularlevel Some receptors are over expressed on the surface ofthem that make the distinguishing feature Attachment ofthe complementary ligands on the surface of nanoparticlesmakes them able to target only the cancerous cells Oncethe nanoparticles bind with the receptors they rapidlyundergo receptor-mediated endocytosis or phagocytosis bycells resulting in cell internalization of the encapsulated drugNumerous works are being done to investigate these ligand-receptor interactions and utilize them for clinical use [5]
311 Specific Receptor Targeting
Folate Receptor Folate receptors are overexpressed in manyneoplastic cells providing a target for certain anticancertherapies Utilizing the concept researchers are designing thesurface of nanoparticles with folic acid [31ndash33] Russell-Joneset al examined the potential of using folic acid as a targetingagent for the delivery of pHPMA conjugated daunomycin infour murine tumor models Folic acid targeted daunomycin-HPMA conjugates were found to increase both the numberof survivors and the survival time of tumor-bearingmiceThedata indicate that folic acidmay be highly effective in enhanc-ing the efficacy of other polymer-bound cytotoxins [34]
ISRN Nanotechnology 3
Another study was done by a team led by Kukowska-Latalloto et al which tests the folate-linked methotrexatedendrimers in immunodeficient athymic nude female miceThe mice were injected with the nanoconjugates twice aweek via a lateral tail vein The results showed that con-jugated methotrexate in dendrimers significantly loweredtoxicity and resulted in a 10-fold higher efficacy comparedto free methotrexate at an equal cumulative dose As aresult mice survived longer [33] The efficacy of nanosizedfolate receptor-targeted doxorubicin aggregates was testedfor cancer treatment Doxorubicin-polyethylene glycol-folateconjugatemicelles were prepared that were 200 nm in averagediameter The polymeric micelles exhibited enhanced andselective targeting to folate receptor positive cancer cellsin vitro The in vivo animal experiments showed that thenanoaggregates caused significant tumor suppression [3536]
Some other preparations include nanoparticles to whichfolate was conjugated covalently using surface carboxylgroups as well as conjugation of folate to hydrazine mod-ified poly-lactic acid nanoparticles Isobutyl-cyanoacrylate(IBCA) nanocapsules were prepared and coated with folatethat showed a significantly increased efficacy of nanocapsulestargeted to the tumor [8] The experiments showed folatereceptors can be targeted very effectively for selective drugdelivery by nanoparticles conjugated to folic acid
Transferrin Receptor Nanoparticles are widely being investi-gated to target the transferrin receptors for binding and cellentry as these are overexpressed by certain tumor cells toincrease their iron uptake Transferrin (Tf) can be conjugatedto a variety of materials for cancer targeting which includeTf-chemotherapeutic agent Tf-toxic protein Tf-RNases Tf-antibody and Tf-peptide [37 38] Kawamoto et al foundthat Tf-lytic hybrid peptide can selectively target cancerouscells They administered Tf-lytic peptide in an athymic micemodel with MDA-MB-231 cells The Tf-lytic hybrid peptideshowed effective cytotoxic activity where normal cells wereless sensitive to this molecule It was additionally revealedthat this preparation can disintegrate the cell membrane ofT47D cancer cells just in 10 min killing them effectively andinducing approximately 80 apoptotic cell death but not innormal cells Thus the intravenous administration of Tf-lyticpeptide in the athymic mice model significantly inhibitedtumor progression [37] Bellocq et al found that at lowtransferrin modification the nanoparticles remain stable inphysiologic salt concentrations and transfect leukemia cellswith increased efficiency The transferrin-modified nanopar-ticles are effective for systemic delivery of nucleic acidtherapeutics for metastatic cancer [39 40]
Luteinizing Hormone-Releasing Hormone Receptor Luteiniz-ing hormone-releasing hormone (LHRH) is being used inmany ongoing researches as a targeting moiety (ligand)to LHRH receptors that are over-expressed in the plasmamembrane of various types of cancer cells like breast cancerovarian cancer and prostate cancer [41 42] FarokhzadLanger and colleagues developed a new technique to deliverthe drugs in cancer cellrsquos internal fluidThey laced tailor-made
tiny sponge-like nanoparticles with the drug docetaxel Theparticles were particularly designed to dissolve the drug in acellrsquos internal fluids controlling the release rate For selectivetargeting the nanoparticles were ldquodecoratedrdquo on the outsidewith targeting molecules called aptamers tiny chunks ofgenetic material The aptamers specifically recognize the sur-face molecules on cancer cells In addition the nanoparticlesalso contained polyethylene glycol molecules to keep themaway from being rapidly destroyed by macrophages [43]
A team led by Prasad developed a method of target-ing LHRH receptor with ferric oxide nanoparticles whichwas prepared by a reverse micelle colloidal reaction Thehydrophilic groups were sequestered in the micelle core andthe hydrophobic groups remained solvent exposed on thesurface of the micelle in a reverse micelle system which wasformed by a surfactant continuous oil phase and waterA tracking agent two-photon dye ASPI-SH was attachedto the surface of the iron oxide Silica was added to formthe structure of the silica shell before additional silica shellgrown by tetraethylorthosilicate hydrolysis The targetingagent LHRH was coupled to the silica shell through carbonspacers so as to prevent stearic hindrance during the interac-tion of the targeting agent with its complementary moleculeon cells After the administration of the nanoparticles thepatients were exposed to a DC magnetic field The selectiveinteraction internalization and so forth were investigatedby using LHRH receptor expressing cells on oral epithelialcarcinoma cells Data clearly showed that the nanoparticlesselectively interacted with the specific cell types [8]
Asialoglycoprotein Asialoglycoprotein (ASGP) anotherreceptor which is overexpressed in hepatoma is utilizedin cancer targeting by nanoparticles for anticancer drugdelivery Sung and coworkers developed a new strategyby which biodegradable nanoparticles with a mean sizeof 140 nm can be prepared to target the hepatoma cellsThey prepared them from poly(-120574-glutamic acid)-poly(lactide) block copolymers loaded with paclitaxel usingemulsion solvent evaporation technique The nanoparticleswere conjugated with galactosamine (GAL) through anamide linkage to enhance hepatoma HepG2 cell uptake bytargeting ASGP receptors Immunofluorescence analysisutilizing a rhodamine-123 probe encapsulated in thehydrophobic core of the gal-nanoparticles revealed thehigh degree of selectivity of the nanoparticles to hepatictumors with enhanced cellular uptake through receptor-mediated endocytosis resulting in subsequent release ofthe encapsulated paclitaxel inside the cytoplasm Thosenanoparticles inhibited the growth of the cells with aconsequent decrease in systemic toxicity compared to freepaclitaxel
A dual-particle tumor targeting systemwas developed forselectively inhibiting angiogenesis in hepatoma Nanoparti-cle encapsulating ganciclovir conjugatedwith galactosaminewas the first component and an enhanced permeability andretention (EPR) mediated targeting nanoparticle containingan HSV thymidine kinase (TK) gene was the second compo-nent of the dual-particle tumor targeting system It was statedthat thymidine kinase would digest ganciclovir to produce
4 ISRN Nanotechnology
cytotoxic effects after cancer cells internalization of the firstand second nanoparticles together Thus it kills the targetedcancer cells [8]
312 Antibody Mediated Targeting Many tumor cells showunusual antigens due to their genetic defects that are eitherinappropriate for the cell type environment or temporalplacement in the organismsrsquo development The immuneresponses educed by tumor antigens are not so strong becausethey are recognized as own cells Highly specific monoclonalantibodies (mAbs) are used to strengthen the immuneresponse and to intensify the immune systemrsquos antitumorcapacityThese antibodies target proteins that are abnormallyexpressed in neoplastic cells and are essential for their growthNanoparticles conjugated with an antibody against a specifictumor antigen are developed for selective drug delivery [7]Most of the mAbs are produced by the clones of a singlehybridoma cell The hybridoma cell results from the fusionof a myeloma that produces antibody and an antigenicallystimulated normal plasma cell to bind specifically to tumorcell antigens After binding with tumor antigens mAbscan destroy cancer cells through a variety of approacheswhich include directly inducing apoptosis blocking growthfactor receptors and anti-idiotype formation They canindirectly eradicate cancer cells by activating complementmediated cellular cytotoxicity and antibody dependent cellmediated cytotoxicity [8] Antibody engineering has recentlyflourished with the outcome of antibody production thatcontains animal and human origins such as chimeric mAbshumanizedmAbs (those with a greater human contribution)and antibody fragments Antibodies can be used in theiroriginal form or as fragments for cancer targeting Howeverthe presence of two binding sites (within a single antibody)gives higher binding opportunity and makes it advantageousto use the intact mAbs Moreover a signaling cascade isinitiated to kill the cancer cells whenmacrophages bind to theFc segment of the antibody The Fc portion of an intact mAbcan also bind to the Fc receptors on normal cells resultingin increased ability to evoke an immune response and liverand spleen uptake of the nanocarrier Stability in long-termstorage is their additional advantage On the other hand anti-body fragments including antigen-binding fragments (Fab)dimers of antigen-binding fragments (F(ab1015840)2) single-chainfragment variables (scFv) and other engineered fragmentsare considered safer with reduced nonspecific binding [544 45] Phage display libraries may be used to rapidly selectantibodies or their fragments that bind to and internalizewithin cancer cells This method generates a combination ofpotentially useful antibodies that bind to different epitopes (apart of a receptor that is recognized by antibodies) of the sametarget cells Thus several epitopes of a single receptor willbe recognized by multiple antibodies proving more accurateand selective action [46ndash48] The efficacy of antibodies canbe increased by conjugating a therapeutic agent directly toit mAbs can act as the highly specific probes when theyare attached to nanoparticles to aid in targeted delivery ofvarious antitumor cytotoxic agents [5] Binding affinity andselectivity to cell surface targets by engineering proteinscan also be increased through the detection of a specific
conformation of a target receptor A fusion protein consistingof an scFv antibody fragment to target and deliver smallinterfering RNA (siRNA) to lymphocytes showed a 10000-fold increased affinity for the target receptor integrin LFA-1in a recent study done by Peer et al [49]
Kuroda and fellows developed a method for the prepara-tion of hollow protein nanoparticles containing ganciclovirwhich encapsulates a hepatic cancer therapeutic gene thymi-dine kinase (HSV1tk) derived from simple herpes virusThe nanoparticles were modified by displaying a hepatitis Bvirus surface-antigen to own hepatocyte recognition abilityand particle formation ability A human hepatoma bearinganimal model demonstrated that when a hepatic cancer-treating gene was encapsulated into hepatitis B virus surface-antigen (HBsAg) particles the gene was specifically deliveredinto a human liver-derived tissue part after administeringthe particles through intravenous injection The therapeuticeffect of the HBsAg-HSV1tk hollow protein nanoparticlesspecific to hepatic cancer was also confirmed They alsodeveloped a method of encapsulating cytotoxic drug con-taining a cancer treating gene within nanoparticles modifiedto display an antibody used for specific targeting of humansquamous carcinoma cells The nanoparticles were modifiedto express an antibody that recognizes the epidermal growthfactor receptor expressed by the cancer cells Animal studiesconfirmed that the transfer and expression of the genewas very specific to the human squamous carcinoma andhighly effective in treatment [8] Wartlick et al developedbiodegradable nanoparticles based on gelatin and humanserum albumin in which the surface of the nanoparticles wasmodified by covalent attachment of the biotin-binding pro-tein NeutrAvidin enabling the binding of biotinylated drugtargeting ligands by avidin-biotin complex formation HER2receptor a member of the epidermal growth factor receptorfamily is overexpressed in certain types of cancer (breastcancer) HER2 receptor specific antibody trastuzumab (her-ceptin) was conjugated to the surface of these nanoparti-cles for targeting HER2-overexpressing cells Confocal laserscanning microscopy showed an effective internalization ofthese nanoparticles by HER2-overexpressing cells throughreceptor-mediated endocytosis [50]
Nanoparticles can be designed to enhance Fas ligandexpression a type-II transmembrane protein which inducesapoptosis when bound with its receptor on the surface ofFas receptor-expressing leukemia cells Fas ligand-receptorinteractions play a significant role in the regulation of theimmune system and the progression of cancer [51 52] Fasagonist CH-11 a monoclonal antibody to the Fas receptoris conventionally used to target the cancer cells The mAbrituximab (Rituxan) was approved in 1997 for the treatmentof patients with non-Hodgkinrsquos lymphoma
313 Antiangiogenesis Angiogenesis is described as thegrowth of new blood vessels from preexisting vesselsTumors cannot grow more than 2mm in diameter with-out angiogenesis [53ndash55] Cancerous cells produce abnor-mal amounts of angiogenic growth factors resulting in anexcessive angiogenesis overwhelming the effects of naturalangiogenesis inhibitors giving rise to leaky and tortuous
ISRN Nanotechnology 5
vessels that are in a constant state of inflammation [54ndash58] Studies on breast cancer showed that the degree ofmetastasis tumor recurrence and shorter survival ratesare correlated with angiogenesis [56 59] Antiangiogenesistherapy is designed based on two mechanisms drugs whichprevent the formation of new blood vessels that supply to thetumor (eg TNP-470 endostatin and angiostatin) or drugsthat destroy the existing blood vessels (eg combretastatin)[60] The objective of antiangiogenic therapy is to delay bothprimary andmetastatic tumor growth by blocking the supplyof essential nutrients and the removal of metabolites causingstunted tumor growth thereby avoiding tumor spread as wellas enhancing the shrinkage of tumors [61] Antiangiogenicdrugs either act directly by targeting endothelial receptorsor indirectly by targeting angiogenic cytokines [62ndash64]Active targeting of the tumor vasculature by nanoparticles isachieved by targeting the VEGF receptors (VEGFRs) 120572]1205733integrin receptors and other angiogenic factors Integrinswhich mediate the attachment between a cell and its sur-roundings are the main component in angiogenesis processand their increase in number enhances the survival growthand invasion of both tumor and endothelial cells [64 65]120572]1205733 integrin antibody has been widely used as a targetingmoiety on nanovectors for anti-angiogenesis therapy due toits pleitropic upregulation in many tumor settings Someof them have passed several clinical trials [66ndash69] Tumorangiogenesis was successfully detected in rabbit and mousemodels by perfluorocarbon nanoparticles conjugated to var-ious contrasting agents (Gadolinium Gd or fluorine isotope19 19F) and linked to an 120572]1205733 integrin antibody [66 68] Theuse of peptides as the targeting agents resulted in increasedintracellular drug delivery in different murine tumor models[70 71] An approach to target integrin overexpressioninvolves using a synthetic peptide containing the recognitionsite for integrins namely an arginine-glycine-aspartic acid(RGD) sequence [67] The first angiogenesis inhibitor forcolorectal cancer therapy bevacizumab (Avastin) an anti-VEGF mAb that inhibits the growth factor of new bloodvessels was approved in 2004 [5 72] Prokop and his teamdeveloped amethod of preparing biocompatible nanoparticlethat can be used as drug delivery vehiclesTheywere designedto retain and deliver Antiangiogenic compounds over anextended period of time for targeting tumor vasculatureNanoparticleswere formulated comprising a hydrophilic coreof sodium alginate cellulose sulfate and Antiangiogenicfactors such as thrombospondin (TSP)-1 or TSP-517 whichwas crosslinked with dextran polyaldehyde with calciumchloride or conjugated to heparin sulfate with sodiumchloride In addition luciferase (bioluminescent agent) orpolymeric gadolinium (contrast agent) was placed withinthe polyanionic core The hydrophilic shell surroundingthe core additionally contained spermine hydrochloridepoly(methylene-co-guanidine) hydrochloride and pluronicF-68 calcium chloride and a targeting ligand conjugatedto an activated polyethylene glycol or crosslinked to dex-tran polyaldehyde Targeted nanoparticles were evaluatedby monitoring luciferase in a murine model [8] Figure 1illustrates the process of active targeting
32 Passive Targeting Nanoparticles can also target cancerthrough passive targeting As apoptosis is stopped in cancer-ous cells they continue sucking nutritious agents abnormallythrough the blood vessels forming wide and leaky bloodvessels around the cells induced by angiogenesis Leaky bloodvessels are formed due to basement membrane abnormalitiesand decreased numbers of pericytes lining rapidly prolif-erating endothelial cells [73] Hence the permeability ofmolecules to pass through the vessel wall into the interstitiumsurrounding tumor cells is increased The size of the poresin leaky endothelial cells ranges from 100 to 780 nm [74ndash76]Thus nanoparticles below that size can easily pass through thepores [77 78] As a result it facilitates to efflux the nanopar-ticles to cluster around the neoplastic cells Nanoparticlescan be targeted to specific area of capillary endothelium toconcentrate the drug within a particular organ and perforatethe tumor cells by passive diffusion or convection Lack oflymphatic drainage eases the diffusion process The tumorinterstitium is composed of a collagen network and a gel likefluid The fluid has high interstitial pressures which resistthe inward flux of molecules Tumors also lack well-definedlymphatic networks having leaky vasculature Thereforedrugs that enter the interstitial area may have extendedretention times in the tumor interstitium This feature iscalled the enhanced permeability and retention (EPR) effectand facilitates tumor interstitial drug accumulation (Figure 1)[79 80] Nanoparticles can easily accumulate selectively byenhanced permeability and retention effect and then diffuseinto the cells [81]
4 Cellular Uptake pH DependentDrug Delivery and Prevention fromLysosomal Degradation
Active or passive targeted nanoparticles face amajor difficultyin releasing drugs in the neoplastic cells since lysosomalenzymes rapidly destroy both the nanoparticles and drugsinside the cells After internalization the colloidal carri-ers usually reach the lysosomal compartment in whichhydrolytic enzymes degrade both the carrier and its contentTherefore the intracellular distribution of the carrier ismodified when the encapsulated drug is a nucleic acidBecause pH around of tumors cells is more acidic carriersthat change solubility at lower pH can be used to targetand release drugs The extracellular environment of solidtumors is acidic and there is an altered pH gradient acrosstheir cell compartments Nanoparticles sensitive to the pHgradients are promising for cancer drug delivery A pH-responsive nanoparticle consists of a shell and a core andit responds to the pH gradient and changes its solubilitypattern The core-shell polymer nanoparticles are designedwith their lower critical solution temperature (LCST) beingdependent on the ambient pH 74 At low pH in and aroundof tumor cells the resulting change in LCST causes the core-shell nanoparticles to deform and precipitate in an acidicenvironment triggering the release the chemotherapeuticsA targeting molecule is additionally conjugated to the shellof the nanoparticles which can recognize tumor cells [82]
6 ISRN Nanotechnology
Passive targeting Active targeting Targeted nanoparticle
Tumor Drug or drug-loaded nanocarriers
Normal tissue Receptor-mediated endocytosis
Figure 1 Active and passive targeting by nanoparticles
Shefer and his team reported a new strategy for preparing apH sensitive sustained release system for cancer treatmentThe system utilizes solid hydrophobic nanospheres contain-ing anticancer drugs that are encapsulated in a pH sensitivemicrosphere It additionally included a bioadhesive materialinto the solid hydrophobic matrix of the nanospheres Thenanosphere hydrophobic matrix was formed by dispersingpaclitaxel into the hotmelt of candelillawaxThemicrosphereof pH sensitive matrix was created by adding the drugwaxmixture into an aqueous solution containing a pH dependentanionic polymer which is stable at pH 74 but solubilizedat pH 6 and lower The prepared suspension was spraydried to produce a free flowing dry powder which consistsof 10 paclitaxel The nanospheres can release the drugover an extended period of time by dissolvingswelling themicrosphere at a lower pH that is typically found in canceroustissue [8] Recently researchers developed a system thateither fuse with the plasmamembrane or have a pH-sensitiveconfiguration that changes conformation in the lysosomesand allows the encapsulated material to escape into thecytoplasm [83] Biodegradable nanoparticles were formu-lated from the copolymers of poly(dl-lactide-co-glycolide)for their rapid endolysosomal escape The system workedby selective reversal of the surface charge of nanoparticles(from anionic to cationic) in the acidic endolysosomalcompartment causing the nanoparticles to interact with theendolysosomal membrane and escape into the cytosol Thesenanoparticles can deliver wide ranged therapeutic agentsincluding macromolecules such as DNA at a slow rate forsustained therapeutic effect For using nanotechnology incancer treatment researchers developed thermoresponsivepH-responsive and biodegradable nanoparticles by graftingbiodegradable poly (dl-lactide) ontoN-isopropyl acrylamideand methacrylic acid It may be sufficient for a carrier systemto concentrate the drug (hydrophobic that crosses the plasmamembrane easily) in the target tissue [84]
5 Hyperthermia
Healthy cells are capable of surviving exposure to temper-atures up to 465∘C Irreversible cell damage occurs to thecancerous cells at temperatures from approximately 40∘C to
about 46∘C due to the disorganized and compact vascularstructure for which they are less stable On the other handsurrounding healthy cells are more readily able to spatterheat and maintain a normal temperature This process statedabove is called hyperthermia which is used for the purpose ofdamaging protein and structures within cancerous cells andin some cases causing tumor cells to directly undergo apop-tosis Nanoparticles are utilized for a variety of purposes inhyperthermia-based treatments which include serving as theactive thermotherapeutic agents sensitizers and are also usedfor targeting purposes like antibody enhanced targeting toincrease efficacy and to reduce hypothermia-associated sideeffects Nanoparticles can locate and specifically target thedeep-seated tissues and organs Magnetic fluid hyperthermiais a well-practiced old method for cancer treatment Smallmagnetic particles are used which respond to an externallyapplied magnetic field by heating up In addition to specifictargeting nanoparticles add another benefit Cells that havepicked up some of the particles cannot get rid of them andthus every daughter cell will have one half of the amount ofparticles present on the mother cell
Handy et al developed a method of manufacturingnanoparticles for targeted delivery of thermotherapy incancer treatment The prepared ferromagnetic nanoparticleswere coated with biocompatible material poly(methacrylicacid-co-hydroxy-ethylmethacrylate) using free-radical poly-merization A stabilizing layer was formed around the mag-netic particles by an ionic surfactant sodiumbis-2-ethylhexylsulfosuccinate For selective targeting antibodies were cova-lently attached to the surface of coatedmagnetic particlesThethermotherapeutic magnetic composition containing single-domain magnetic particles attached to a target specific ligandwas inductively heated using amagnetic field High efficiencyof the bioprobes was determined in animal model [8 31]
6 Combination of Drugs Having DifferentPhysical Properties
Several studies have recently shown that combination therapyis more effective than a single drug for many types ofcancer Drugs having different physical properties could notbe combined into a single particle before Furthermore
ISRN Nanotechnology 7
it has always been difficult to get the right amount of drugto the tumor Langer and fellows developed a new method todevelop nanoparticles in which they incorporated drugs withdifferent physical properties which had been impossible withprevious drug delivering nanoparticles Earlier generations ofnanoparticles mean encapsulation in a polymer coating bywhich drugs with different charges or different affinity couldnot be carried together The new technique called ldquodrug-polymer blendingrdquo allowed the researchers to hang the drugmolecules like pendants from individual units of the poly-mer before the units assemble into a polymer nanoparticleThey developed nanoparticles with hydrophobic docetaxeland hydrophilic cisplatin After loading the drugs into thenanoparticle the researchers added a tag that binds to amolecule called prostate-specificmembrane antigen (PSMA)which is a type 2 integral membrane glycoprotein presenton the surfaces of most prostate cancer cells This tag allowsthe nanoparticles to bypass healthy tissues and reduce theside effects caused by most chemotherapy drugs As a resultthey go directly to their target region The new techniquefacilitated them to precisely control the ratio of drugs loadedinto the particle They were also able to control release rate ofthe drugs after they entered the tumor cells [85]
7 Overcoming Other Limitations ofConventional Chemotherapy
Lack of solubility is one of the major limitations of mostchemotherapeutic agents Nanoparticles can effectively solvethe solubility problem Hydrophobic drugs can be encap-sulated in micelles to increase their solubility [86 87]Dendrimers contain many binding sites with which bothhydrophobic and hydrophilic molecules can bind Liposomesalso allow encapsulating hydrophobic drugs and transport-ing them to the desired area soon after administration[87] Several approaches have been taken to overcome P-glycoproteinmediated drug resistance P-glycoprotein locatesdrugs which are localized in the plasmamembrane only Onestrategy is to use the inhibiting agents such as verapamil orcyclosporine when concurrently administered with a cyto-toxic drug can restrain P-glycoproteinThus both chemother-apeutic agent and inhibiting agent are incorporated intothe nanoparticles to overcome the problem associated withP-glycoprotein [25 88 89] A new strategy was devel-oped for inhibition of the P-glycoprotein-mediated effluxof vincristine where vincristine-loaded lipid nanoparticlesconjugated to an anti-P-glycoprotein monoclonal antibody(MRK-16) showed greater cytotoxicity in resistant humanmyelogenous leukaemia cell lines than nontargeted particles[90] Danson et al developed SP1049C a nonionic blockcopolymer composed of a hydrophobic core and hydrophilictail that contains doxorubicin which was able to circumventP-glycoprotein mediated drug resistance in a mouse modelof leukaemia and is now under clinical evaluation [9192] In another study folic acid attached to polyethylenel-glycol derivatized distearoyl-phosphatidylethanolamine wasused to target in vitro doxorubicin loaded liposomes to
folate receptor overexpressing tumor cells Folate receptor-mediated cell uptake of targeted liposomal doxorubicin intoa multidrug resistant subline of M109-HiFR cells (M109R-HiFR) was clearly unaffected by P-glycoprotein-mediateddrug efflux in sharp contrast to uptake of free doxorubicin[93]
8 Targeting Agents
Nanocarriers are used as targeting agents for cancer ther-apy comprising anticancer drugs targeting moieties andpolymers There are a variety of nanocarriers such as lipo-somes dendrimers micelles carbon nanotubes nanocap-sules nanospheres and so forth Therapeutic agents canbe entrapped covalently bound encapsulated or adsorbedto the nanoparticles [5 8] Liposomes are composed oflipid bilayers where the core can be either hydrophilic orhydrophobic depending on the number of lipid bilayers[102 103] Liposomes having a single lipid bilayer contain anaqueous core for encapsulating water soluble drugs whereasother liposomes having more than a single bilayer entraplipid soluble drugs [103 104] They are readily cleared by themacrophages and are therefore coated with inert polymersfor stabilization in the physiological conditions Liposomesare commonly coated with polyethylene glycol (PEG) [2125 105ndash107] In vivo study shows that liposomes coated withhyaluronan (HA) improves circulation time and enhancestargeting to HA receptor-expressing tumors [108 109]Bothactive and passive targeting can be achieved with liposomaldrug delivery Liposomal nanoparticles can conjugate witheither antibodies or ligands for selective drug delivery [110111] They possess some advantages that they are biodegrada-tion nonantigenic and have a high transport rate [112] Theycan also be designed for pH sensitive drug delivery or ther-motherapy [113ndash115] Dendrimers are branched three dimen-sional tree-like structures with a multifunctional core Theyare synthesized fromeither synthetic or natural elements suchas amino acids sugars and nucleotides [116] Dendrimers canbe prepared by controlled polymerization of the monomersmaintaining desired shape and size Multiple entities includ-ing both hydrophobic and hydrophilic molecules can beconjugated to dendrimers due to their exclusive branchingpoint [103 117ndash119] They can also be loaded with drugsusing the cavities in their cores through hydrophobic interac-tions hydrogen bonds or chemical linkages Dendrimers arecapable of delivering genes drugs anticancer agents and soforth [103] Micelles are spherical structures where moleculeswith a hydrophobic end aggregate to form the central coreand the hydrophilic ends of other molecules are in contactwith the liquid environment surrounding the core Micellesare effective carrier for the delivery of water insoluble drugscarried in the hydrophobic core [103 118] Nanospheres arespherical in shape that is composed of a matrix system inwhich drug is evenly distributed by entrapment attachmentor encapsulation The surface of these nanoparticles can bemodified by the addition of ligands or antibodies for targetingpurposes On the other hand nanocapsules are like vesiclesthat have a central core where a drug is confined and a core is
8 ISRN Nanotechnology
Table 1 Some formulations of nanoparticles with positive results in the recent investigations
Type ofnanoparticle Anticancer drug Targeting agent Name of the polymers used Outcome Reference
Polymericnanoparticle Cystatin Cytokeratin specific
surrounded by a polymeric membrane Targeting ligands orantibodies can be attached to the surface [25 102] Fullerenes(also called bucky balls) and nanotubes are a family ofmolecules composed of carbon in the form of a hollow sphereor ellipsoid tube Atoms may be trapped inside fullereneswhile antibodies or ligands are bound to the surface fortargeting [103 117] Carbon nanotubes are modified to makethem water-soluble and functionalized as they can be linkedto a variety of active molecules such as peptides proteinsnucleic acids and therapeutic agents [120 121] Nanotubescan be single walled or multiwalled [102] Suitable polymersfor nanoparticle preparation include poly (alkyl cyanoacry-lates) poly(methylidenemalonate) and polyesters such aspoly(lactic acid) poly(glycolic acid) poly(e-caprolactone)and their copolymers poly(120576-caprolactone) poly(lactic acid)(PLA) poly(glycolic acid) (PGA) and their copolymers aremost extensively researched due to their biocompatibility andbiodegradability [83 101] Table 1 illustrates some polymerbased formulations that brought out positive results in recentresearch
9 Conclusion
Nanotechnology has already revolutionized cancer therapyin many aspects and is radically changing the treatmentpattern It hasmade a great impact on selective recognizing ofthe cancerous cells targeted drug delivery and overcominglimitations of the conventional chemotherapies Some nan-otechnology based formulations have already been launchedin the market and many are undergoing research and clinical
trials The side effects of the traditional chemotherapies cangreatly be removed by these novel active or passive targetingwhich can substantially increase the survival rate As canceris one of the most serious lethal diseases the contributionof nanotechnology in precise treatment avoiding the lifethreatening side effects can potentially contribute to a positivemovement in clinical practice for life saving approach
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] D J Bharali and S A Mousa ldquoEmerging nanomedicines forearly cancer detection and improved treatment current per-spective and future promiserdquo Pharmacology and Therapeuticsvol 128 no 2 pp 324ndash335 2010
[2] G Zhao and B L Rodriguez ldquoMolecular targeting of liposomalnanoparticlesto tumor microenvironmentrdquo International Jour-nal of Nanomedicine vol 8 pp 61ndash71 2013
[3] N R Jabir S Tabrez GMAshraf S Shakil G ADamanhouriand M A Kamal ldquoNanotechnology-based approaches in anti-cancer researchrdquo International Journal of Nanomedicine vol 7pp 4391ndash4408 2012
[4] S A Mousa and D J Bharali ldquoNanotechnology-based detec-tion and targeted therapy in cancer nano-bio paradigms andapplicationsrdquo Cancers vol 3 no 3 pp 2888ndash2903 2011
[5] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancer
ISRN Nanotechnology 9
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
[16] M M Gottesman C A Hrycyna P V Schoenlein U AGermann and I Pastan ldquoGenetic analysis of the multidrugtransporterrdquo Annual Review of Genetics vol 29 pp 607ndash6491995
[17] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008
[18] X Guo and F C Szoka Jr ldquoChemical approaches to triggerablelipid vesicles for drug and gene deliveryrdquo Accounts of ChemicalResearch vol 36 no 5 pp 335ndash341 2003
[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
[20] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008
[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
[28] M F Francis M Cristea and F M Winnik ldquoPolymericmicelles for oral drug delivery why and howrdquo Pure and AppliedChemistry vol 76 no 7-8 pp 1321ndash1335 2004
[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
[32] J Sudimack and R J Lee ldquoTargeted drug delivery via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 41 no 2 pp147ndash162 2000
[33] J F Kukowska-Latallo K A Candido Z Cao et al ldquoNanoparti-cle targeting of anticancer drug improves therapeutic responsein animal model of human epithelial cancerrdquo Cancer Researchvol 65 no 12 pp 5317ndash5324 2005
[34] G Russell-Jones K McTavish J McEwan and B ThurmondldquoIncreasing the tumoricidal activity of daunomycin-pHPMAconjugates using vitamin B12 as a targeting agentrdquo Journal ofCancer Research Updates vol 1 no 2 pp 1ndash6 2012
[35] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 Article ID 18496 3 pages 2012
[36] H S Yoo and T G Park ldquoFolate-receptor-targeted delivery ofdoxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugaterdquo Journal of Controlled Release vol 100 no 2pp 247ndash256 2004
[37] M Kawamoto T Horibe M Kohno and K Kawakami ldquoAnovel transferrin receptor-targeted hybrid peptide disintegratescancer cell membrane to induce rapid killing of cancer cellsrdquoBMC Cancer vol 11 article 359 2011
[38] T R Daniels B Bernabeu J A Rodrıguez et al ldquoTransferrinreceptors and the targeted delivery of therapeutic agents againstcancerrdquo Biochimica et Biophysica Acta vol 1820 no 3 pp 291ndash317 2012
[39] N C Bellocq S H Pun G S Jensen and M E DavisldquoTransferrin-containing cyclodextrin polymer-based particlesfor tumor-targeted gene deliveryrdquo Bioconjugate Chemistry vol14 no 6 pp 1122ndash1132 2003
[40] C R Dass and P F M Choong ldquoTargeting of small moleculeanticancer drugs to the tumour and its vasculature using
10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
[41] H K Sun H J Ji H L Soo W K Sung and G P TaeldquoLHRH receptor-mediated delivery of siRNA using polyelec-trolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEIrdquo Bioconjugate Chemistry vol 19 no11 pp 2156ndash2162 2008
[42] S S Dharap Y Wang P Chandna et al ldquoTumor-specifictargeting of an anticancer drug delivery system by LHRHpeptiderdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 102 no 36 pp 12962ndash12967 2005
[43] httpwebmitedunewsoffice2006prostatehtml[44] T M Allen ldquoLigand-targeted therapeutics in anticancer ther-
apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
therapiesrdquoNature Reviews Cancer vol 1 no 2 pp 118ndash129 2001[46] W H Ouwehand R Finnern B D Gorick et al ldquoSelection of
internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
[47] J DMarksW H Ouwehand J M Bye et al ldquoHuman antibodyfragments specific for human blood group antigens from aphage display libraryrdquo BioTechnology vol 11 no 10 pp 1145ndash1149 1993
[48] B Liu F Conrad M R Cooperberg D B Kirpotin and JD Marks ldquoMapping tumor epitope space by direct selectionof single-chain Fv antibody libraries on prostate cancer cellsrdquoCancer Research vol 64 no 2 pp 704ndash710 2004
[49] D Peer P Zhu C V Carman J Lieberman and M ShimaokaldquoSelective gene silencing in activated leukocytes by target-ing siRNAs to the integrin lymphocyte function-associatedantigen-1rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 10 pp 4095ndash4100 2007
[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
[51] S Sudarshan D H Holman M L Hyer C Voelkel-JohnsonJ-Y Dong and J S Norris ldquoIn vitro efficacy of Fas ligandgene therapy for the treatment of bladder cancerrdquo Cancer GeneTherapy vol 12 no 1 pp 12ndash18 2005
[52] O Micheau E Solary A Hammann F Martin and M-TDimanche-Boitrel ldquoSensitization of cancer cells treated withcytotoxic drugs to fas-mediated cytotoxicityrdquo Journal of theNational Cancer Institute vol 89 no 11 pp 783ndash789 1997
[53] G N Naumov L A Akslen and J Folkman ldquoRole of angio-genesis in human tumor dormancy animal models of theangiogenic switchrdquoCell Cycle vol 5 no 16 pp 1779ndash1787 2006
[54] M A J Chaplain ldquoMathematical modelling of angiogenesisrdquoJournal of Neuro-Oncology vol 50 no 1-2 pp 37ndash51 2000
[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
[56] N Weidner J Folkman F Pozza et al ldquoTumor angiogenesis anew significant and independent prognostic indicator in early-stage breast carcinomardquo Journal of the National Cancer Institutevol 84 no 24 pp 1875ndash1887 1992
[57] D Fukumura and R K Jain ldquoImaging angiogenesis and themicroenvironmentrdquoAPMIS vol 116 no 7-8 pp 695ndash715 2008
[58] M Dhanabal M Jeffers andW J LaRochelle ldquoAnti-angiogenictherapy as a cancer treatment paradigmrdquo Current MedicinalChemistry vol 5 no 2 pp 115ndash130 2005
[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
[61] D Banerjee R Harfouche and S Sengupta ldquoNanotechnology-mediated targeting of tumor angiogenesisrdquoVascular Cell vol 3article 3 2011
[62] N Boudreau and C Myers ldquoBreast cancer-induced angiogen-esis multiple mechanisms and the role of the microenviron-mentrdquo Breast Cancer Research vol 5 no 3 pp 140ndash146 2003
[63] N N Khodarev J Yu E Labay et al ldquoTumour-endotheliuminteractions in co-culture coordinated changes of gene expres-sion profiles and phenotypic properties of endothelial cellsrdquoJournal of Cell Science vol 116 no 6 pp 1013ndash1022 2003
[64] J S Desgrosellier and D A Cheresh ldquoIntegrins in cancerbiological implications and therapeutic opportunitiesrdquo NatureReviews Cancer vol 10 no 1 pp 9ndash22 2010
[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
[66] S A Anderson R K Rader W F Westlin et al ldquoMag-netic resonance contrast enhancement of neovasculature withalpha(v)beta(3)-targeted nanoparticlesrdquoMagnetic Resonance inMedicine vol 44 pp 433ndash439 2000
[67] J H Park S Kwon J-O Nam et al ldquoSelf-assembled nanoparti-cles based on glycol chitosan bearing 5120573-cholanic acid for RGDpeptide deliveryrdquo Journal of Controlled Release vol 95 no 3 pp579ndash588 2004
[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
[70] J Li J Ji L M Holmes et al ldquoFusion protein from RGDpeptide and Fc fragment of mouse immunoglobulin G inhibitsangiogenesis in tumorrdquo Cancer Gene Therapy vol 11 no 5 pp363ndash370 2004
[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
[72] N Ferrara ldquoVEGF as a therapeutic target in cancerrdquo Oncologyvol 69 no 3 pp 11ndash16 2005
[73] D F Baban and L W Seymour ldquoControl of tumour vascularpermeabilityrdquo Advanced Drug Delivery Reviews vol 34 no 1pp 109ndash119 1998
[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
ISRN Nanotechnology 11
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
and treatment of the disease Various researches are beingcarried out in order to discover more accurate nanotechnol-ogy based cancer treatment minimizing the side effects of theconventional ones [5] Nanoparticles are now being designedto assist therapeutic agents to pass through biologic barriersto mediate molecular interactions and to identify molecularchanges They have larger surface area with modifiable opti-cal electronicmagnetic and biologic properties compared tomacroparticles Current nanotechnology based drug deliverysystems for cancer treatment which are alreadymarketed andunder research and evaluation include liposomes polymericmicelles dendrimers nanospheres nanocapsules and nan-otubes [8 9] Nanotechnology based formulations that havealready been marketed are DOXIL (liposomal doxorubicin)and Abraxane (albumin bound paclitaxel) [10]
2 Limitations of Conventional Chemotherapy
Conventional chemotherapeutic agents work by destroyingrapidly dividing cells which is the main property of neo-plastic cells This is why chemotherapy also damages normalhealthy cells that divide rapidly such as cells in the bonemarrow macrophages digestive tract and hair follicles [2]The main drawback of conventional chemotherapy is thatit cannot give selective action only to the cancerous cellsThis results in common side effects of most chemotherapeu-tic agents which include myelosuppression (decreased pro-duction of white blood cells causing immunosuppression)mucositis (inflammation of the lining of the digestive tract)alopecia (hair loss) organ dysfunction and even anemia orthrombocytopeniaThese side effects sometimes impose dosereduction treatment delay or discontinuance of the giventherapy [11 12] In case of solid tumors cell division maybe effectively ceased near the center making chemother-apeutic agents insensitive to chemotherapy Furthermorechemotherapeutic agents often cannot penetrate and reachthe core of solid tumors failing to kill the cancerous cells [13]
Traditional chemotherapeutic agents often get washedout from the circulation being engulfed by macrophagesThus they remain in the circulation for a very short timeand cannot interact with the cancerous cells making thechemotherapy completely ineffective The poor solubilityof the drugs is also a major problem in conventionalchemotherapy making them unable to penetrate the biolog-ical membranes [4] Another problem is associated with P-glycoprotein a multidrug resistance protein that is overex-pressed on the surface of the cancerous cells which preventsdrug accumulation inside the tumor acting as the effluxpump and often mediates the development of resistanceto anticancer drugs Thus the administered drugs remainunsuccessful or cannot bring the desired output [14ndash17]
3 Nanotechnology in Cancer Targeting
Nanotechnology has made a great revolution in selectivecancer targeting Nanoparticles can be designed throughvarious modifications such as changing their size shapechemical and physical properties and so forth to program
them for targeting the desired cells They can target theneoplastic cells either through active or passive targeting
31 Active Targeting In case of active targeting nanoparticlescontaining the chemotherapeutic agents are designed insuch a way as they directly interact with the defected cellsActive targeting is based on molecular recognition Hencethe surface of the nanoparticles is modified to target thecancerous cells Usually targeting agents are attachedwith thesurface of nanoparticles for molecular recognition Designednanoparticles target the cancerous cells either by ligand-receptor interaction or antibody-antigen recognition [18ndash20]Nanotechnology based targeted delivery system has threemain components (i) an apoptosis-inducing agent (anti-cancer drug) (ii) a targeting moiety-penetration enhancerand (iii) a carrier A variety of substances are used to constructa nanoparticle Commonly used materials include ceramicpolymers lipids and metals [21] Natural and syntheticpolymers and lipids are typically used as drug delivery vectors[22ndash24] Particles containing chemotherapeutic agents areengulfed by phagocytes and rapidly cleared by the retic-uloendothelial system (RES) A variety of strategies weredeveloped to sustain the nanoparticles in blood stream oneof which is the alteration of the polymeric composition of thecarrier Nanoparticles are coated with hydrophilic polymersto avoid wash out and remain in the bloodstream for a longerperiod of time that can sufficiently target cancerous cellsHydrophilic polymer coating on the nanoparticle surfacerepels plasma proteins and escapes from being opsonized andcleared This is described as a ldquocloudrdquo effect [25ndash28] Com-monly used hydrophilic polymers include polyethylene glycol(PEG) poloxamines poloxamers polysaccharides and soforth [29 30] Cancerous cells have some unique propertiesthat differentiate them from the healthy cells at molecularlevel Some receptors are over expressed on the surface ofthem that make the distinguishing feature Attachment ofthe complementary ligands on the surface of nanoparticlesmakes them able to target only the cancerous cells Oncethe nanoparticles bind with the receptors they rapidlyundergo receptor-mediated endocytosis or phagocytosis bycells resulting in cell internalization of the encapsulated drugNumerous works are being done to investigate these ligand-receptor interactions and utilize them for clinical use [5]
311 Specific Receptor Targeting
Folate Receptor Folate receptors are overexpressed in manyneoplastic cells providing a target for certain anticancertherapies Utilizing the concept researchers are designing thesurface of nanoparticles with folic acid [31ndash33] Russell-Joneset al examined the potential of using folic acid as a targetingagent for the delivery of pHPMA conjugated daunomycin infour murine tumor models Folic acid targeted daunomycin-HPMA conjugates were found to increase both the numberof survivors and the survival time of tumor-bearingmiceThedata indicate that folic acidmay be highly effective in enhanc-ing the efficacy of other polymer-bound cytotoxins [34]
ISRN Nanotechnology 3
Another study was done by a team led by Kukowska-Latalloto et al which tests the folate-linked methotrexatedendrimers in immunodeficient athymic nude female miceThe mice were injected with the nanoconjugates twice aweek via a lateral tail vein The results showed that con-jugated methotrexate in dendrimers significantly loweredtoxicity and resulted in a 10-fold higher efficacy comparedto free methotrexate at an equal cumulative dose As aresult mice survived longer [33] The efficacy of nanosizedfolate receptor-targeted doxorubicin aggregates was testedfor cancer treatment Doxorubicin-polyethylene glycol-folateconjugatemicelles were prepared that were 200 nm in averagediameter The polymeric micelles exhibited enhanced andselective targeting to folate receptor positive cancer cellsin vitro The in vivo animal experiments showed that thenanoaggregates caused significant tumor suppression [3536]
Some other preparations include nanoparticles to whichfolate was conjugated covalently using surface carboxylgroups as well as conjugation of folate to hydrazine mod-ified poly-lactic acid nanoparticles Isobutyl-cyanoacrylate(IBCA) nanocapsules were prepared and coated with folatethat showed a significantly increased efficacy of nanocapsulestargeted to the tumor [8] The experiments showed folatereceptors can be targeted very effectively for selective drugdelivery by nanoparticles conjugated to folic acid
Transferrin Receptor Nanoparticles are widely being investi-gated to target the transferrin receptors for binding and cellentry as these are overexpressed by certain tumor cells toincrease their iron uptake Transferrin (Tf) can be conjugatedto a variety of materials for cancer targeting which includeTf-chemotherapeutic agent Tf-toxic protein Tf-RNases Tf-antibody and Tf-peptide [37 38] Kawamoto et al foundthat Tf-lytic hybrid peptide can selectively target cancerouscells They administered Tf-lytic peptide in an athymic micemodel with MDA-MB-231 cells The Tf-lytic hybrid peptideshowed effective cytotoxic activity where normal cells wereless sensitive to this molecule It was additionally revealedthat this preparation can disintegrate the cell membrane ofT47D cancer cells just in 10 min killing them effectively andinducing approximately 80 apoptotic cell death but not innormal cells Thus the intravenous administration of Tf-lyticpeptide in the athymic mice model significantly inhibitedtumor progression [37] Bellocq et al found that at lowtransferrin modification the nanoparticles remain stable inphysiologic salt concentrations and transfect leukemia cellswith increased efficiency The transferrin-modified nanopar-ticles are effective for systemic delivery of nucleic acidtherapeutics for metastatic cancer [39 40]
Luteinizing Hormone-Releasing Hormone Receptor Luteiniz-ing hormone-releasing hormone (LHRH) is being used inmany ongoing researches as a targeting moiety (ligand)to LHRH receptors that are over-expressed in the plasmamembrane of various types of cancer cells like breast cancerovarian cancer and prostate cancer [41 42] FarokhzadLanger and colleagues developed a new technique to deliverthe drugs in cancer cellrsquos internal fluidThey laced tailor-made
tiny sponge-like nanoparticles with the drug docetaxel Theparticles were particularly designed to dissolve the drug in acellrsquos internal fluids controlling the release rate For selectivetargeting the nanoparticles were ldquodecoratedrdquo on the outsidewith targeting molecules called aptamers tiny chunks ofgenetic material The aptamers specifically recognize the sur-face molecules on cancer cells In addition the nanoparticlesalso contained polyethylene glycol molecules to keep themaway from being rapidly destroyed by macrophages [43]
A team led by Prasad developed a method of target-ing LHRH receptor with ferric oxide nanoparticles whichwas prepared by a reverse micelle colloidal reaction Thehydrophilic groups were sequestered in the micelle core andthe hydrophobic groups remained solvent exposed on thesurface of the micelle in a reverse micelle system which wasformed by a surfactant continuous oil phase and waterA tracking agent two-photon dye ASPI-SH was attachedto the surface of the iron oxide Silica was added to formthe structure of the silica shell before additional silica shellgrown by tetraethylorthosilicate hydrolysis The targetingagent LHRH was coupled to the silica shell through carbonspacers so as to prevent stearic hindrance during the interac-tion of the targeting agent with its complementary moleculeon cells After the administration of the nanoparticles thepatients were exposed to a DC magnetic field The selectiveinteraction internalization and so forth were investigatedby using LHRH receptor expressing cells on oral epithelialcarcinoma cells Data clearly showed that the nanoparticlesselectively interacted with the specific cell types [8]
Asialoglycoprotein Asialoglycoprotein (ASGP) anotherreceptor which is overexpressed in hepatoma is utilizedin cancer targeting by nanoparticles for anticancer drugdelivery Sung and coworkers developed a new strategyby which biodegradable nanoparticles with a mean sizeof 140 nm can be prepared to target the hepatoma cellsThey prepared them from poly(-120574-glutamic acid)-poly(lactide) block copolymers loaded with paclitaxel usingemulsion solvent evaporation technique The nanoparticleswere conjugated with galactosamine (GAL) through anamide linkage to enhance hepatoma HepG2 cell uptake bytargeting ASGP receptors Immunofluorescence analysisutilizing a rhodamine-123 probe encapsulated in thehydrophobic core of the gal-nanoparticles revealed thehigh degree of selectivity of the nanoparticles to hepatictumors with enhanced cellular uptake through receptor-mediated endocytosis resulting in subsequent release ofthe encapsulated paclitaxel inside the cytoplasm Thosenanoparticles inhibited the growth of the cells with aconsequent decrease in systemic toxicity compared to freepaclitaxel
A dual-particle tumor targeting systemwas developed forselectively inhibiting angiogenesis in hepatoma Nanoparti-cle encapsulating ganciclovir conjugatedwith galactosaminewas the first component and an enhanced permeability andretention (EPR) mediated targeting nanoparticle containingan HSV thymidine kinase (TK) gene was the second compo-nent of the dual-particle tumor targeting system It was statedthat thymidine kinase would digest ganciclovir to produce
4 ISRN Nanotechnology
cytotoxic effects after cancer cells internalization of the firstand second nanoparticles together Thus it kills the targetedcancer cells [8]
312 Antibody Mediated Targeting Many tumor cells showunusual antigens due to their genetic defects that are eitherinappropriate for the cell type environment or temporalplacement in the organismsrsquo development The immuneresponses educed by tumor antigens are not so strong becausethey are recognized as own cells Highly specific monoclonalantibodies (mAbs) are used to strengthen the immuneresponse and to intensify the immune systemrsquos antitumorcapacityThese antibodies target proteins that are abnormallyexpressed in neoplastic cells and are essential for their growthNanoparticles conjugated with an antibody against a specifictumor antigen are developed for selective drug delivery [7]Most of the mAbs are produced by the clones of a singlehybridoma cell The hybridoma cell results from the fusionof a myeloma that produces antibody and an antigenicallystimulated normal plasma cell to bind specifically to tumorcell antigens After binding with tumor antigens mAbscan destroy cancer cells through a variety of approacheswhich include directly inducing apoptosis blocking growthfactor receptors and anti-idiotype formation They canindirectly eradicate cancer cells by activating complementmediated cellular cytotoxicity and antibody dependent cellmediated cytotoxicity [8] Antibody engineering has recentlyflourished with the outcome of antibody production thatcontains animal and human origins such as chimeric mAbshumanizedmAbs (those with a greater human contribution)and antibody fragments Antibodies can be used in theiroriginal form or as fragments for cancer targeting Howeverthe presence of two binding sites (within a single antibody)gives higher binding opportunity and makes it advantageousto use the intact mAbs Moreover a signaling cascade isinitiated to kill the cancer cells whenmacrophages bind to theFc segment of the antibody The Fc portion of an intact mAbcan also bind to the Fc receptors on normal cells resultingin increased ability to evoke an immune response and liverand spleen uptake of the nanocarrier Stability in long-termstorage is their additional advantage On the other hand anti-body fragments including antigen-binding fragments (Fab)dimers of antigen-binding fragments (F(ab1015840)2) single-chainfragment variables (scFv) and other engineered fragmentsare considered safer with reduced nonspecific binding [544 45] Phage display libraries may be used to rapidly selectantibodies or their fragments that bind to and internalizewithin cancer cells This method generates a combination ofpotentially useful antibodies that bind to different epitopes (apart of a receptor that is recognized by antibodies) of the sametarget cells Thus several epitopes of a single receptor willbe recognized by multiple antibodies proving more accurateand selective action [46ndash48] The efficacy of antibodies canbe increased by conjugating a therapeutic agent directly toit mAbs can act as the highly specific probes when theyare attached to nanoparticles to aid in targeted delivery ofvarious antitumor cytotoxic agents [5] Binding affinity andselectivity to cell surface targets by engineering proteinscan also be increased through the detection of a specific
conformation of a target receptor A fusion protein consistingof an scFv antibody fragment to target and deliver smallinterfering RNA (siRNA) to lymphocytes showed a 10000-fold increased affinity for the target receptor integrin LFA-1in a recent study done by Peer et al [49]
Kuroda and fellows developed a method for the prepara-tion of hollow protein nanoparticles containing ganciclovirwhich encapsulates a hepatic cancer therapeutic gene thymi-dine kinase (HSV1tk) derived from simple herpes virusThe nanoparticles were modified by displaying a hepatitis Bvirus surface-antigen to own hepatocyte recognition abilityand particle formation ability A human hepatoma bearinganimal model demonstrated that when a hepatic cancer-treating gene was encapsulated into hepatitis B virus surface-antigen (HBsAg) particles the gene was specifically deliveredinto a human liver-derived tissue part after administeringthe particles through intravenous injection The therapeuticeffect of the HBsAg-HSV1tk hollow protein nanoparticlesspecific to hepatic cancer was also confirmed They alsodeveloped a method of encapsulating cytotoxic drug con-taining a cancer treating gene within nanoparticles modifiedto display an antibody used for specific targeting of humansquamous carcinoma cells The nanoparticles were modifiedto express an antibody that recognizes the epidermal growthfactor receptor expressed by the cancer cells Animal studiesconfirmed that the transfer and expression of the genewas very specific to the human squamous carcinoma andhighly effective in treatment [8] Wartlick et al developedbiodegradable nanoparticles based on gelatin and humanserum albumin in which the surface of the nanoparticles wasmodified by covalent attachment of the biotin-binding pro-tein NeutrAvidin enabling the binding of biotinylated drugtargeting ligands by avidin-biotin complex formation HER2receptor a member of the epidermal growth factor receptorfamily is overexpressed in certain types of cancer (breastcancer) HER2 receptor specific antibody trastuzumab (her-ceptin) was conjugated to the surface of these nanoparti-cles for targeting HER2-overexpressing cells Confocal laserscanning microscopy showed an effective internalization ofthese nanoparticles by HER2-overexpressing cells throughreceptor-mediated endocytosis [50]
Nanoparticles can be designed to enhance Fas ligandexpression a type-II transmembrane protein which inducesapoptosis when bound with its receptor on the surface ofFas receptor-expressing leukemia cells Fas ligand-receptorinteractions play a significant role in the regulation of theimmune system and the progression of cancer [51 52] Fasagonist CH-11 a monoclonal antibody to the Fas receptoris conventionally used to target the cancer cells The mAbrituximab (Rituxan) was approved in 1997 for the treatmentof patients with non-Hodgkinrsquos lymphoma
313 Antiangiogenesis Angiogenesis is described as thegrowth of new blood vessels from preexisting vesselsTumors cannot grow more than 2mm in diameter with-out angiogenesis [53ndash55] Cancerous cells produce abnor-mal amounts of angiogenic growth factors resulting in anexcessive angiogenesis overwhelming the effects of naturalangiogenesis inhibitors giving rise to leaky and tortuous
ISRN Nanotechnology 5
vessels that are in a constant state of inflammation [54ndash58] Studies on breast cancer showed that the degree ofmetastasis tumor recurrence and shorter survival ratesare correlated with angiogenesis [56 59] Antiangiogenesistherapy is designed based on two mechanisms drugs whichprevent the formation of new blood vessels that supply to thetumor (eg TNP-470 endostatin and angiostatin) or drugsthat destroy the existing blood vessels (eg combretastatin)[60] The objective of antiangiogenic therapy is to delay bothprimary andmetastatic tumor growth by blocking the supplyof essential nutrients and the removal of metabolites causingstunted tumor growth thereby avoiding tumor spread as wellas enhancing the shrinkage of tumors [61] Antiangiogenicdrugs either act directly by targeting endothelial receptorsor indirectly by targeting angiogenic cytokines [62ndash64]Active targeting of the tumor vasculature by nanoparticles isachieved by targeting the VEGF receptors (VEGFRs) 120572]1205733integrin receptors and other angiogenic factors Integrinswhich mediate the attachment between a cell and its sur-roundings are the main component in angiogenesis processand their increase in number enhances the survival growthand invasion of both tumor and endothelial cells [64 65]120572]1205733 integrin antibody has been widely used as a targetingmoiety on nanovectors for anti-angiogenesis therapy due toits pleitropic upregulation in many tumor settings Someof them have passed several clinical trials [66ndash69] Tumorangiogenesis was successfully detected in rabbit and mousemodels by perfluorocarbon nanoparticles conjugated to var-ious contrasting agents (Gadolinium Gd or fluorine isotope19 19F) and linked to an 120572]1205733 integrin antibody [66 68] Theuse of peptides as the targeting agents resulted in increasedintracellular drug delivery in different murine tumor models[70 71] An approach to target integrin overexpressioninvolves using a synthetic peptide containing the recognitionsite for integrins namely an arginine-glycine-aspartic acid(RGD) sequence [67] The first angiogenesis inhibitor forcolorectal cancer therapy bevacizumab (Avastin) an anti-VEGF mAb that inhibits the growth factor of new bloodvessels was approved in 2004 [5 72] Prokop and his teamdeveloped amethod of preparing biocompatible nanoparticlethat can be used as drug delivery vehiclesTheywere designedto retain and deliver Antiangiogenic compounds over anextended period of time for targeting tumor vasculatureNanoparticleswere formulated comprising a hydrophilic coreof sodium alginate cellulose sulfate and Antiangiogenicfactors such as thrombospondin (TSP)-1 or TSP-517 whichwas crosslinked with dextran polyaldehyde with calciumchloride or conjugated to heparin sulfate with sodiumchloride In addition luciferase (bioluminescent agent) orpolymeric gadolinium (contrast agent) was placed withinthe polyanionic core The hydrophilic shell surroundingthe core additionally contained spermine hydrochloridepoly(methylene-co-guanidine) hydrochloride and pluronicF-68 calcium chloride and a targeting ligand conjugatedto an activated polyethylene glycol or crosslinked to dex-tran polyaldehyde Targeted nanoparticles were evaluatedby monitoring luciferase in a murine model [8] Figure 1illustrates the process of active targeting
32 Passive Targeting Nanoparticles can also target cancerthrough passive targeting As apoptosis is stopped in cancer-ous cells they continue sucking nutritious agents abnormallythrough the blood vessels forming wide and leaky bloodvessels around the cells induced by angiogenesis Leaky bloodvessels are formed due to basement membrane abnormalitiesand decreased numbers of pericytes lining rapidly prolif-erating endothelial cells [73] Hence the permeability ofmolecules to pass through the vessel wall into the interstitiumsurrounding tumor cells is increased The size of the poresin leaky endothelial cells ranges from 100 to 780 nm [74ndash76]Thus nanoparticles below that size can easily pass through thepores [77 78] As a result it facilitates to efflux the nanopar-ticles to cluster around the neoplastic cells Nanoparticlescan be targeted to specific area of capillary endothelium toconcentrate the drug within a particular organ and perforatethe tumor cells by passive diffusion or convection Lack oflymphatic drainage eases the diffusion process The tumorinterstitium is composed of a collagen network and a gel likefluid The fluid has high interstitial pressures which resistthe inward flux of molecules Tumors also lack well-definedlymphatic networks having leaky vasculature Thereforedrugs that enter the interstitial area may have extendedretention times in the tumor interstitium This feature iscalled the enhanced permeability and retention (EPR) effectand facilitates tumor interstitial drug accumulation (Figure 1)[79 80] Nanoparticles can easily accumulate selectively byenhanced permeability and retention effect and then diffuseinto the cells [81]
4 Cellular Uptake pH DependentDrug Delivery and Prevention fromLysosomal Degradation
Active or passive targeted nanoparticles face amajor difficultyin releasing drugs in the neoplastic cells since lysosomalenzymes rapidly destroy both the nanoparticles and drugsinside the cells After internalization the colloidal carri-ers usually reach the lysosomal compartment in whichhydrolytic enzymes degrade both the carrier and its contentTherefore the intracellular distribution of the carrier ismodified when the encapsulated drug is a nucleic acidBecause pH around of tumors cells is more acidic carriersthat change solubility at lower pH can be used to targetand release drugs The extracellular environment of solidtumors is acidic and there is an altered pH gradient acrosstheir cell compartments Nanoparticles sensitive to the pHgradients are promising for cancer drug delivery A pH-responsive nanoparticle consists of a shell and a core andit responds to the pH gradient and changes its solubilitypattern The core-shell polymer nanoparticles are designedwith their lower critical solution temperature (LCST) beingdependent on the ambient pH 74 At low pH in and aroundof tumor cells the resulting change in LCST causes the core-shell nanoparticles to deform and precipitate in an acidicenvironment triggering the release the chemotherapeuticsA targeting molecule is additionally conjugated to the shellof the nanoparticles which can recognize tumor cells [82]
6 ISRN Nanotechnology
Passive targeting Active targeting Targeted nanoparticle
Tumor Drug or drug-loaded nanocarriers
Normal tissue Receptor-mediated endocytosis
Figure 1 Active and passive targeting by nanoparticles
Shefer and his team reported a new strategy for preparing apH sensitive sustained release system for cancer treatmentThe system utilizes solid hydrophobic nanospheres contain-ing anticancer drugs that are encapsulated in a pH sensitivemicrosphere It additionally included a bioadhesive materialinto the solid hydrophobic matrix of the nanospheres Thenanosphere hydrophobic matrix was formed by dispersingpaclitaxel into the hotmelt of candelillawaxThemicrosphereof pH sensitive matrix was created by adding the drugwaxmixture into an aqueous solution containing a pH dependentanionic polymer which is stable at pH 74 but solubilizedat pH 6 and lower The prepared suspension was spraydried to produce a free flowing dry powder which consistsof 10 paclitaxel The nanospheres can release the drugover an extended period of time by dissolvingswelling themicrosphere at a lower pH that is typically found in canceroustissue [8] Recently researchers developed a system thateither fuse with the plasmamembrane or have a pH-sensitiveconfiguration that changes conformation in the lysosomesand allows the encapsulated material to escape into thecytoplasm [83] Biodegradable nanoparticles were formu-lated from the copolymers of poly(dl-lactide-co-glycolide)for their rapid endolysosomal escape The system workedby selective reversal of the surface charge of nanoparticles(from anionic to cationic) in the acidic endolysosomalcompartment causing the nanoparticles to interact with theendolysosomal membrane and escape into the cytosol Thesenanoparticles can deliver wide ranged therapeutic agentsincluding macromolecules such as DNA at a slow rate forsustained therapeutic effect For using nanotechnology incancer treatment researchers developed thermoresponsivepH-responsive and biodegradable nanoparticles by graftingbiodegradable poly (dl-lactide) ontoN-isopropyl acrylamideand methacrylic acid It may be sufficient for a carrier systemto concentrate the drug (hydrophobic that crosses the plasmamembrane easily) in the target tissue [84]
5 Hyperthermia
Healthy cells are capable of surviving exposure to temper-atures up to 465∘C Irreversible cell damage occurs to thecancerous cells at temperatures from approximately 40∘C to
about 46∘C due to the disorganized and compact vascularstructure for which they are less stable On the other handsurrounding healthy cells are more readily able to spatterheat and maintain a normal temperature This process statedabove is called hyperthermia which is used for the purpose ofdamaging protein and structures within cancerous cells andin some cases causing tumor cells to directly undergo apop-tosis Nanoparticles are utilized for a variety of purposes inhyperthermia-based treatments which include serving as theactive thermotherapeutic agents sensitizers and are also usedfor targeting purposes like antibody enhanced targeting toincrease efficacy and to reduce hypothermia-associated sideeffects Nanoparticles can locate and specifically target thedeep-seated tissues and organs Magnetic fluid hyperthermiais a well-practiced old method for cancer treatment Smallmagnetic particles are used which respond to an externallyapplied magnetic field by heating up In addition to specifictargeting nanoparticles add another benefit Cells that havepicked up some of the particles cannot get rid of them andthus every daughter cell will have one half of the amount ofparticles present on the mother cell
Handy et al developed a method of manufacturingnanoparticles for targeted delivery of thermotherapy incancer treatment The prepared ferromagnetic nanoparticleswere coated with biocompatible material poly(methacrylicacid-co-hydroxy-ethylmethacrylate) using free-radical poly-merization A stabilizing layer was formed around the mag-netic particles by an ionic surfactant sodiumbis-2-ethylhexylsulfosuccinate For selective targeting antibodies were cova-lently attached to the surface of coatedmagnetic particlesThethermotherapeutic magnetic composition containing single-domain magnetic particles attached to a target specific ligandwas inductively heated using amagnetic field High efficiencyof the bioprobes was determined in animal model [8 31]
6 Combination of Drugs Having DifferentPhysical Properties
Several studies have recently shown that combination therapyis more effective than a single drug for many types ofcancer Drugs having different physical properties could notbe combined into a single particle before Furthermore
ISRN Nanotechnology 7
it has always been difficult to get the right amount of drugto the tumor Langer and fellows developed a new method todevelop nanoparticles in which they incorporated drugs withdifferent physical properties which had been impossible withprevious drug delivering nanoparticles Earlier generations ofnanoparticles mean encapsulation in a polymer coating bywhich drugs with different charges or different affinity couldnot be carried together The new technique called ldquodrug-polymer blendingrdquo allowed the researchers to hang the drugmolecules like pendants from individual units of the poly-mer before the units assemble into a polymer nanoparticleThey developed nanoparticles with hydrophobic docetaxeland hydrophilic cisplatin After loading the drugs into thenanoparticle the researchers added a tag that binds to amolecule called prostate-specificmembrane antigen (PSMA)which is a type 2 integral membrane glycoprotein presenton the surfaces of most prostate cancer cells This tag allowsthe nanoparticles to bypass healthy tissues and reduce theside effects caused by most chemotherapy drugs As a resultthey go directly to their target region The new techniquefacilitated them to precisely control the ratio of drugs loadedinto the particle They were also able to control release rate ofthe drugs after they entered the tumor cells [85]
7 Overcoming Other Limitations ofConventional Chemotherapy
Lack of solubility is one of the major limitations of mostchemotherapeutic agents Nanoparticles can effectively solvethe solubility problem Hydrophobic drugs can be encap-sulated in micelles to increase their solubility [86 87]Dendrimers contain many binding sites with which bothhydrophobic and hydrophilic molecules can bind Liposomesalso allow encapsulating hydrophobic drugs and transport-ing them to the desired area soon after administration[87] Several approaches have been taken to overcome P-glycoproteinmediated drug resistance P-glycoprotein locatesdrugs which are localized in the plasmamembrane only Onestrategy is to use the inhibiting agents such as verapamil orcyclosporine when concurrently administered with a cyto-toxic drug can restrain P-glycoproteinThus both chemother-apeutic agent and inhibiting agent are incorporated intothe nanoparticles to overcome the problem associated withP-glycoprotein [25 88 89] A new strategy was devel-oped for inhibition of the P-glycoprotein-mediated effluxof vincristine where vincristine-loaded lipid nanoparticlesconjugated to an anti-P-glycoprotein monoclonal antibody(MRK-16) showed greater cytotoxicity in resistant humanmyelogenous leukaemia cell lines than nontargeted particles[90] Danson et al developed SP1049C a nonionic blockcopolymer composed of a hydrophobic core and hydrophilictail that contains doxorubicin which was able to circumventP-glycoprotein mediated drug resistance in a mouse modelof leukaemia and is now under clinical evaluation [9192] In another study folic acid attached to polyethylenel-glycol derivatized distearoyl-phosphatidylethanolamine wasused to target in vitro doxorubicin loaded liposomes to
folate receptor overexpressing tumor cells Folate receptor-mediated cell uptake of targeted liposomal doxorubicin intoa multidrug resistant subline of M109-HiFR cells (M109R-HiFR) was clearly unaffected by P-glycoprotein-mediateddrug efflux in sharp contrast to uptake of free doxorubicin[93]
8 Targeting Agents
Nanocarriers are used as targeting agents for cancer ther-apy comprising anticancer drugs targeting moieties andpolymers There are a variety of nanocarriers such as lipo-somes dendrimers micelles carbon nanotubes nanocap-sules nanospheres and so forth Therapeutic agents canbe entrapped covalently bound encapsulated or adsorbedto the nanoparticles [5 8] Liposomes are composed oflipid bilayers where the core can be either hydrophilic orhydrophobic depending on the number of lipid bilayers[102 103] Liposomes having a single lipid bilayer contain anaqueous core for encapsulating water soluble drugs whereasother liposomes having more than a single bilayer entraplipid soluble drugs [103 104] They are readily cleared by themacrophages and are therefore coated with inert polymersfor stabilization in the physiological conditions Liposomesare commonly coated with polyethylene glycol (PEG) [2125 105ndash107] In vivo study shows that liposomes coated withhyaluronan (HA) improves circulation time and enhancestargeting to HA receptor-expressing tumors [108 109]Bothactive and passive targeting can be achieved with liposomaldrug delivery Liposomal nanoparticles can conjugate witheither antibodies or ligands for selective drug delivery [110111] They possess some advantages that they are biodegrada-tion nonantigenic and have a high transport rate [112] Theycan also be designed for pH sensitive drug delivery or ther-motherapy [113ndash115] Dendrimers are branched three dimen-sional tree-like structures with a multifunctional core Theyare synthesized fromeither synthetic or natural elements suchas amino acids sugars and nucleotides [116] Dendrimers canbe prepared by controlled polymerization of the monomersmaintaining desired shape and size Multiple entities includ-ing both hydrophobic and hydrophilic molecules can beconjugated to dendrimers due to their exclusive branchingpoint [103 117ndash119] They can also be loaded with drugsusing the cavities in their cores through hydrophobic interac-tions hydrogen bonds or chemical linkages Dendrimers arecapable of delivering genes drugs anticancer agents and soforth [103] Micelles are spherical structures where moleculeswith a hydrophobic end aggregate to form the central coreand the hydrophilic ends of other molecules are in contactwith the liquid environment surrounding the core Micellesare effective carrier for the delivery of water insoluble drugscarried in the hydrophobic core [103 118] Nanospheres arespherical in shape that is composed of a matrix system inwhich drug is evenly distributed by entrapment attachmentor encapsulation The surface of these nanoparticles can bemodified by the addition of ligands or antibodies for targetingpurposes On the other hand nanocapsules are like vesiclesthat have a central core where a drug is confined and a core is
8 ISRN Nanotechnology
Table 1 Some formulations of nanoparticles with positive results in the recent investigations
Type ofnanoparticle Anticancer drug Targeting agent Name of the polymers used Outcome Reference
Polymericnanoparticle Cystatin Cytokeratin specific
surrounded by a polymeric membrane Targeting ligands orantibodies can be attached to the surface [25 102] Fullerenes(also called bucky balls) and nanotubes are a family ofmolecules composed of carbon in the form of a hollow sphereor ellipsoid tube Atoms may be trapped inside fullereneswhile antibodies or ligands are bound to the surface fortargeting [103 117] Carbon nanotubes are modified to makethem water-soluble and functionalized as they can be linkedto a variety of active molecules such as peptides proteinsnucleic acids and therapeutic agents [120 121] Nanotubescan be single walled or multiwalled [102] Suitable polymersfor nanoparticle preparation include poly (alkyl cyanoacry-lates) poly(methylidenemalonate) and polyesters such aspoly(lactic acid) poly(glycolic acid) poly(e-caprolactone)and their copolymers poly(120576-caprolactone) poly(lactic acid)(PLA) poly(glycolic acid) (PGA) and their copolymers aremost extensively researched due to their biocompatibility andbiodegradability [83 101] Table 1 illustrates some polymerbased formulations that brought out positive results in recentresearch
9 Conclusion
Nanotechnology has already revolutionized cancer therapyin many aspects and is radically changing the treatmentpattern It hasmade a great impact on selective recognizing ofthe cancerous cells targeted drug delivery and overcominglimitations of the conventional chemotherapies Some nan-otechnology based formulations have already been launchedin the market and many are undergoing research and clinical
trials The side effects of the traditional chemotherapies cangreatly be removed by these novel active or passive targetingwhich can substantially increase the survival rate As canceris one of the most serious lethal diseases the contributionof nanotechnology in precise treatment avoiding the lifethreatening side effects can potentially contribute to a positivemovement in clinical practice for life saving approach
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] D J Bharali and S A Mousa ldquoEmerging nanomedicines forearly cancer detection and improved treatment current per-spective and future promiserdquo Pharmacology and Therapeuticsvol 128 no 2 pp 324ndash335 2010
[2] G Zhao and B L Rodriguez ldquoMolecular targeting of liposomalnanoparticlesto tumor microenvironmentrdquo International Jour-nal of Nanomedicine vol 8 pp 61ndash71 2013
[3] N R Jabir S Tabrez GMAshraf S Shakil G ADamanhouriand M A Kamal ldquoNanotechnology-based approaches in anti-cancer researchrdquo International Journal of Nanomedicine vol 7pp 4391ndash4408 2012
[4] S A Mousa and D J Bharali ldquoNanotechnology-based detec-tion and targeted therapy in cancer nano-bio paradigms andapplicationsrdquo Cancers vol 3 no 3 pp 2888ndash2903 2011
[5] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancer
ISRN Nanotechnology 9
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
[16] M M Gottesman C A Hrycyna P V Schoenlein U AGermann and I Pastan ldquoGenetic analysis of the multidrugtransporterrdquo Annual Review of Genetics vol 29 pp 607ndash6491995
[17] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008
[18] X Guo and F C Szoka Jr ldquoChemical approaches to triggerablelipid vesicles for drug and gene deliveryrdquo Accounts of ChemicalResearch vol 36 no 5 pp 335ndash341 2003
[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
[20] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008
[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
[28] M F Francis M Cristea and F M Winnik ldquoPolymericmicelles for oral drug delivery why and howrdquo Pure and AppliedChemistry vol 76 no 7-8 pp 1321ndash1335 2004
[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
[32] J Sudimack and R J Lee ldquoTargeted drug delivery via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 41 no 2 pp147ndash162 2000
[33] J F Kukowska-Latallo K A Candido Z Cao et al ldquoNanoparti-cle targeting of anticancer drug improves therapeutic responsein animal model of human epithelial cancerrdquo Cancer Researchvol 65 no 12 pp 5317ndash5324 2005
[34] G Russell-Jones K McTavish J McEwan and B ThurmondldquoIncreasing the tumoricidal activity of daunomycin-pHPMAconjugates using vitamin B12 as a targeting agentrdquo Journal ofCancer Research Updates vol 1 no 2 pp 1ndash6 2012
[35] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 Article ID 18496 3 pages 2012
[36] H S Yoo and T G Park ldquoFolate-receptor-targeted delivery ofdoxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugaterdquo Journal of Controlled Release vol 100 no 2pp 247ndash256 2004
[37] M Kawamoto T Horibe M Kohno and K Kawakami ldquoAnovel transferrin receptor-targeted hybrid peptide disintegratescancer cell membrane to induce rapid killing of cancer cellsrdquoBMC Cancer vol 11 article 359 2011
[38] T R Daniels B Bernabeu J A Rodrıguez et al ldquoTransferrinreceptors and the targeted delivery of therapeutic agents againstcancerrdquo Biochimica et Biophysica Acta vol 1820 no 3 pp 291ndash317 2012
[39] N C Bellocq S H Pun G S Jensen and M E DavisldquoTransferrin-containing cyclodextrin polymer-based particlesfor tumor-targeted gene deliveryrdquo Bioconjugate Chemistry vol14 no 6 pp 1122ndash1132 2003
[40] C R Dass and P F M Choong ldquoTargeting of small moleculeanticancer drugs to the tumour and its vasculature using
10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
[41] H K Sun H J Ji H L Soo W K Sung and G P TaeldquoLHRH receptor-mediated delivery of siRNA using polyelec-trolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEIrdquo Bioconjugate Chemistry vol 19 no11 pp 2156ndash2162 2008
[42] S S Dharap Y Wang P Chandna et al ldquoTumor-specifictargeting of an anticancer drug delivery system by LHRHpeptiderdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 102 no 36 pp 12962ndash12967 2005
[43] httpwebmitedunewsoffice2006prostatehtml[44] T M Allen ldquoLigand-targeted therapeutics in anticancer ther-
apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
therapiesrdquoNature Reviews Cancer vol 1 no 2 pp 118ndash129 2001[46] W H Ouwehand R Finnern B D Gorick et al ldquoSelection of
internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
[47] J DMarksW H Ouwehand J M Bye et al ldquoHuman antibodyfragments specific for human blood group antigens from aphage display libraryrdquo BioTechnology vol 11 no 10 pp 1145ndash1149 1993
[48] B Liu F Conrad M R Cooperberg D B Kirpotin and JD Marks ldquoMapping tumor epitope space by direct selectionof single-chain Fv antibody libraries on prostate cancer cellsrdquoCancer Research vol 64 no 2 pp 704ndash710 2004
[49] D Peer P Zhu C V Carman J Lieberman and M ShimaokaldquoSelective gene silencing in activated leukocytes by target-ing siRNAs to the integrin lymphocyte function-associatedantigen-1rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 10 pp 4095ndash4100 2007
[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
[51] S Sudarshan D H Holman M L Hyer C Voelkel-JohnsonJ-Y Dong and J S Norris ldquoIn vitro efficacy of Fas ligandgene therapy for the treatment of bladder cancerrdquo Cancer GeneTherapy vol 12 no 1 pp 12ndash18 2005
[52] O Micheau E Solary A Hammann F Martin and M-TDimanche-Boitrel ldquoSensitization of cancer cells treated withcytotoxic drugs to fas-mediated cytotoxicityrdquo Journal of theNational Cancer Institute vol 89 no 11 pp 783ndash789 1997
[53] G N Naumov L A Akslen and J Folkman ldquoRole of angio-genesis in human tumor dormancy animal models of theangiogenic switchrdquoCell Cycle vol 5 no 16 pp 1779ndash1787 2006
[54] M A J Chaplain ldquoMathematical modelling of angiogenesisrdquoJournal of Neuro-Oncology vol 50 no 1-2 pp 37ndash51 2000
[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
[56] N Weidner J Folkman F Pozza et al ldquoTumor angiogenesis anew significant and independent prognostic indicator in early-stage breast carcinomardquo Journal of the National Cancer Institutevol 84 no 24 pp 1875ndash1887 1992
[57] D Fukumura and R K Jain ldquoImaging angiogenesis and themicroenvironmentrdquoAPMIS vol 116 no 7-8 pp 695ndash715 2008
[58] M Dhanabal M Jeffers andW J LaRochelle ldquoAnti-angiogenictherapy as a cancer treatment paradigmrdquo Current MedicinalChemistry vol 5 no 2 pp 115ndash130 2005
[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
[61] D Banerjee R Harfouche and S Sengupta ldquoNanotechnology-mediated targeting of tumor angiogenesisrdquoVascular Cell vol 3article 3 2011
[62] N Boudreau and C Myers ldquoBreast cancer-induced angiogen-esis multiple mechanisms and the role of the microenviron-mentrdquo Breast Cancer Research vol 5 no 3 pp 140ndash146 2003
[63] N N Khodarev J Yu E Labay et al ldquoTumour-endotheliuminteractions in co-culture coordinated changes of gene expres-sion profiles and phenotypic properties of endothelial cellsrdquoJournal of Cell Science vol 116 no 6 pp 1013ndash1022 2003
[64] J S Desgrosellier and D A Cheresh ldquoIntegrins in cancerbiological implications and therapeutic opportunitiesrdquo NatureReviews Cancer vol 10 no 1 pp 9ndash22 2010
[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
[66] S A Anderson R K Rader W F Westlin et al ldquoMag-netic resonance contrast enhancement of neovasculature withalpha(v)beta(3)-targeted nanoparticlesrdquoMagnetic Resonance inMedicine vol 44 pp 433ndash439 2000
[67] J H Park S Kwon J-O Nam et al ldquoSelf-assembled nanoparti-cles based on glycol chitosan bearing 5120573-cholanic acid for RGDpeptide deliveryrdquo Journal of Controlled Release vol 95 no 3 pp579ndash588 2004
[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
[70] J Li J Ji L M Holmes et al ldquoFusion protein from RGDpeptide and Fc fragment of mouse immunoglobulin G inhibitsangiogenesis in tumorrdquo Cancer Gene Therapy vol 11 no 5 pp363ndash370 2004
[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
[72] N Ferrara ldquoVEGF as a therapeutic target in cancerrdquo Oncologyvol 69 no 3 pp 11ndash16 2005
[73] D F Baban and L W Seymour ldquoControl of tumour vascularpermeabilityrdquo Advanced Drug Delivery Reviews vol 34 no 1pp 109ndash119 1998
[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
ISRN Nanotechnology 11
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
Another study was done by a team led by Kukowska-Latalloto et al which tests the folate-linked methotrexatedendrimers in immunodeficient athymic nude female miceThe mice were injected with the nanoconjugates twice aweek via a lateral tail vein The results showed that con-jugated methotrexate in dendrimers significantly loweredtoxicity and resulted in a 10-fold higher efficacy comparedto free methotrexate at an equal cumulative dose As aresult mice survived longer [33] The efficacy of nanosizedfolate receptor-targeted doxorubicin aggregates was testedfor cancer treatment Doxorubicin-polyethylene glycol-folateconjugatemicelles were prepared that were 200 nm in averagediameter The polymeric micelles exhibited enhanced andselective targeting to folate receptor positive cancer cellsin vitro The in vivo animal experiments showed that thenanoaggregates caused significant tumor suppression [3536]
Some other preparations include nanoparticles to whichfolate was conjugated covalently using surface carboxylgroups as well as conjugation of folate to hydrazine mod-ified poly-lactic acid nanoparticles Isobutyl-cyanoacrylate(IBCA) nanocapsules were prepared and coated with folatethat showed a significantly increased efficacy of nanocapsulestargeted to the tumor [8] The experiments showed folatereceptors can be targeted very effectively for selective drugdelivery by nanoparticles conjugated to folic acid
Transferrin Receptor Nanoparticles are widely being investi-gated to target the transferrin receptors for binding and cellentry as these are overexpressed by certain tumor cells toincrease their iron uptake Transferrin (Tf) can be conjugatedto a variety of materials for cancer targeting which includeTf-chemotherapeutic agent Tf-toxic protein Tf-RNases Tf-antibody and Tf-peptide [37 38] Kawamoto et al foundthat Tf-lytic hybrid peptide can selectively target cancerouscells They administered Tf-lytic peptide in an athymic micemodel with MDA-MB-231 cells The Tf-lytic hybrid peptideshowed effective cytotoxic activity where normal cells wereless sensitive to this molecule It was additionally revealedthat this preparation can disintegrate the cell membrane ofT47D cancer cells just in 10 min killing them effectively andinducing approximately 80 apoptotic cell death but not innormal cells Thus the intravenous administration of Tf-lyticpeptide in the athymic mice model significantly inhibitedtumor progression [37] Bellocq et al found that at lowtransferrin modification the nanoparticles remain stable inphysiologic salt concentrations and transfect leukemia cellswith increased efficiency The transferrin-modified nanopar-ticles are effective for systemic delivery of nucleic acidtherapeutics for metastatic cancer [39 40]
Luteinizing Hormone-Releasing Hormone Receptor Luteiniz-ing hormone-releasing hormone (LHRH) is being used inmany ongoing researches as a targeting moiety (ligand)to LHRH receptors that are over-expressed in the plasmamembrane of various types of cancer cells like breast cancerovarian cancer and prostate cancer [41 42] FarokhzadLanger and colleagues developed a new technique to deliverthe drugs in cancer cellrsquos internal fluidThey laced tailor-made
tiny sponge-like nanoparticles with the drug docetaxel Theparticles were particularly designed to dissolve the drug in acellrsquos internal fluids controlling the release rate For selectivetargeting the nanoparticles were ldquodecoratedrdquo on the outsidewith targeting molecules called aptamers tiny chunks ofgenetic material The aptamers specifically recognize the sur-face molecules on cancer cells In addition the nanoparticlesalso contained polyethylene glycol molecules to keep themaway from being rapidly destroyed by macrophages [43]
A team led by Prasad developed a method of target-ing LHRH receptor with ferric oxide nanoparticles whichwas prepared by a reverse micelle colloidal reaction Thehydrophilic groups were sequestered in the micelle core andthe hydrophobic groups remained solvent exposed on thesurface of the micelle in a reverse micelle system which wasformed by a surfactant continuous oil phase and waterA tracking agent two-photon dye ASPI-SH was attachedto the surface of the iron oxide Silica was added to formthe structure of the silica shell before additional silica shellgrown by tetraethylorthosilicate hydrolysis The targetingagent LHRH was coupled to the silica shell through carbonspacers so as to prevent stearic hindrance during the interac-tion of the targeting agent with its complementary moleculeon cells After the administration of the nanoparticles thepatients were exposed to a DC magnetic field The selectiveinteraction internalization and so forth were investigatedby using LHRH receptor expressing cells on oral epithelialcarcinoma cells Data clearly showed that the nanoparticlesselectively interacted with the specific cell types [8]
Asialoglycoprotein Asialoglycoprotein (ASGP) anotherreceptor which is overexpressed in hepatoma is utilizedin cancer targeting by nanoparticles for anticancer drugdelivery Sung and coworkers developed a new strategyby which biodegradable nanoparticles with a mean sizeof 140 nm can be prepared to target the hepatoma cellsThey prepared them from poly(-120574-glutamic acid)-poly(lactide) block copolymers loaded with paclitaxel usingemulsion solvent evaporation technique The nanoparticleswere conjugated with galactosamine (GAL) through anamide linkage to enhance hepatoma HepG2 cell uptake bytargeting ASGP receptors Immunofluorescence analysisutilizing a rhodamine-123 probe encapsulated in thehydrophobic core of the gal-nanoparticles revealed thehigh degree of selectivity of the nanoparticles to hepatictumors with enhanced cellular uptake through receptor-mediated endocytosis resulting in subsequent release ofthe encapsulated paclitaxel inside the cytoplasm Thosenanoparticles inhibited the growth of the cells with aconsequent decrease in systemic toxicity compared to freepaclitaxel
A dual-particle tumor targeting systemwas developed forselectively inhibiting angiogenesis in hepatoma Nanoparti-cle encapsulating ganciclovir conjugatedwith galactosaminewas the first component and an enhanced permeability andretention (EPR) mediated targeting nanoparticle containingan HSV thymidine kinase (TK) gene was the second compo-nent of the dual-particle tumor targeting system It was statedthat thymidine kinase would digest ganciclovir to produce
4 ISRN Nanotechnology
cytotoxic effects after cancer cells internalization of the firstand second nanoparticles together Thus it kills the targetedcancer cells [8]
312 Antibody Mediated Targeting Many tumor cells showunusual antigens due to their genetic defects that are eitherinappropriate for the cell type environment or temporalplacement in the organismsrsquo development The immuneresponses educed by tumor antigens are not so strong becausethey are recognized as own cells Highly specific monoclonalantibodies (mAbs) are used to strengthen the immuneresponse and to intensify the immune systemrsquos antitumorcapacityThese antibodies target proteins that are abnormallyexpressed in neoplastic cells and are essential for their growthNanoparticles conjugated with an antibody against a specifictumor antigen are developed for selective drug delivery [7]Most of the mAbs are produced by the clones of a singlehybridoma cell The hybridoma cell results from the fusionof a myeloma that produces antibody and an antigenicallystimulated normal plasma cell to bind specifically to tumorcell antigens After binding with tumor antigens mAbscan destroy cancer cells through a variety of approacheswhich include directly inducing apoptosis blocking growthfactor receptors and anti-idiotype formation They canindirectly eradicate cancer cells by activating complementmediated cellular cytotoxicity and antibody dependent cellmediated cytotoxicity [8] Antibody engineering has recentlyflourished with the outcome of antibody production thatcontains animal and human origins such as chimeric mAbshumanizedmAbs (those with a greater human contribution)and antibody fragments Antibodies can be used in theiroriginal form or as fragments for cancer targeting Howeverthe presence of two binding sites (within a single antibody)gives higher binding opportunity and makes it advantageousto use the intact mAbs Moreover a signaling cascade isinitiated to kill the cancer cells whenmacrophages bind to theFc segment of the antibody The Fc portion of an intact mAbcan also bind to the Fc receptors on normal cells resultingin increased ability to evoke an immune response and liverand spleen uptake of the nanocarrier Stability in long-termstorage is their additional advantage On the other hand anti-body fragments including antigen-binding fragments (Fab)dimers of antigen-binding fragments (F(ab1015840)2) single-chainfragment variables (scFv) and other engineered fragmentsare considered safer with reduced nonspecific binding [544 45] Phage display libraries may be used to rapidly selectantibodies or their fragments that bind to and internalizewithin cancer cells This method generates a combination ofpotentially useful antibodies that bind to different epitopes (apart of a receptor that is recognized by antibodies) of the sametarget cells Thus several epitopes of a single receptor willbe recognized by multiple antibodies proving more accurateand selective action [46ndash48] The efficacy of antibodies canbe increased by conjugating a therapeutic agent directly toit mAbs can act as the highly specific probes when theyare attached to nanoparticles to aid in targeted delivery ofvarious antitumor cytotoxic agents [5] Binding affinity andselectivity to cell surface targets by engineering proteinscan also be increased through the detection of a specific
conformation of a target receptor A fusion protein consistingof an scFv antibody fragment to target and deliver smallinterfering RNA (siRNA) to lymphocytes showed a 10000-fold increased affinity for the target receptor integrin LFA-1in a recent study done by Peer et al [49]
Kuroda and fellows developed a method for the prepara-tion of hollow protein nanoparticles containing ganciclovirwhich encapsulates a hepatic cancer therapeutic gene thymi-dine kinase (HSV1tk) derived from simple herpes virusThe nanoparticles were modified by displaying a hepatitis Bvirus surface-antigen to own hepatocyte recognition abilityand particle formation ability A human hepatoma bearinganimal model demonstrated that when a hepatic cancer-treating gene was encapsulated into hepatitis B virus surface-antigen (HBsAg) particles the gene was specifically deliveredinto a human liver-derived tissue part after administeringthe particles through intravenous injection The therapeuticeffect of the HBsAg-HSV1tk hollow protein nanoparticlesspecific to hepatic cancer was also confirmed They alsodeveloped a method of encapsulating cytotoxic drug con-taining a cancer treating gene within nanoparticles modifiedto display an antibody used for specific targeting of humansquamous carcinoma cells The nanoparticles were modifiedto express an antibody that recognizes the epidermal growthfactor receptor expressed by the cancer cells Animal studiesconfirmed that the transfer and expression of the genewas very specific to the human squamous carcinoma andhighly effective in treatment [8] Wartlick et al developedbiodegradable nanoparticles based on gelatin and humanserum albumin in which the surface of the nanoparticles wasmodified by covalent attachment of the biotin-binding pro-tein NeutrAvidin enabling the binding of biotinylated drugtargeting ligands by avidin-biotin complex formation HER2receptor a member of the epidermal growth factor receptorfamily is overexpressed in certain types of cancer (breastcancer) HER2 receptor specific antibody trastuzumab (her-ceptin) was conjugated to the surface of these nanoparti-cles for targeting HER2-overexpressing cells Confocal laserscanning microscopy showed an effective internalization ofthese nanoparticles by HER2-overexpressing cells throughreceptor-mediated endocytosis [50]
Nanoparticles can be designed to enhance Fas ligandexpression a type-II transmembrane protein which inducesapoptosis when bound with its receptor on the surface ofFas receptor-expressing leukemia cells Fas ligand-receptorinteractions play a significant role in the regulation of theimmune system and the progression of cancer [51 52] Fasagonist CH-11 a monoclonal antibody to the Fas receptoris conventionally used to target the cancer cells The mAbrituximab (Rituxan) was approved in 1997 for the treatmentof patients with non-Hodgkinrsquos lymphoma
313 Antiangiogenesis Angiogenesis is described as thegrowth of new blood vessels from preexisting vesselsTumors cannot grow more than 2mm in diameter with-out angiogenesis [53ndash55] Cancerous cells produce abnor-mal amounts of angiogenic growth factors resulting in anexcessive angiogenesis overwhelming the effects of naturalangiogenesis inhibitors giving rise to leaky and tortuous
ISRN Nanotechnology 5
vessels that are in a constant state of inflammation [54ndash58] Studies on breast cancer showed that the degree ofmetastasis tumor recurrence and shorter survival ratesare correlated with angiogenesis [56 59] Antiangiogenesistherapy is designed based on two mechanisms drugs whichprevent the formation of new blood vessels that supply to thetumor (eg TNP-470 endostatin and angiostatin) or drugsthat destroy the existing blood vessels (eg combretastatin)[60] The objective of antiangiogenic therapy is to delay bothprimary andmetastatic tumor growth by blocking the supplyof essential nutrients and the removal of metabolites causingstunted tumor growth thereby avoiding tumor spread as wellas enhancing the shrinkage of tumors [61] Antiangiogenicdrugs either act directly by targeting endothelial receptorsor indirectly by targeting angiogenic cytokines [62ndash64]Active targeting of the tumor vasculature by nanoparticles isachieved by targeting the VEGF receptors (VEGFRs) 120572]1205733integrin receptors and other angiogenic factors Integrinswhich mediate the attachment between a cell and its sur-roundings are the main component in angiogenesis processand their increase in number enhances the survival growthand invasion of both tumor and endothelial cells [64 65]120572]1205733 integrin antibody has been widely used as a targetingmoiety on nanovectors for anti-angiogenesis therapy due toits pleitropic upregulation in many tumor settings Someof them have passed several clinical trials [66ndash69] Tumorangiogenesis was successfully detected in rabbit and mousemodels by perfluorocarbon nanoparticles conjugated to var-ious contrasting agents (Gadolinium Gd or fluorine isotope19 19F) and linked to an 120572]1205733 integrin antibody [66 68] Theuse of peptides as the targeting agents resulted in increasedintracellular drug delivery in different murine tumor models[70 71] An approach to target integrin overexpressioninvolves using a synthetic peptide containing the recognitionsite for integrins namely an arginine-glycine-aspartic acid(RGD) sequence [67] The first angiogenesis inhibitor forcolorectal cancer therapy bevacizumab (Avastin) an anti-VEGF mAb that inhibits the growth factor of new bloodvessels was approved in 2004 [5 72] Prokop and his teamdeveloped amethod of preparing biocompatible nanoparticlethat can be used as drug delivery vehiclesTheywere designedto retain and deliver Antiangiogenic compounds over anextended period of time for targeting tumor vasculatureNanoparticleswere formulated comprising a hydrophilic coreof sodium alginate cellulose sulfate and Antiangiogenicfactors such as thrombospondin (TSP)-1 or TSP-517 whichwas crosslinked with dextran polyaldehyde with calciumchloride or conjugated to heparin sulfate with sodiumchloride In addition luciferase (bioluminescent agent) orpolymeric gadolinium (contrast agent) was placed withinthe polyanionic core The hydrophilic shell surroundingthe core additionally contained spermine hydrochloridepoly(methylene-co-guanidine) hydrochloride and pluronicF-68 calcium chloride and a targeting ligand conjugatedto an activated polyethylene glycol or crosslinked to dex-tran polyaldehyde Targeted nanoparticles were evaluatedby monitoring luciferase in a murine model [8] Figure 1illustrates the process of active targeting
32 Passive Targeting Nanoparticles can also target cancerthrough passive targeting As apoptosis is stopped in cancer-ous cells they continue sucking nutritious agents abnormallythrough the blood vessels forming wide and leaky bloodvessels around the cells induced by angiogenesis Leaky bloodvessels are formed due to basement membrane abnormalitiesand decreased numbers of pericytes lining rapidly prolif-erating endothelial cells [73] Hence the permeability ofmolecules to pass through the vessel wall into the interstitiumsurrounding tumor cells is increased The size of the poresin leaky endothelial cells ranges from 100 to 780 nm [74ndash76]Thus nanoparticles below that size can easily pass through thepores [77 78] As a result it facilitates to efflux the nanopar-ticles to cluster around the neoplastic cells Nanoparticlescan be targeted to specific area of capillary endothelium toconcentrate the drug within a particular organ and perforatethe tumor cells by passive diffusion or convection Lack oflymphatic drainage eases the diffusion process The tumorinterstitium is composed of a collagen network and a gel likefluid The fluid has high interstitial pressures which resistthe inward flux of molecules Tumors also lack well-definedlymphatic networks having leaky vasculature Thereforedrugs that enter the interstitial area may have extendedretention times in the tumor interstitium This feature iscalled the enhanced permeability and retention (EPR) effectand facilitates tumor interstitial drug accumulation (Figure 1)[79 80] Nanoparticles can easily accumulate selectively byenhanced permeability and retention effect and then diffuseinto the cells [81]
4 Cellular Uptake pH DependentDrug Delivery and Prevention fromLysosomal Degradation
Active or passive targeted nanoparticles face amajor difficultyin releasing drugs in the neoplastic cells since lysosomalenzymes rapidly destroy both the nanoparticles and drugsinside the cells After internalization the colloidal carri-ers usually reach the lysosomal compartment in whichhydrolytic enzymes degrade both the carrier and its contentTherefore the intracellular distribution of the carrier ismodified when the encapsulated drug is a nucleic acidBecause pH around of tumors cells is more acidic carriersthat change solubility at lower pH can be used to targetand release drugs The extracellular environment of solidtumors is acidic and there is an altered pH gradient acrosstheir cell compartments Nanoparticles sensitive to the pHgradients are promising for cancer drug delivery A pH-responsive nanoparticle consists of a shell and a core andit responds to the pH gradient and changes its solubilitypattern The core-shell polymer nanoparticles are designedwith their lower critical solution temperature (LCST) beingdependent on the ambient pH 74 At low pH in and aroundof tumor cells the resulting change in LCST causes the core-shell nanoparticles to deform and precipitate in an acidicenvironment triggering the release the chemotherapeuticsA targeting molecule is additionally conjugated to the shellof the nanoparticles which can recognize tumor cells [82]
6 ISRN Nanotechnology
Passive targeting Active targeting Targeted nanoparticle
Tumor Drug or drug-loaded nanocarriers
Normal tissue Receptor-mediated endocytosis
Figure 1 Active and passive targeting by nanoparticles
Shefer and his team reported a new strategy for preparing apH sensitive sustained release system for cancer treatmentThe system utilizes solid hydrophobic nanospheres contain-ing anticancer drugs that are encapsulated in a pH sensitivemicrosphere It additionally included a bioadhesive materialinto the solid hydrophobic matrix of the nanospheres Thenanosphere hydrophobic matrix was formed by dispersingpaclitaxel into the hotmelt of candelillawaxThemicrosphereof pH sensitive matrix was created by adding the drugwaxmixture into an aqueous solution containing a pH dependentanionic polymer which is stable at pH 74 but solubilizedat pH 6 and lower The prepared suspension was spraydried to produce a free flowing dry powder which consistsof 10 paclitaxel The nanospheres can release the drugover an extended period of time by dissolvingswelling themicrosphere at a lower pH that is typically found in canceroustissue [8] Recently researchers developed a system thateither fuse with the plasmamembrane or have a pH-sensitiveconfiguration that changes conformation in the lysosomesand allows the encapsulated material to escape into thecytoplasm [83] Biodegradable nanoparticles were formu-lated from the copolymers of poly(dl-lactide-co-glycolide)for their rapid endolysosomal escape The system workedby selective reversal of the surface charge of nanoparticles(from anionic to cationic) in the acidic endolysosomalcompartment causing the nanoparticles to interact with theendolysosomal membrane and escape into the cytosol Thesenanoparticles can deliver wide ranged therapeutic agentsincluding macromolecules such as DNA at a slow rate forsustained therapeutic effect For using nanotechnology incancer treatment researchers developed thermoresponsivepH-responsive and biodegradable nanoparticles by graftingbiodegradable poly (dl-lactide) ontoN-isopropyl acrylamideand methacrylic acid It may be sufficient for a carrier systemto concentrate the drug (hydrophobic that crosses the plasmamembrane easily) in the target tissue [84]
5 Hyperthermia
Healthy cells are capable of surviving exposure to temper-atures up to 465∘C Irreversible cell damage occurs to thecancerous cells at temperatures from approximately 40∘C to
about 46∘C due to the disorganized and compact vascularstructure for which they are less stable On the other handsurrounding healthy cells are more readily able to spatterheat and maintain a normal temperature This process statedabove is called hyperthermia which is used for the purpose ofdamaging protein and structures within cancerous cells andin some cases causing tumor cells to directly undergo apop-tosis Nanoparticles are utilized for a variety of purposes inhyperthermia-based treatments which include serving as theactive thermotherapeutic agents sensitizers and are also usedfor targeting purposes like antibody enhanced targeting toincrease efficacy and to reduce hypothermia-associated sideeffects Nanoparticles can locate and specifically target thedeep-seated tissues and organs Magnetic fluid hyperthermiais a well-practiced old method for cancer treatment Smallmagnetic particles are used which respond to an externallyapplied magnetic field by heating up In addition to specifictargeting nanoparticles add another benefit Cells that havepicked up some of the particles cannot get rid of them andthus every daughter cell will have one half of the amount ofparticles present on the mother cell
Handy et al developed a method of manufacturingnanoparticles for targeted delivery of thermotherapy incancer treatment The prepared ferromagnetic nanoparticleswere coated with biocompatible material poly(methacrylicacid-co-hydroxy-ethylmethacrylate) using free-radical poly-merization A stabilizing layer was formed around the mag-netic particles by an ionic surfactant sodiumbis-2-ethylhexylsulfosuccinate For selective targeting antibodies were cova-lently attached to the surface of coatedmagnetic particlesThethermotherapeutic magnetic composition containing single-domain magnetic particles attached to a target specific ligandwas inductively heated using amagnetic field High efficiencyof the bioprobes was determined in animal model [8 31]
6 Combination of Drugs Having DifferentPhysical Properties
Several studies have recently shown that combination therapyis more effective than a single drug for many types ofcancer Drugs having different physical properties could notbe combined into a single particle before Furthermore
ISRN Nanotechnology 7
it has always been difficult to get the right amount of drugto the tumor Langer and fellows developed a new method todevelop nanoparticles in which they incorporated drugs withdifferent physical properties which had been impossible withprevious drug delivering nanoparticles Earlier generations ofnanoparticles mean encapsulation in a polymer coating bywhich drugs with different charges or different affinity couldnot be carried together The new technique called ldquodrug-polymer blendingrdquo allowed the researchers to hang the drugmolecules like pendants from individual units of the poly-mer before the units assemble into a polymer nanoparticleThey developed nanoparticles with hydrophobic docetaxeland hydrophilic cisplatin After loading the drugs into thenanoparticle the researchers added a tag that binds to amolecule called prostate-specificmembrane antigen (PSMA)which is a type 2 integral membrane glycoprotein presenton the surfaces of most prostate cancer cells This tag allowsthe nanoparticles to bypass healthy tissues and reduce theside effects caused by most chemotherapy drugs As a resultthey go directly to their target region The new techniquefacilitated them to precisely control the ratio of drugs loadedinto the particle They were also able to control release rate ofthe drugs after they entered the tumor cells [85]
7 Overcoming Other Limitations ofConventional Chemotherapy
Lack of solubility is one of the major limitations of mostchemotherapeutic agents Nanoparticles can effectively solvethe solubility problem Hydrophobic drugs can be encap-sulated in micelles to increase their solubility [86 87]Dendrimers contain many binding sites with which bothhydrophobic and hydrophilic molecules can bind Liposomesalso allow encapsulating hydrophobic drugs and transport-ing them to the desired area soon after administration[87] Several approaches have been taken to overcome P-glycoproteinmediated drug resistance P-glycoprotein locatesdrugs which are localized in the plasmamembrane only Onestrategy is to use the inhibiting agents such as verapamil orcyclosporine when concurrently administered with a cyto-toxic drug can restrain P-glycoproteinThus both chemother-apeutic agent and inhibiting agent are incorporated intothe nanoparticles to overcome the problem associated withP-glycoprotein [25 88 89] A new strategy was devel-oped for inhibition of the P-glycoprotein-mediated effluxof vincristine where vincristine-loaded lipid nanoparticlesconjugated to an anti-P-glycoprotein monoclonal antibody(MRK-16) showed greater cytotoxicity in resistant humanmyelogenous leukaemia cell lines than nontargeted particles[90] Danson et al developed SP1049C a nonionic blockcopolymer composed of a hydrophobic core and hydrophilictail that contains doxorubicin which was able to circumventP-glycoprotein mediated drug resistance in a mouse modelof leukaemia and is now under clinical evaluation [9192] In another study folic acid attached to polyethylenel-glycol derivatized distearoyl-phosphatidylethanolamine wasused to target in vitro doxorubicin loaded liposomes to
folate receptor overexpressing tumor cells Folate receptor-mediated cell uptake of targeted liposomal doxorubicin intoa multidrug resistant subline of M109-HiFR cells (M109R-HiFR) was clearly unaffected by P-glycoprotein-mediateddrug efflux in sharp contrast to uptake of free doxorubicin[93]
8 Targeting Agents
Nanocarriers are used as targeting agents for cancer ther-apy comprising anticancer drugs targeting moieties andpolymers There are a variety of nanocarriers such as lipo-somes dendrimers micelles carbon nanotubes nanocap-sules nanospheres and so forth Therapeutic agents canbe entrapped covalently bound encapsulated or adsorbedto the nanoparticles [5 8] Liposomes are composed oflipid bilayers where the core can be either hydrophilic orhydrophobic depending on the number of lipid bilayers[102 103] Liposomes having a single lipid bilayer contain anaqueous core for encapsulating water soluble drugs whereasother liposomes having more than a single bilayer entraplipid soluble drugs [103 104] They are readily cleared by themacrophages and are therefore coated with inert polymersfor stabilization in the physiological conditions Liposomesare commonly coated with polyethylene glycol (PEG) [2125 105ndash107] In vivo study shows that liposomes coated withhyaluronan (HA) improves circulation time and enhancestargeting to HA receptor-expressing tumors [108 109]Bothactive and passive targeting can be achieved with liposomaldrug delivery Liposomal nanoparticles can conjugate witheither antibodies or ligands for selective drug delivery [110111] They possess some advantages that they are biodegrada-tion nonantigenic and have a high transport rate [112] Theycan also be designed for pH sensitive drug delivery or ther-motherapy [113ndash115] Dendrimers are branched three dimen-sional tree-like structures with a multifunctional core Theyare synthesized fromeither synthetic or natural elements suchas amino acids sugars and nucleotides [116] Dendrimers canbe prepared by controlled polymerization of the monomersmaintaining desired shape and size Multiple entities includ-ing both hydrophobic and hydrophilic molecules can beconjugated to dendrimers due to their exclusive branchingpoint [103 117ndash119] They can also be loaded with drugsusing the cavities in their cores through hydrophobic interac-tions hydrogen bonds or chemical linkages Dendrimers arecapable of delivering genes drugs anticancer agents and soforth [103] Micelles are spherical structures where moleculeswith a hydrophobic end aggregate to form the central coreand the hydrophilic ends of other molecules are in contactwith the liquid environment surrounding the core Micellesare effective carrier for the delivery of water insoluble drugscarried in the hydrophobic core [103 118] Nanospheres arespherical in shape that is composed of a matrix system inwhich drug is evenly distributed by entrapment attachmentor encapsulation The surface of these nanoparticles can bemodified by the addition of ligands or antibodies for targetingpurposes On the other hand nanocapsules are like vesiclesthat have a central core where a drug is confined and a core is
8 ISRN Nanotechnology
Table 1 Some formulations of nanoparticles with positive results in the recent investigations
Type ofnanoparticle Anticancer drug Targeting agent Name of the polymers used Outcome Reference
Polymericnanoparticle Cystatin Cytokeratin specific
surrounded by a polymeric membrane Targeting ligands orantibodies can be attached to the surface [25 102] Fullerenes(also called bucky balls) and nanotubes are a family ofmolecules composed of carbon in the form of a hollow sphereor ellipsoid tube Atoms may be trapped inside fullereneswhile antibodies or ligands are bound to the surface fortargeting [103 117] Carbon nanotubes are modified to makethem water-soluble and functionalized as they can be linkedto a variety of active molecules such as peptides proteinsnucleic acids and therapeutic agents [120 121] Nanotubescan be single walled or multiwalled [102] Suitable polymersfor nanoparticle preparation include poly (alkyl cyanoacry-lates) poly(methylidenemalonate) and polyesters such aspoly(lactic acid) poly(glycolic acid) poly(e-caprolactone)and their copolymers poly(120576-caprolactone) poly(lactic acid)(PLA) poly(glycolic acid) (PGA) and their copolymers aremost extensively researched due to their biocompatibility andbiodegradability [83 101] Table 1 illustrates some polymerbased formulations that brought out positive results in recentresearch
9 Conclusion
Nanotechnology has already revolutionized cancer therapyin many aspects and is radically changing the treatmentpattern It hasmade a great impact on selective recognizing ofthe cancerous cells targeted drug delivery and overcominglimitations of the conventional chemotherapies Some nan-otechnology based formulations have already been launchedin the market and many are undergoing research and clinical
trials The side effects of the traditional chemotherapies cangreatly be removed by these novel active or passive targetingwhich can substantially increase the survival rate As canceris one of the most serious lethal diseases the contributionof nanotechnology in precise treatment avoiding the lifethreatening side effects can potentially contribute to a positivemovement in clinical practice for life saving approach
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] D J Bharali and S A Mousa ldquoEmerging nanomedicines forearly cancer detection and improved treatment current per-spective and future promiserdquo Pharmacology and Therapeuticsvol 128 no 2 pp 324ndash335 2010
[2] G Zhao and B L Rodriguez ldquoMolecular targeting of liposomalnanoparticlesto tumor microenvironmentrdquo International Jour-nal of Nanomedicine vol 8 pp 61ndash71 2013
[3] N R Jabir S Tabrez GMAshraf S Shakil G ADamanhouriand M A Kamal ldquoNanotechnology-based approaches in anti-cancer researchrdquo International Journal of Nanomedicine vol 7pp 4391ndash4408 2012
[4] S A Mousa and D J Bharali ldquoNanotechnology-based detec-tion and targeted therapy in cancer nano-bio paradigms andapplicationsrdquo Cancers vol 3 no 3 pp 2888ndash2903 2011
[5] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancer
ISRN Nanotechnology 9
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
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[17] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008
[18] X Guo and F C Szoka Jr ldquoChemical approaches to triggerablelipid vesicles for drug and gene deliveryrdquo Accounts of ChemicalResearch vol 36 no 5 pp 335ndash341 2003
[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
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[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
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[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
[32] J Sudimack and R J Lee ldquoTargeted drug delivery via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 41 no 2 pp147ndash162 2000
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[34] G Russell-Jones K McTavish J McEwan and B ThurmondldquoIncreasing the tumoricidal activity of daunomycin-pHPMAconjugates using vitamin B12 as a targeting agentrdquo Journal ofCancer Research Updates vol 1 no 2 pp 1ndash6 2012
[35] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 Article ID 18496 3 pages 2012
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[39] N C Bellocq S H Pun G S Jensen and M E DavisldquoTransferrin-containing cyclodextrin polymer-based particlesfor tumor-targeted gene deliveryrdquo Bioconjugate Chemistry vol14 no 6 pp 1122ndash1132 2003
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10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
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apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
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internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
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[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
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[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
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[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
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[64] J S Desgrosellier and D A Cheresh ldquoIntegrins in cancerbiological implications and therapeutic opportunitiesrdquo NatureReviews Cancer vol 10 no 1 pp 9ndash22 2010
[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
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[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
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[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
[72] N Ferrara ldquoVEGF as a therapeutic target in cancerrdquo Oncologyvol 69 no 3 pp 11ndash16 2005
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[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
ISRN Nanotechnology 11
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
cytotoxic effects after cancer cells internalization of the firstand second nanoparticles together Thus it kills the targetedcancer cells [8]
312 Antibody Mediated Targeting Many tumor cells showunusual antigens due to their genetic defects that are eitherinappropriate for the cell type environment or temporalplacement in the organismsrsquo development The immuneresponses educed by tumor antigens are not so strong becausethey are recognized as own cells Highly specific monoclonalantibodies (mAbs) are used to strengthen the immuneresponse and to intensify the immune systemrsquos antitumorcapacityThese antibodies target proteins that are abnormallyexpressed in neoplastic cells and are essential for their growthNanoparticles conjugated with an antibody against a specifictumor antigen are developed for selective drug delivery [7]Most of the mAbs are produced by the clones of a singlehybridoma cell The hybridoma cell results from the fusionof a myeloma that produces antibody and an antigenicallystimulated normal plasma cell to bind specifically to tumorcell antigens After binding with tumor antigens mAbscan destroy cancer cells through a variety of approacheswhich include directly inducing apoptosis blocking growthfactor receptors and anti-idiotype formation They canindirectly eradicate cancer cells by activating complementmediated cellular cytotoxicity and antibody dependent cellmediated cytotoxicity [8] Antibody engineering has recentlyflourished with the outcome of antibody production thatcontains animal and human origins such as chimeric mAbshumanizedmAbs (those with a greater human contribution)and antibody fragments Antibodies can be used in theiroriginal form or as fragments for cancer targeting Howeverthe presence of two binding sites (within a single antibody)gives higher binding opportunity and makes it advantageousto use the intact mAbs Moreover a signaling cascade isinitiated to kill the cancer cells whenmacrophages bind to theFc segment of the antibody The Fc portion of an intact mAbcan also bind to the Fc receptors on normal cells resultingin increased ability to evoke an immune response and liverand spleen uptake of the nanocarrier Stability in long-termstorage is their additional advantage On the other hand anti-body fragments including antigen-binding fragments (Fab)dimers of antigen-binding fragments (F(ab1015840)2) single-chainfragment variables (scFv) and other engineered fragmentsare considered safer with reduced nonspecific binding [544 45] Phage display libraries may be used to rapidly selectantibodies or their fragments that bind to and internalizewithin cancer cells This method generates a combination ofpotentially useful antibodies that bind to different epitopes (apart of a receptor that is recognized by antibodies) of the sametarget cells Thus several epitopes of a single receptor willbe recognized by multiple antibodies proving more accurateand selective action [46ndash48] The efficacy of antibodies canbe increased by conjugating a therapeutic agent directly toit mAbs can act as the highly specific probes when theyare attached to nanoparticles to aid in targeted delivery ofvarious antitumor cytotoxic agents [5] Binding affinity andselectivity to cell surface targets by engineering proteinscan also be increased through the detection of a specific
conformation of a target receptor A fusion protein consistingof an scFv antibody fragment to target and deliver smallinterfering RNA (siRNA) to lymphocytes showed a 10000-fold increased affinity for the target receptor integrin LFA-1in a recent study done by Peer et al [49]
Kuroda and fellows developed a method for the prepara-tion of hollow protein nanoparticles containing ganciclovirwhich encapsulates a hepatic cancer therapeutic gene thymi-dine kinase (HSV1tk) derived from simple herpes virusThe nanoparticles were modified by displaying a hepatitis Bvirus surface-antigen to own hepatocyte recognition abilityand particle formation ability A human hepatoma bearinganimal model demonstrated that when a hepatic cancer-treating gene was encapsulated into hepatitis B virus surface-antigen (HBsAg) particles the gene was specifically deliveredinto a human liver-derived tissue part after administeringthe particles through intravenous injection The therapeuticeffect of the HBsAg-HSV1tk hollow protein nanoparticlesspecific to hepatic cancer was also confirmed They alsodeveloped a method of encapsulating cytotoxic drug con-taining a cancer treating gene within nanoparticles modifiedto display an antibody used for specific targeting of humansquamous carcinoma cells The nanoparticles were modifiedto express an antibody that recognizes the epidermal growthfactor receptor expressed by the cancer cells Animal studiesconfirmed that the transfer and expression of the genewas very specific to the human squamous carcinoma andhighly effective in treatment [8] Wartlick et al developedbiodegradable nanoparticles based on gelatin and humanserum albumin in which the surface of the nanoparticles wasmodified by covalent attachment of the biotin-binding pro-tein NeutrAvidin enabling the binding of biotinylated drugtargeting ligands by avidin-biotin complex formation HER2receptor a member of the epidermal growth factor receptorfamily is overexpressed in certain types of cancer (breastcancer) HER2 receptor specific antibody trastuzumab (her-ceptin) was conjugated to the surface of these nanoparti-cles for targeting HER2-overexpressing cells Confocal laserscanning microscopy showed an effective internalization ofthese nanoparticles by HER2-overexpressing cells throughreceptor-mediated endocytosis [50]
Nanoparticles can be designed to enhance Fas ligandexpression a type-II transmembrane protein which inducesapoptosis when bound with its receptor on the surface ofFas receptor-expressing leukemia cells Fas ligand-receptorinteractions play a significant role in the regulation of theimmune system and the progression of cancer [51 52] Fasagonist CH-11 a monoclonal antibody to the Fas receptoris conventionally used to target the cancer cells The mAbrituximab (Rituxan) was approved in 1997 for the treatmentof patients with non-Hodgkinrsquos lymphoma
313 Antiangiogenesis Angiogenesis is described as thegrowth of new blood vessels from preexisting vesselsTumors cannot grow more than 2mm in diameter with-out angiogenesis [53ndash55] Cancerous cells produce abnor-mal amounts of angiogenic growth factors resulting in anexcessive angiogenesis overwhelming the effects of naturalangiogenesis inhibitors giving rise to leaky and tortuous
ISRN Nanotechnology 5
vessels that are in a constant state of inflammation [54ndash58] Studies on breast cancer showed that the degree ofmetastasis tumor recurrence and shorter survival ratesare correlated with angiogenesis [56 59] Antiangiogenesistherapy is designed based on two mechanisms drugs whichprevent the formation of new blood vessels that supply to thetumor (eg TNP-470 endostatin and angiostatin) or drugsthat destroy the existing blood vessels (eg combretastatin)[60] The objective of antiangiogenic therapy is to delay bothprimary andmetastatic tumor growth by blocking the supplyof essential nutrients and the removal of metabolites causingstunted tumor growth thereby avoiding tumor spread as wellas enhancing the shrinkage of tumors [61] Antiangiogenicdrugs either act directly by targeting endothelial receptorsor indirectly by targeting angiogenic cytokines [62ndash64]Active targeting of the tumor vasculature by nanoparticles isachieved by targeting the VEGF receptors (VEGFRs) 120572]1205733integrin receptors and other angiogenic factors Integrinswhich mediate the attachment between a cell and its sur-roundings are the main component in angiogenesis processand their increase in number enhances the survival growthand invasion of both tumor and endothelial cells [64 65]120572]1205733 integrin antibody has been widely used as a targetingmoiety on nanovectors for anti-angiogenesis therapy due toits pleitropic upregulation in many tumor settings Someof them have passed several clinical trials [66ndash69] Tumorangiogenesis was successfully detected in rabbit and mousemodels by perfluorocarbon nanoparticles conjugated to var-ious contrasting agents (Gadolinium Gd or fluorine isotope19 19F) and linked to an 120572]1205733 integrin antibody [66 68] Theuse of peptides as the targeting agents resulted in increasedintracellular drug delivery in different murine tumor models[70 71] An approach to target integrin overexpressioninvolves using a synthetic peptide containing the recognitionsite for integrins namely an arginine-glycine-aspartic acid(RGD) sequence [67] The first angiogenesis inhibitor forcolorectal cancer therapy bevacizumab (Avastin) an anti-VEGF mAb that inhibits the growth factor of new bloodvessels was approved in 2004 [5 72] Prokop and his teamdeveloped amethod of preparing biocompatible nanoparticlethat can be used as drug delivery vehiclesTheywere designedto retain and deliver Antiangiogenic compounds over anextended period of time for targeting tumor vasculatureNanoparticleswere formulated comprising a hydrophilic coreof sodium alginate cellulose sulfate and Antiangiogenicfactors such as thrombospondin (TSP)-1 or TSP-517 whichwas crosslinked with dextran polyaldehyde with calciumchloride or conjugated to heparin sulfate with sodiumchloride In addition luciferase (bioluminescent agent) orpolymeric gadolinium (contrast agent) was placed withinthe polyanionic core The hydrophilic shell surroundingthe core additionally contained spermine hydrochloridepoly(methylene-co-guanidine) hydrochloride and pluronicF-68 calcium chloride and a targeting ligand conjugatedto an activated polyethylene glycol or crosslinked to dex-tran polyaldehyde Targeted nanoparticles were evaluatedby monitoring luciferase in a murine model [8] Figure 1illustrates the process of active targeting
32 Passive Targeting Nanoparticles can also target cancerthrough passive targeting As apoptosis is stopped in cancer-ous cells they continue sucking nutritious agents abnormallythrough the blood vessels forming wide and leaky bloodvessels around the cells induced by angiogenesis Leaky bloodvessels are formed due to basement membrane abnormalitiesand decreased numbers of pericytes lining rapidly prolif-erating endothelial cells [73] Hence the permeability ofmolecules to pass through the vessel wall into the interstitiumsurrounding tumor cells is increased The size of the poresin leaky endothelial cells ranges from 100 to 780 nm [74ndash76]Thus nanoparticles below that size can easily pass through thepores [77 78] As a result it facilitates to efflux the nanopar-ticles to cluster around the neoplastic cells Nanoparticlescan be targeted to specific area of capillary endothelium toconcentrate the drug within a particular organ and perforatethe tumor cells by passive diffusion or convection Lack oflymphatic drainage eases the diffusion process The tumorinterstitium is composed of a collagen network and a gel likefluid The fluid has high interstitial pressures which resistthe inward flux of molecules Tumors also lack well-definedlymphatic networks having leaky vasculature Thereforedrugs that enter the interstitial area may have extendedretention times in the tumor interstitium This feature iscalled the enhanced permeability and retention (EPR) effectand facilitates tumor interstitial drug accumulation (Figure 1)[79 80] Nanoparticles can easily accumulate selectively byenhanced permeability and retention effect and then diffuseinto the cells [81]
4 Cellular Uptake pH DependentDrug Delivery and Prevention fromLysosomal Degradation
Active or passive targeted nanoparticles face amajor difficultyin releasing drugs in the neoplastic cells since lysosomalenzymes rapidly destroy both the nanoparticles and drugsinside the cells After internalization the colloidal carri-ers usually reach the lysosomal compartment in whichhydrolytic enzymes degrade both the carrier and its contentTherefore the intracellular distribution of the carrier ismodified when the encapsulated drug is a nucleic acidBecause pH around of tumors cells is more acidic carriersthat change solubility at lower pH can be used to targetand release drugs The extracellular environment of solidtumors is acidic and there is an altered pH gradient acrosstheir cell compartments Nanoparticles sensitive to the pHgradients are promising for cancer drug delivery A pH-responsive nanoparticle consists of a shell and a core andit responds to the pH gradient and changes its solubilitypattern The core-shell polymer nanoparticles are designedwith their lower critical solution temperature (LCST) beingdependent on the ambient pH 74 At low pH in and aroundof tumor cells the resulting change in LCST causes the core-shell nanoparticles to deform and precipitate in an acidicenvironment triggering the release the chemotherapeuticsA targeting molecule is additionally conjugated to the shellof the nanoparticles which can recognize tumor cells [82]
6 ISRN Nanotechnology
Passive targeting Active targeting Targeted nanoparticle
Tumor Drug or drug-loaded nanocarriers
Normal tissue Receptor-mediated endocytosis
Figure 1 Active and passive targeting by nanoparticles
Shefer and his team reported a new strategy for preparing apH sensitive sustained release system for cancer treatmentThe system utilizes solid hydrophobic nanospheres contain-ing anticancer drugs that are encapsulated in a pH sensitivemicrosphere It additionally included a bioadhesive materialinto the solid hydrophobic matrix of the nanospheres Thenanosphere hydrophobic matrix was formed by dispersingpaclitaxel into the hotmelt of candelillawaxThemicrosphereof pH sensitive matrix was created by adding the drugwaxmixture into an aqueous solution containing a pH dependentanionic polymer which is stable at pH 74 but solubilizedat pH 6 and lower The prepared suspension was spraydried to produce a free flowing dry powder which consistsof 10 paclitaxel The nanospheres can release the drugover an extended period of time by dissolvingswelling themicrosphere at a lower pH that is typically found in canceroustissue [8] Recently researchers developed a system thateither fuse with the plasmamembrane or have a pH-sensitiveconfiguration that changes conformation in the lysosomesand allows the encapsulated material to escape into thecytoplasm [83] Biodegradable nanoparticles were formu-lated from the copolymers of poly(dl-lactide-co-glycolide)for their rapid endolysosomal escape The system workedby selective reversal of the surface charge of nanoparticles(from anionic to cationic) in the acidic endolysosomalcompartment causing the nanoparticles to interact with theendolysosomal membrane and escape into the cytosol Thesenanoparticles can deliver wide ranged therapeutic agentsincluding macromolecules such as DNA at a slow rate forsustained therapeutic effect For using nanotechnology incancer treatment researchers developed thermoresponsivepH-responsive and biodegradable nanoparticles by graftingbiodegradable poly (dl-lactide) ontoN-isopropyl acrylamideand methacrylic acid It may be sufficient for a carrier systemto concentrate the drug (hydrophobic that crosses the plasmamembrane easily) in the target tissue [84]
5 Hyperthermia
Healthy cells are capable of surviving exposure to temper-atures up to 465∘C Irreversible cell damage occurs to thecancerous cells at temperatures from approximately 40∘C to
about 46∘C due to the disorganized and compact vascularstructure for which they are less stable On the other handsurrounding healthy cells are more readily able to spatterheat and maintain a normal temperature This process statedabove is called hyperthermia which is used for the purpose ofdamaging protein and structures within cancerous cells andin some cases causing tumor cells to directly undergo apop-tosis Nanoparticles are utilized for a variety of purposes inhyperthermia-based treatments which include serving as theactive thermotherapeutic agents sensitizers and are also usedfor targeting purposes like antibody enhanced targeting toincrease efficacy and to reduce hypothermia-associated sideeffects Nanoparticles can locate and specifically target thedeep-seated tissues and organs Magnetic fluid hyperthermiais a well-practiced old method for cancer treatment Smallmagnetic particles are used which respond to an externallyapplied magnetic field by heating up In addition to specifictargeting nanoparticles add another benefit Cells that havepicked up some of the particles cannot get rid of them andthus every daughter cell will have one half of the amount ofparticles present on the mother cell
Handy et al developed a method of manufacturingnanoparticles for targeted delivery of thermotherapy incancer treatment The prepared ferromagnetic nanoparticleswere coated with biocompatible material poly(methacrylicacid-co-hydroxy-ethylmethacrylate) using free-radical poly-merization A stabilizing layer was formed around the mag-netic particles by an ionic surfactant sodiumbis-2-ethylhexylsulfosuccinate For selective targeting antibodies were cova-lently attached to the surface of coatedmagnetic particlesThethermotherapeutic magnetic composition containing single-domain magnetic particles attached to a target specific ligandwas inductively heated using amagnetic field High efficiencyof the bioprobes was determined in animal model [8 31]
6 Combination of Drugs Having DifferentPhysical Properties
Several studies have recently shown that combination therapyis more effective than a single drug for many types ofcancer Drugs having different physical properties could notbe combined into a single particle before Furthermore
ISRN Nanotechnology 7
it has always been difficult to get the right amount of drugto the tumor Langer and fellows developed a new method todevelop nanoparticles in which they incorporated drugs withdifferent physical properties which had been impossible withprevious drug delivering nanoparticles Earlier generations ofnanoparticles mean encapsulation in a polymer coating bywhich drugs with different charges or different affinity couldnot be carried together The new technique called ldquodrug-polymer blendingrdquo allowed the researchers to hang the drugmolecules like pendants from individual units of the poly-mer before the units assemble into a polymer nanoparticleThey developed nanoparticles with hydrophobic docetaxeland hydrophilic cisplatin After loading the drugs into thenanoparticle the researchers added a tag that binds to amolecule called prostate-specificmembrane antigen (PSMA)which is a type 2 integral membrane glycoprotein presenton the surfaces of most prostate cancer cells This tag allowsthe nanoparticles to bypass healthy tissues and reduce theside effects caused by most chemotherapy drugs As a resultthey go directly to their target region The new techniquefacilitated them to precisely control the ratio of drugs loadedinto the particle They were also able to control release rate ofthe drugs after they entered the tumor cells [85]
7 Overcoming Other Limitations ofConventional Chemotherapy
Lack of solubility is one of the major limitations of mostchemotherapeutic agents Nanoparticles can effectively solvethe solubility problem Hydrophobic drugs can be encap-sulated in micelles to increase their solubility [86 87]Dendrimers contain many binding sites with which bothhydrophobic and hydrophilic molecules can bind Liposomesalso allow encapsulating hydrophobic drugs and transport-ing them to the desired area soon after administration[87] Several approaches have been taken to overcome P-glycoproteinmediated drug resistance P-glycoprotein locatesdrugs which are localized in the plasmamembrane only Onestrategy is to use the inhibiting agents such as verapamil orcyclosporine when concurrently administered with a cyto-toxic drug can restrain P-glycoproteinThus both chemother-apeutic agent and inhibiting agent are incorporated intothe nanoparticles to overcome the problem associated withP-glycoprotein [25 88 89] A new strategy was devel-oped for inhibition of the P-glycoprotein-mediated effluxof vincristine where vincristine-loaded lipid nanoparticlesconjugated to an anti-P-glycoprotein monoclonal antibody(MRK-16) showed greater cytotoxicity in resistant humanmyelogenous leukaemia cell lines than nontargeted particles[90] Danson et al developed SP1049C a nonionic blockcopolymer composed of a hydrophobic core and hydrophilictail that contains doxorubicin which was able to circumventP-glycoprotein mediated drug resistance in a mouse modelof leukaemia and is now under clinical evaluation [9192] In another study folic acid attached to polyethylenel-glycol derivatized distearoyl-phosphatidylethanolamine wasused to target in vitro doxorubicin loaded liposomes to
folate receptor overexpressing tumor cells Folate receptor-mediated cell uptake of targeted liposomal doxorubicin intoa multidrug resistant subline of M109-HiFR cells (M109R-HiFR) was clearly unaffected by P-glycoprotein-mediateddrug efflux in sharp contrast to uptake of free doxorubicin[93]
8 Targeting Agents
Nanocarriers are used as targeting agents for cancer ther-apy comprising anticancer drugs targeting moieties andpolymers There are a variety of nanocarriers such as lipo-somes dendrimers micelles carbon nanotubes nanocap-sules nanospheres and so forth Therapeutic agents canbe entrapped covalently bound encapsulated or adsorbedto the nanoparticles [5 8] Liposomes are composed oflipid bilayers where the core can be either hydrophilic orhydrophobic depending on the number of lipid bilayers[102 103] Liposomes having a single lipid bilayer contain anaqueous core for encapsulating water soluble drugs whereasother liposomes having more than a single bilayer entraplipid soluble drugs [103 104] They are readily cleared by themacrophages and are therefore coated with inert polymersfor stabilization in the physiological conditions Liposomesare commonly coated with polyethylene glycol (PEG) [2125 105ndash107] In vivo study shows that liposomes coated withhyaluronan (HA) improves circulation time and enhancestargeting to HA receptor-expressing tumors [108 109]Bothactive and passive targeting can be achieved with liposomaldrug delivery Liposomal nanoparticles can conjugate witheither antibodies or ligands for selective drug delivery [110111] They possess some advantages that they are biodegrada-tion nonantigenic and have a high transport rate [112] Theycan also be designed for pH sensitive drug delivery or ther-motherapy [113ndash115] Dendrimers are branched three dimen-sional tree-like structures with a multifunctional core Theyare synthesized fromeither synthetic or natural elements suchas amino acids sugars and nucleotides [116] Dendrimers canbe prepared by controlled polymerization of the monomersmaintaining desired shape and size Multiple entities includ-ing both hydrophobic and hydrophilic molecules can beconjugated to dendrimers due to their exclusive branchingpoint [103 117ndash119] They can also be loaded with drugsusing the cavities in their cores through hydrophobic interac-tions hydrogen bonds or chemical linkages Dendrimers arecapable of delivering genes drugs anticancer agents and soforth [103] Micelles are spherical structures where moleculeswith a hydrophobic end aggregate to form the central coreand the hydrophilic ends of other molecules are in contactwith the liquid environment surrounding the core Micellesare effective carrier for the delivery of water insoluble drugscarried in the hydrophobic core [103 118] Nanospheres arespherical in shape that is composed of a matrix system inwhich drug is evenly distributed by entrapment attachmentor encapsulation The surface of these nanoparticles can bemodified by the addition of ligands or antibodies for targetingpurposes On the other hand nanocapsules are like vesiclesthat have a central core where a drug is confined and a core is
8 ISRN Nanotechnology
Table 1 Some formulations of nanoparticles with positive results in the recent investigations
Type ofnanoparticle Anticancer drug Targeting agent Name of the polymers used Outcome Reference
Polymericnanoparticle Cystatin Cytokeratin specific
surrounded by a polymeric membrane Targeting ligands orantibodies can be attached to the surface [25 102] Fullerenes(also called bucky balls) and nanotubes are a family ofmolecules composed of carbon in the form of a hollow sphereor ellipsoid tube Atoms may be trapped inside fullereneswhile antibodies or ligands are bound to the surface fortargeting [103 117] Carbon nanotubes are modified to makethem water-soluble and functionalized as they can be linkedto a variety of active molecules such as peptides proteinsnucleic acids and therapeutic agents [120 121] Nanotubescan be single walled or multiwalled [102] Suitable polymersfor nanoparticle preparation include poly (alkyl cyanoacry-lates) poly(methylidenemalonate) and polyesters such aspoly(lactic acid) poly(glycolic acid) poly(e-caprolactone)and their copolymers poly(120576-caprolactone) poly(lactic acid)(PLA) poly(glycolic acid) (PGA) and their copolymers aremost extensively researched due to their biocompatibility andbiodegradability [83 101] Table 1 illustrates some polymerbased formulations that brought out positive results in recentresearch
9 Conclusion
Nanotechnology has already revolutionized cancer therapyin many aspects and is radically changing the treatmentpattern It hasmade a great impact on selective recognizing ofthe cancerous cells targeted drug delivery and overcominglimitations of the conventional chemotherapies Some nan-otechnology based formulations have already been launchedin the market and many are undergoing research and clinical
trials The side effects of the traditional chemotherapies cangreatly be removed by these novel active or passive targetingwhich can substantially increase the survival rate As canceris one of the most serious lethal diseases the contributionof nanotechnology in precise treatment avoiding the lifethreatening side effects can potentially contribute to a positivemovement in clinical practice for life saving approach
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] D J Bharali and S A Mousa ldquoEmerging nanomedicines forearly cancer detection and improved treatment current per-spective and future promiserdquo Pharmacology and Therapeuticsvol 128 no 2 pp 324ndash335 2010
[2] G Zhao and B L Rodriguez ldquoMolecular targeting of liposomalnanoparticlesto tumor microenvironmentrdquo International Jour-nal of Nanomedicine vol 8 pp 61ndash71 2013
[3] N R Jabir S Tabrez GMAshraf S Shakil G ADamanhouriand M A Kamal ldquoNanotechnology-based approaches in anti-cancer researchrdquo International Journal of Nanomedicine vol 7pp 4391ndash4408 2012
[4] S A Mousa and D J Bharali ldquoNanotechnology-based detec-tion and targeted therapy in cancer nano-bio paradigms andapplicationsrdquo Cancers vol 3 no 3 pp 2888ndash2903 2011
[5] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancer
ISRN Nanotechnology 9
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
[16] M M Gottesman C A Hrycyna P V Schoenlein U AGermann and I Pastan ldquoGenetic analysis of the multidrugtransporterrdquo Annual Review of Genetics vol 29 pp 607ndash6491995
[17] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008
[18] X Guo and F C Szoka Jr ldquoChemical approaches to triggerablelipid vesicles for drug and gene deliveryrdquo Accounts of ChemicalResearch vol 36 no 5 pp 335ndash341 2003
[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
[20] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008
[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
[28] M F Francis M Cristea and F M Winnik ldquoPolymericmicelles for oral drug delivery why and howrdquo Pure and AppliedChemistry vol 76 no 7-8 pp 1321ndash1335 2004
[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
[32] J Sudimack and R J Lee ldquoTargeted drug delivery via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 41 no 2 pp147ndash162 2000
[33] J F Kukowska-Latallo K A Candido Z Cao et al ldquoNanoparti-cle targeting of anticancer drug improves therapeutic responsein animal model of human epithelial cancerrdquo Cancer Researchvol 65 no 12 pp 5317ndash5324 2005
[34] G Russell-Jones K McTavish J McEwan and B ThurmondldquoIncreasing the tumoricidal activity of daunomycin-pHPMAconjugates using vitamin B12 as a targeting agentrdquo Journal ofCancer Research Updates vol 1 no 2 pp 1ndash6 2012
[35] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 Article ID 18496 3 pages 2012
[36] H S Yoo and T G Park ldquoFolate-receptor-targeted delivery ofdoxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugaterdquo Journal of Controlled Release vol 100 no 2pp 247ndash256 2004
[37] M Kawamoto T Horibe M Kohno and K Kawakami ldquoAnovel transferrin receptor-targeted hybrid peptide disintegratescancer cell membrane to induce rapid killing of cancer cellsrdquoBMC Cancer vol 11 article 359 2011
[38] T R Daniels B Bernabeu J A Rodrıguez et al ldquoTransferrinreceptors and the targeted delivery of therapeutic agents againstcancerrdquo Biochimica et Biophysica Acta vol 1820 no 3 pp 291ndash317 2012
[39] N C Bellocq S H Pun G S Jensen and M E DavisldquoTransferrin-containing cyclodextrin polymer-based particlesfor tumor-targeted gene deliveryrdquo Bioconjugate Chemistry vol14 no 6 pp 1122ndash1132 2003
[40] C R Dass and P F M Choong ldquoTargeting of small moleculeanticancer drugs to the tumour and its vasculature using
10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
[41] H K Sun H J Ji H L Soo W K Sung and G P TaeldquoLHRH receptor-mediated delivery of siRNA using polyelec-trolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEIrdquo Bioconjugate Chemistry vol 19 no11 pp 2156ndash2162 2008
[42] S S Dharap Y Wang P Chandna et al ldquoTumor-specifictargeting of an anticancer drug delivery system by LHRHpeptiderdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 102 no 36 pp 12962ndash12967 2005
[43] httpwebmitedunewsoffice2006prostatehtml[44] T M Allen ldquoLigand-targeted therapeutics in anticancer ther-
apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
therapiesrdquoNature Reviews Cancer vol 1 no 2 pp 118ndash129 2001[46] W H Ouwehand R Finnern B D Gorick et al ldquoSelection of
internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
[47] J DMarksW H Ouwehand J M Bye et al ldquoHuman antibodyfragments specific for human blood group antigens from aphage display libraryrdquo BioTechnology vol 11 no 10 pp 1145ndash1149 1993
[48] B Liu F Conrad M R Cooperberg D B Kirpotin and JD Marks ldquoMapping tumor epitope space by direct selectionof single-chain Fv antibody libraries on prostate cancer cellsrdquoCancer Research vol 64 no 2 pp 704ndash710 2004
[49] D Peer P Zhu C V Carman J Lieberman and M ShimaokaldquoSelective gene silencing in activated leukocytes by target-ing siRNAs to the integrin lymphocyte function-associatedantigen-1rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 10 pp 4095ndash4100 2007
[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
[51] S Sudarshan D H Holman M L Hyer C Voelkel-JohnsonJ-Y Dong and J S Norris ldquoIn vitro efficacy of Fas ligandgene therapy for the treatment of bladder cancerrdquo Cancer GeneTherapy vol 12 no 1 pp 12ndash18 2005
[52] O Micheau E Solary A Hammann F Martin and M-TDimanche-Boitrel ldquoSensitization of cancer cells treated withcytotoxic drugs to fas-mediated cytotoxicityrdquo Journal of theNational Cancer Institute vol 89 no 11 pp 783ndash789 1997
[53] G N Naumov L A Akslen and J Folkman ldquoRole of angio-genesis in human tumor dormancy animal models of theangiogenic switchrdquoCell Cycle vol 5 no 16 pp 1779ndash1787 2006
[54] M A J Chaplain ldquoMathematical modelling of angiogenesisrdquoJournal of Neuro-Oncology vol 50 no 1-2 pp 37ndash51 2000
[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
[56] N Weidner J Folkman F Pozza et al ldquoTumor angiogenesis anew significant and independent prognostic indicator in early-stage breast carcinomardquo Journal of the National Cancer Institutevol 84 no 24 pp 1875ndash1887 1992
[57] D Fukumura and R K Jain ldquoImaging angiogenesis and themicroenvironmentrdquoAPMIS vol 116 no 7-8 pp 695ndash715 2008
[58] M Dhanabal M Jeffers andW J LaRochelle ldquoAnti-angiogenictherapy as a cancer treatment paradigmrdquo Current MedicinalChemistry vol 5 no 2 pp 115ndash130 2005
[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
[61] D Banerjee R Harfouche and S Sengupta ldquoNanotechnology-mediated targeting of tumor angiogenesisrdquoVascular Cell vol 3article 3 2011
[62] N Boudreau and C Myers ldquoBreast cancer-induced angiogen-esis multiple mechanisms and the role of the microenviron-mentrdquo Breast Cancer Research vol 5 no 3 pp 140ndash146 2003
[63] N N Khodarev J Yu E Labay et al ldquoTumour-endotheliuminteractions in co-culture coordinated changes of gene expres-sion profiles and phenotypic properties of endothelial cellsrdquoJournal of Cell Science vol 116 no 6 pp 1013ndash1022 2003
[64] J S Desgrosellier and D A Cheresh ldquoIntegrins in cancerbiological implications and therapeutic opportunitiesrdquo NatureReviews Cancer vol 10 no 1 pp 9ndash22 2010
[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
[66] S A Anderson R K Rader W F Westlin et al ldquoMag-netic resonance contrast enhancement of neovasculature withalpha(v)beta(3)-targeted nanoparticlesrdquoMagnetic Resonance inMedicine vol 44 pp 433ndash439 2000
[67] J H Park S Kwon J-O Nam et al ldquoSelf-assembled nanoparti-cles based on glycol chitosan bearing 5120573-cholanic acid for RGDpeptide deliveryrdquo Journal of Controlled Release vol 95 no 3 pp579ndash588 2004
[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
[70] J Li J Ji L M Holmes et al ldquoFusion protein from RGDpeptide and Fc fragment of mouse immunoglobulin G inhibitsangiogenesis in tumorrdquo Cancer Gene Therapy vol 11 no 5 pp363ndash370 2004
[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
[72] N Ferrara ldquoVEGF as a therapeutic target in cancerrdquo Oncologyvol 69 no 3 pp 11ndash16 2005
[73] D F Baban and L W Seymour ldquoControl of tumour vascularpermeabilityrdquo Advanced Drug Delivery Reviews vol 34 no 1pp 109ndash119 1998
[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
ISRN Nanotechnology 11
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
vessels that are in a constant state of inflammation [54ndash58] Studies on breast cancer showed that the degree ofmetastasis tumor recurrence and shorter survival ratesare correlated with angiogenesis [56 59] Antiangiogenesistherapy is designed based on two mechanisms drugs whichprevent the formation of new blood vessels that supply to thetumor (eg TNP-470 endostatin and angiostatin) or drugsthat destroy the existing blood vessels (eg combretastatin)[60] The objective of antiangiogenic therapy is to delay bothprimary andmetastatic tumor growth by blocking the supplyof essential nutrients and the removal of metabolites causingstunted tumor growth thereby avoiding tumor spread as wellas enhancing the shrinkage of tumors [61] Antiangiogenicdrugs either act directly by targeting endothelial receptorsor indirectly by targeting angiogenic cytokines [62ndash64]Active targeting of the tumor vasculature by nanoparticles isachieved by targeting the VEGF receptors (VEGFRs) 120572]1205733integrin receptors and other angiogenic factors Integrinswhich mediate the attachment between a cell and its sur-roundings are the main component in angiogenesis processand their increase in number enhances the survival growthand invasion of both tumor and endothelial cells [64 65]120572]1205733 integrin antibody has been widely used as a targetingmoiety on nanovectors for anti-angiogenesis therapy due toits pleitropic upregulation in many tumor settings Someof them have passed several clinical trials [66ndash69] Tumorangiogenesis was successfully detected in rabbit and mousemodels by perfluorocarbon nanoparticles conjugated to var-ious contrasting agents (Gadolinium Gd or fluorine isotope19 19F) and linked to an 120572]1205733 integrin antibody [66 68] Theuse of peptides as the targeting agents resulted in increasedintracellular drug delivery in different murine tumor models[70 71] An approach to target integrin overexpressioninvolves using a synthetic peptide containing the recognitionsite for integrins namely an arginine-glycine-aspartic acid(RGD) sequence [67] The first angiogenesis inhibitor forcolorectal cancer therapy bevacizumab (Avastin) an anti-VEGF mAb that inhibits the growth factor of new bloodvessels was approved in 2004 [5 72] Prokop and his teamdeveloped amethod of preparing biocompatible nanoparticlethat can be used as drug delivery vehiclesTheywere designedto retain and deliver Antiangiogenic compounds over anextended period of time for targeting tumor vasculatureNanoparticleswere formulated comprising a hydrophilic coreof sodium alginate cellulose sulfate and Antiangiogenicfactors such as thrombospondin (TSP)-1 or TSP-517 whichwas crosslinked with dextran polyaldehyde with calciumchloride or conjugated to heparin sulfate with sodiumchloride In addition luciferase (bioluminescent agent) orpolymeric gadolinium (contrast agent) was placed withinthe polyanionic core The hydrophilic shell surroundingthe core additionally contained spermine hydrochloridepoly(methylene-co-guanidine) hydrochloride and pluronicF-68 calcium chloride and a targeting ligand conjugatedto an activated polyethylene glycol or crosslinked to dex-tran polyaldehyde Targeted nanoparticles were evaluatedby monitoring luciferase in a murine model [8] Figure 1illustrates the process of active targeting
32 Passive Targeting Nanoparticles can also target cancerthrough passive targeting As apoptosis is stopped in cancer-ous cells they continue sucking nutritious agents abnormallythrough the blood vessels forming wide and leaky bloodvessels around the cells induced by angiogenesis Leaky bloodvessels are formed due to basement membrane abnormalitiesand decreased numbers of pericytes lining rapidly prolif-erating endothelial cells [73] Hence the permeability ofmolecules to pass through the vessel wall into the interstitiumsurrounding tumor cells is increased The size of the poresin leaky endothelial cells ranges from 100 to 780 nm [74ndash76]Thus nanoparticles below that size can easily pass through thepores [77 78] As a result it facilitates to efflux the nanopar-ticles to cluster around the neoplastic cells Nanoparticlescan be targeted to specific area of capillary endothelium toconcentrate the drug within a particular organ and perforatethe tumor cells by passive diffusion or convection Lack oflymphatic drainage eases the diffusion process The tumorinterstitium is composed of a collagen network and a gel likefluid The fluid has high interstitial pressures which resistthe inward flux of molecules Tumors also lack well-definedlymphatic networks having leaky vasculature Thereforedrugs that enter the interstitial area may have extendedretention times in the tumor interstitium This feature iscalled the enhanced permeability and retention (EPR) effectand facilitates tumor interstitial drug accumulation (Figure 1)[79 80] Nanoparticles can easily accumulate selectively byenhanced permeability and retention effect and then diffuseinto the cells [81]
4 Cellular Uptake pH DependentDrug Delivery and Prevention fromLysosomal Degradation
Active or passive targeted nanoparticles face amajor difficultyin releasing drugs in the neoplastic cells since lysosomalenzymes rapidly destroy both the nanoparticles and drugsinside the cells After internalization the colloidal carri-ers usually reach the lysosomal compartment in whichhydrolytic enzymes degrade both the carrier and its contentTherefore the intracellular distribution of the carrier ismodified when the encapsulated drug is a nucleic acidBecause pH around of tumors cells is more acidic carriersthat change solubility at lower pH can be used to targetand release drugs The extracellular environment of solidtumors is acidic and there is an altered pH gradient acrosstheir cell compartments Nanoparticles sensitive to the pHgradients are promising for cancer drug delivery A pH-responsive nanoparticle consists of a shell and a core andit responds to the pH gradient and changes its solubilitypattern The core-shell polymer nanoparticles are designedwith their lower critical solution temperature (LCST) beingdependent on the ambient pH 74 At low pH in and aroundof tumor cells the resulting change in LCST causes the core-shell nanoparticles to deform and precipitate in an acidicenvironment triggering the release the chemotherapeuticsA targeting molecule is additionally conjugated to the shellof the nanoparticles which can recognize tumor cells [82]
6 ISRN Nanotechnology
Passive targeting Active targeting Targeted nanoparticle
Tumor Drug or drug-loaded nanocarriers
Normal tissue Receptor-mediated endocytosis
Figure 1 Active and passive targeting by nanoparticles
Shefer and his team reported a new strategy for preparing apH sensitive sustained release system for cancer treatmentThe system utilizes solid hydrophobic nanospheres contain-ing anticancer drugs that are encapsulated in a pH sensitivemicrosphere It additionally included a bioadhesive materialinto the solid hydrophobic matrix of the nanospheres Thenanosphere hydrophobic matrix was formed by dispersingpaclitaxel into the hotmelt of candelillawaxThemicrosphereof pH sensitive matrix was created by adding the drugwaxmixture into an aqueous solution containing a pH dependentanionic polymer which is stable at pH 74 but solubilizedat pH 6 and lower The prepared suspension was spraydried to produce a free flowing dry powder which consistsof 10 paclitaxel The nanospheres can release the drugover an extended period of time by dissolvingswelling themicrosphere at a lower pH that is typically found in canceroustissue [8] Recently researchers developed a system thateither fuse with the plasmamembrane or have a pH-sensitiveconfiguration that changes conformation in the lysosomesand allows the encapsulated material to escape into thecytoplasm [83] Biodegradable nanoparticles were formu-lated from the copolymers of poly(dl-lactide-co-glycolide)for their rapid endolysosomal escape The system workedby selective reversal of the surface charge of nanoparticles(from anionic to cationic) in the acidic endolysosomalcompartment causing the nanoparticles to interact with theendolysosomal membrane and escape into the cytosol Thesenanoparticles can deliver wide ranged therapeutic agentsincluding macromolecules such as DNA at a slow rate forsustained therapeutic effect For using nanotechnology incancer treatment researchers developed thermoresponsivepH-responsive and biodegradable nanoparticles by graftingbiodegradable poly (dl-lactide) ontoN-isopropyl acrylamideand methacrylic acid It may be sufficient for a carrier systemto concentrate the drug (hydrophobic that crosses the plasmamembrane easily) in the target tissue [84]
5 Hyperthermia
Healthy cells are capable of surviving exposure to temper-atures up to 465∘C Irreversible cell damage occurs to thecancerous cells at temperatures from approximately 40∘C to
about 46∘C due to the disorganized and compact vascularstructure for which they are less stable On the other handsurrounding healthy cells are more readily able to spatterheat and maintain a normal temperature This process statedabove is called hyperthermia which is used for the purpose ofdamaging protein and structures within cancerous cells andin some cases causing tumor cells to directly undergo apop-tosis Nanoparticles are utilized for a variety of purposes inhyperthermia-based treatments which include serving as theactive thermotherapeutic agents sensitizers and are also usedfor targeting purposes like antibody enhanced targeting toincrease efficacy and to reduce hypothermia-associated sideeffects Nanoparticles can locate and specifically target thedeep-seated tissues and organs Magnetic fluid hyperthermiais a well-practiced old method for cancer treatment Smallmagnetic particles are used which respond to an externallyapplied magnetic field by heating up In addition to specifictargeting nanoparticles add another benefit Cells that havepicked up some of the particles cannot get rid of them andthus every daughter cell will have one half of the amount ofparticles present on the mother cell
Handy et al developed a method of manufacturingnanoparticles for targeted delivery of thermotherapy incancer treatment The prepared ferromagnetic nanoparticleswere coated with biocompatible material poly(methacrylicacid-co-hydroxy-ethylmethacrylate) using free-radical poly-merization A stabilizing layer was formed around the mag-netic particles by an ionic surfactant sodiumbis-2-ethylhexylsulfosuccinate For selective targeting antibodies were cova-lently attached to the surface of coatedmagnetic particlesThethermotherapeutic magnetic composition containing single-domain magnetic particles attached to a target specific ligandwas inductively heated using amagnetic field High efficiencyof the bioprobes was determined in animal model [8 31]
6 Combination of Drugs Having DifferentPhysical Properties
Several studies have recently shown that combination therapyis more effective than a single drug for many types ofcancer Drugs having different physical properties could notbe combined into a single particle before Furthermore
ISRN Nanotechnology 7
it has always been difficult to get the right amount of drugto the tumor Langer and fellows developed a new method todevelop nanoparticles in which they incorporated drugs withdifferent physical properties which had been impossible withprevious drug delivering nanoparticles Earlier generations ofnanoparticles mean encapsulation in a polymer coating bywhich drugs with different charges or different affinity couldnot be carried together The new technique called ldquodrug-polymer blendingrdquo allowed the researchers to hang the drugmolecules like pendants from individual units of the poly-mer before the units assemble into a polymer nanoparticleThey developed nanoparticles with hydrophobic docetaxeland hydrophilic cisplatin After loading the drugs into thenanoparticle the researchers added a tag that binds to amolecule called prostate-specificmembrane antigen (PSMA)which is a type 2 integral membrane glycoprotein presenton the surfaces of most prostate cancer cells This tag allowsthe nanoparticles to bypass healthy tissues and reduce theside effects caused by most chemotherapy drugs As a resultthey go directly to their target region The new techniquefacilitated them to precisely control the ratio of drugs loadedinto the particle They were also able to control release rate ofthe drugs after they entered the tumor cells [85]
7 Overcoming Other Limitations ofConventional Chemotherapy
Lack of solubility is one of the major limitations of mostchemotherapeutic agents Nanoparticles can effectively solvethe solubility problem Hydrophobic drugs can be encap-sulated in micelles to increase their solubility [86 87]Dendrimers contain many binding sites with which bothhydrophobic and hydrophilic molecules can bind Liposomesalso allow encapsulating hydrophobic drugs and transport-ing them to the desired area soon after administration[87] Several approaches have been taken to overcome P-glycoproteinmediated drug resistance P-glycoprotein locatesdrugs which are localized in the plasmamembrane only Onestrategy is to use the inhibiting agents such as verapamil orcyclosporine when concurrently administered with a cyto-toxic drug can restrain P-glycoproteinThus both chemother-apeutic agent and inhibiting agent are incorporated intothe nanoparticles to overcome the problem associated withP-glycoprotein [25 88 89] A new strategy was devel-oped for inhibition of the P-glycoprotein-mediated effluxof vincristine where vincristine-loaded lipid nanoparticlesconjugated to an anti-P-glycoprotein monoclonal antibody(MRK-16) showed greater cytotoxicity in resistant humanmyelogenous leukaemia cell lines than nontargeted particles[90] Danson et al developed SP1049C a nonionic blockcopolymer composed of a hydrophobic core and hydrophilictail that contains doxorubicin which was able to circumventP-glycoprotein mediated drug resistance in a mouse modelof leukaemia and is now under clinical evaluation [9192] In another study folic acid attached to polyethylenel-glycol derivatized distearoyl-phosphatidylethanolamine wasused to target in vitro doxorubicin loaded liposomes to
folate receptor overexpressing tumor cells Folate receptor-mediated cell uptake of targeted liposomal doxorubicin intoa multidrug resistant subline of M109-HiFR cells (M109R-HiFR) was clearly unaffected by P-glycoprotein-mediateddrug efflux in sharp contrast to uptake of free doxorubicin[93]
8 Targeting Agents
Nanocarriers are used as targeting agents for cancer ther-apy comprising anticancer drugs targeting moieties andpolymers There are a variety of nanocarriers such as lipo-somes dendrimers micelles carbon nanotubes nanocap-sules nanospheres and so forth Therapeutic agents canbe entrapped covalently bound encapsulated or adsorbedto the nanoparticles [5 8] Liposomes are composed oflipid bilayers where the core can be either hydrophilic orhydrophobic depending on the number of lipid bilayers[102 103] Liposomes having a single lipid bilayer contain anaqueous core for encapsulating water soluble drugs whereasother liposomes having more than a single bilayer entraplipid soluble drugs [103 104] They are readily cleared by themacrophages and are therefore coated with inert polymersfor stabilization in the physiological conditions Liposomesare commonly coated with polyethylene glycol (PEG) [2125 105ndash107] In vivo study shows that liposomes coated withhyaluronan (HA) improves circulation time and enhancestargeting to HA receptor-expressing tumors [108 109]Bothactive and passive targeting can be achieved with liposomaldrug delivery Liposomal nanoparticles can conjugate witheither antibodies or ligands for selective drug delivery [110111] They possess some advantages that they are biodegrada-tion nonantigenic and have a high transport rate [112] Theycan also be designed for pH sensitive drug delivery or ther-motherapy [113ndash115] Dendrimers are branched three dimen-sional tree-like structures with a multifunctional core Theyare synthesized fromeither synthetic or natural elements suchas amino acids sugars and nucleotides [116] Dendrimers canbe prepared by controlled polymerization of the monomersmaintaining desired shape and size Multiple entities includ-ing both hydrophobic and hydrophilic molecules can beconjugated to dendrimers due to their exclusive branchingpoint [103 117ndash119] They can also be loaded with drugsusing the cavities in their cores through hydrophobic interac-tions hydrogen bonds or chemical linkages Dendrimers arecapable of delivering genes drugs anticancer agents and soforth [103] Micelles are spherical structures where moleculeswith a hydrophobic end aggregate to form the central coreand the hydrophilic ends of other molecules are in contactwith the liquid environment surrounding the core Micellesare effective carrier for the delivery of water insoluble drugscarried in the hydrophobic core [103 118] Nanospheres arespherical in shape that is composed of a matrix system inwhich drug is evenly distributed by entrapment attachmentor encapsulation The surface of these nanoparticles can bemodified by the addition of ligands or antibodies for targetingpurposes On the other hand nanocapsules are like vesiclesthat have a central core where a drug is confined and a core is
8 ISRN Nanotechnology
Table 1 Some formulations of nanoparticles with positive results in the recent investigations
Type ofnanoparticle Anticancer drug Targeting agent Name of the polymers used Outcome Reference
Polymericnanoparticle Cystatin Cytokeratin specific
surrounded by a polymeric membrane Targeting ligands orantibodies can be attached to the surface [25 102] Fullerenes(also called bucky balls) and nanotubes are a family ofmolecules composed of carbon in the form of a hollow sphereor ellipsoid tube Atoms may be trapped inside fullereneswhile antibodies or ligands are bound to the surface fortargeting [103 117] Carbon nanotubes are modified to makethem water-soluble and functionalized as they can be linkedto a variety of active molecules such as peptides proteinsnucleic acids and therapeutic agents [120 121] Nanotubescan be single walled or multiwalled [102] Suitable polymersfor nanoparticle preparation include poly (alkyl cyanoacry-lates) poly(methylidenemalonate) and polyesters such aspoly(lactic acid) poly(glycolic acid) poly(e-caprolactone)and their copolymers poly(120576-caprolactone) poly(lactic acid)(PLA) poly(glycolic acid) (PGA) and their copolymers aremost extensively researched due to their biocompatibility andbiodegradability [83 101] Table 1 illustrates some polymerbased formulations that brought out positive results in recentresearch
9 Conclusion
Nanotechnology has already revolutionized cancer therapyin many aspects and is radically changing the treatmentpattern It hasmade a great impact on selective recognizing ofthe cancerous cells targeted drug delivery and overcominglimitations of the conventional chemotherapies Some nan-otechnology based formulations have already been launchedin the market and many are undergoing research and clinical
trials The side effects of the traditional chemotherapies cangreatly be removed by these novel active or passive targetingwhich can substantially increase the survival rate As canceris one of the most serious lethal diseases the contributionof nanotechnology in precise treatment avoiding the lifethreatening side effects can potentially contribute to a positivemovement in clinical practice for life saving approach
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] D J Bharali and S A Mousa ldquoEmerging nanomedicines forearly cancer detection and improved treatment current per-spective and future promiserdquo Pharmacology and Therapeuticsvol 128 no 2 pp 324ndash335 2010
[2] G Zhao and B L Rodriguez ldquoMolecular targeting of liposomalnanoparticlesto tumor microenvironmentrdquo International Jour-nal of Nanomedicine vol 8 pp 61ndash71 2013
[3] N R Jabir S Tabrez GMAshraf S Shakil G ADamanhouriand M A Kamal ldquoNanotechnology-based approaches in anti-cancer researchrdquo International Journal of Nanomedicine vol 7pp 4391ndash4408 2012
[4] S A Mousa and D J Bharali ldquoNanotechnology-based detec-tion and targeted therapy in cancer nano-bio paradigms andapplicationsrdquo Cancers vol 3 no 3 pp 2888ndash2903 2011
[5] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancer
ISRN Nanotechnology 9
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
[16] M M Gottesman C A Hrycyna P V Schoenlein U AGermann and I Pastan ldquoGenetic analysis of the multidrugtransporterrdquo Annual Review of Genetics vol 29 pp 607ndash6491995
[17] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008
[18] X Guo and F C Szoka Jr ldquoChemical approaches to triggerablelipid vesicles for drug and gene deliveryrdquo Accounts of ChemicalResearch vol 36 no 5 pp 335ndash341 2003
[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
[20] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008
[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
[28] M F Francis M Cristea and F M Winnik ldquoPolymericmicelles for oral drug delivery why and howrdquo Pure and AppliedChemistry vol 76 no 7-8 pp 1321ndash1335 2004
[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
[32] J Sudimack and R J Lee ldquoTargeted drug delivery via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 41 no 2 pp147ndash162 2000
[33] J F Kukowska-Latallo K A Candido Z Cao et al ldquoNanoparti-cle targeting of anticancer drug improves therapeutic responsein animal model of human epithelial cancerrdquo Cancer Researchvol 65 no 12 pp 5317ndash5324 2005
[34] G Russell-Jones K McTavish J McEwan and B ThurmondldquoIncreasing the tumoricidal activity of daunomycin-pHPMAconjugates using vitamin B12 as a targeting agentrdquo Journal ofCancer Research Updates vol 1 no 2 pp 1ndash6 2012
[35] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 Article ID 18496 3 pages 2012
[36] H S Yoo and T G Park ldquoFolate-receptor-targeted delivery ofdoxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugaterdquo Journal of Controlled Release vol 100 no 2pp 247ndash256 2004
[37] M Kawamoto T Horibe M Kohno and K Kawakami ldquoAnovel transferrin receptor-targeted hybrid peptide disintegratescancer cell membrane to induce rapid killing of cancer cellsrdquoBMC Cancer vol 11 article 359 2011
[38] T R Daniels B Bernabeu J A Rodrıguez et al ldquoTransferrinreceptors and the targeted delivery of therapeutic agents againstcancerrdquo Biochimica et Biophysica Acta vol 1820 no 3 pp 291ndash317 2012
[39] N C Bellocq S H Pun G S Jensen and M E DavisldquoTransferrin-containing cyclodextrin polymer-based particlesfor tumor-targeted gene deliveryrdquo Bioconjugate Chemistry vol14 no 6 pp 1122ndash1132 2003
[40] C R Dass and P F M Choong ldquoTargeting of small moleculeanticancer drugs to the tumour and its vasculature using
10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
[41] H K Sun H J Ji H L Soo W K Sung and G P TaeldquoLHRH receptor-mediated delivery of siRNA using polyelec-trolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEIrdquo Bioconjugate Chemistry vol 19 no11 pp 2156ndash2162 2008
[42] S S Dharap Y Wang P Chandna et al ldquoTumor-specifictargeting of an anticancer drug delivery system by LHRHpeptiderdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 102 no 36 pp 12962ndash12967 2005
[43] httpwebmitedunewsoffice2006prostatehtml[44] T M Allen ldquoLigand-targeted therapeutics in anticancer ther-
apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
therapiesrdquoNature Reviews Cancer vol 1 no 2 pp 118ndash129 2001[46] W H Ouwehand R Finnern B D Gorick et al ldquoSelection of
internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
[47] J DMarksW H Ouwehand J M Bye et al ldquoHuman antibodyfragments specific for human blood group antigens from aphage display libraryrdquo BioTechnology vol 11 no 10 pp 1145ndash1149 1993
[48] B Liu F Conrad M R Cooperberg D B Kirpotin and JD Marks ldquoMapping tumor epitope space by direct selectionof single-chain Fv antibody libraries on prostate cancer cellsrdquoCancer Research vol 64 no 2 pp 704ndash710 2004
[49] D Peer P Zhu C V Carman J Lieberman and M ShimaokaldquoSelective gene silencing in activated leukocytes by target-ing siRNAs to the integrin lymphocyte function-associatedantigen-1rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 10 pp 4095ndash4100 2007
[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
[51] S Sudarshan D H Holman M L Hyer C Voelkel-JohnsonJ-Y Dong and J S Norris ldquoIn vitro efficacy of Fas ligandgene therapy for the treatment of bladder cancerrdquo Cancer GeneTherapy vol 12 no 1 pp 12ndash18 2005
[52] O Micheau E Solary A Hammann F Martin and M-TDimanche-Boitrel ldquoSensitization of cancer cells treated withcytotoxic drugs to fas-mediated cytotoxicityrdquo Journal of theNational Cancer Institute vol 89 no 11 pp 783ndash789 1997
[53] G N Naumov L A Akslen and J Folkman ldquoRole of angio-genesis in human tumor dormancy animal models of theangiogenic switchrdquoCell Cycle vol 5 no 16 pp 1779ndash1787 2006
[54] M A J Chaplain ldquoMathematical modelling of angiogenesisrdquoJournal of Neuro-Oncology vol 50 no 1-2 pp 37ndash51 2000
[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
[56] N Weidner J Folkman F Pozza et al ldquoTumor angiogenesis anew significant and independent prognostic indicator in early-stage breast carcinomardquo Journal of the National Cancer Institutevol 84 no 24 pp 1875ndash1887 1992
[57] D Fukumura and R K Jain ldquoImaging angiogenesis and themicroenvironmentrdquoAPMIS vol 116 no 7-8 pp 695ndash715 2008
[58] M Dhanabal M Jeffers andW J LaRochelle ldquoAnti-angiogenictherapy as a cancer treatment paradigmrdquo Current MedicinalChemistry vol 5 no 2 pp 115ndash130 2005
[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
[61] D Banerjee R Harfouche and S Sengupta ldquoNanotechnology-mediated targeting of tumor angiogenesisrdquoVascular Cell vol 3article 3 2011
[62] N Boudreau and C Myers ldquoBreast cancer-induced angiogen-esis multiple mechanisms and the role of the microenviron-mentrdquo Breast Cancer Research vol 5 no 3 pp 140ndash146 2003
[63] N N Khodarev J Yu E Labay et al ldquoTumour-endotheliuminteractions in co-culture coordinated changes of gene expres-sion profiles and phenotypic properties of endothelial cellsrdquoJournal of Cell Science vol 116 no 6 pp 1013ndash1022 2003
[64] J S Desgrosellier and D A Cheresh ldquoIntegrins in cancerbiological implications and therapeutic opportunitiesrdquo NatureReviews Cancer vol 10 no 1 pp 9ndash22 2010
[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
[66] S A Anderson R K Rader W F Westlin et al ldquoMag-netic resonance contrast enhancement of neovasculature withalpha(v)beta(3)-targeted nanoparticlesrdquoMagnetic Resonance inMedicine vol 44 pp 433ndash439 2000
[67] J H Park S Kwon J-O Nam et al ldquoSelf-assembled nanoparti-cles based on glycol chitosan bearing 5120573-cholanic acid for RGDpeptide deliveryrdquo Journal of Controlled Release vol 95 no 3 pp579ndash588 2004
[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
[70] J Li J Ji L M Holmes et al ldquoFusion protein from RGDpeptide and Fc fragment of mouse immunoglobulin G inhibitsangiogenesis in tumorrdquo Cancer Gene Therapy vol 11 no 5 pp363ndash370 2004
[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
[72] N Ferrara ldquoVEGF as a therapeutic target in cancerrdquo Oncologyvol 69 no 3 pp 11ndash16 2005
[73] D F Baban and L W Seymour ldquoControl of tumour vascularpermeabilityrdquo Advanced Drug Delivery Reviews vol 34 no 1pp 109ndash119 1998
[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
ISRN Nanotechnology 11
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
Passive targeting Active targeting Targeted nanoparticle
Tumor Drug or drug-loaded nanocarriers
Normal tissue Receptor-mediated endocytosis
Figure 1 Active and passive targeting by nanoparticles
Shefer and his team reported a new strategy for preparing apH sensitive sustained release system for cancer treatmentThe system utilizes solid hydrophobic nanospheres contain-ing anticancer drugs that are encapsulated in a pH sensitivemicrosphere It additionally included a bioadhesive materialinto the solid hydrophobic matrix of the nanospheres Thenanosphere hydrophobic matrix was formed by dispersingpaclitaxel into the hotmelt of candelillawaxThemicrosphereof pH sensitive matrix was created by adding the drugwaxmixture into an aqueous solution containing a pH dependentanionic polymer which is stable at pH 74 but solubilizedat pH 6 and lower The prepared suspension was spraydried to produce a free flowing dry powder which consistsof 10 paclitaxel The nanospheres can release the drugover an extended period of time by dissolvingswelling themicrosphere at a lower pH that is typically found in canceroustissue [8] Recently researchers developed a system thateither fuse with the plasmamembrane or have a pH-sensitiveconfiguration that changes conformation in the lysosomesand allows the encapsulated material to escape into thecytoplasm [83] Biodegradable nanoparticles were formu-lated from the copolymers of poly(dl-lactide-co-glycolide)for their rapid endolysosomal escape The system workedby selective reversal of the surface charge of nanoparticles(from anionic to cationic) in the acidic endolysosomalcompartment causing the nanoparticles to interact with theendolysosomal membrane and escape into the cytosol Thesenanoparticles can deliver wide ranged therapeutic agentsincluding macromolecules such as DNA at a slow rate forsustained therapeutic effect For using nanotechnology incancer treatment researchers developed thermoresponsivepH-responsive and biodegradable nanoparticles by graftingbiodegradable poly (dl-lactide) ontoN-isopropyl acrylamideand methacrylic acid It may be sufficient for a carrier systemto concentrate the drug (hydrophobic that crosses the plasmamembrane easily) in the target tissue [84]
5 Hyperthermia
Healthy cells are capable of surviving exposure to temper-atures up to 465∘C Irreversible cell damage occurs to thecancerous cells at temperatures from approximately 40∘C to
about 46∘C due to the disorganized and compact vascularstructure for which they are less stable On the other handsurrounding healthy cells are more readily able to spatterheat and maintain a normal temperature This process statedabove is called hyperthermia which is used for the purpose ofdamaging protein and structures within cancerous cells andin some cases causing tumor cells to directly undergo apop-tosis Nanoparticles are utilized for a variety of purposes inhyperthermia-based treatments which include serving as theactive thermotherapeutic agents sensitizers and are also usedfor targeting purposes like antibody enhanced targeting toincrease efficacy and to reduce hypothermia-associated sideeffects Nanoparticles can locate and specifically target thedeep-seated tissues and organs Magnetic fluid hyperthermiais a well-practiced old method for cancer treatment Smallmagnetic particles are used which respond to an externallyapplied magnetic field by heating up In addition to specifictargeting nanoparticles add another benefit Cells that havepicked up some of the particles cannot get rid of them andthus every daughter cell will have one half of the amount ofparticles present on the mother cell
Handy et al developed a method of manufacturingnanoparticles for targeted delivery of thermotherapy incancer treatment The prepared ferromagnetic nanoparticleswere coated with biocompatible material poly(methacrylicacid-co-hydroxy-ethylmethacrylate) using free-radical poly-merization A stabilizing layer was formed around the mag-netic particles by an ionic surfactant sodiumbis-2-ethylhexylsulfosuccinate For selective targeting antibodies were cova-lently attached to the surface of coatedmagnetic particlesThethermotherapeutic magnetic composition containing single-domain magnetic particles attached to a target specific ligandwas inductively heated using amagnetic field High efficiencyof the bioprobes was determined in animal model [8 31]
6 Combination of Drugs Having DifferentPhysical Properties
Several studies have recently shown that combination therapyis more effective than a single drug for many types ofcancer Drugs having different physical properties could notbe combined into a single particle before Furthermore
ISRN Nanotechnology 7
it has always been difficult to get the right amount of drugto the tumor Langer and fellows developed a new method todevelop nanoparticles in which they incorporated drugs withdifferent physical properties which had been impossible withprevious drug delivering nanoparticles Earlier generations ofnanoparticles mean encapsulation in a polymer coating bywhich drugs with different charges or different affinity couldnot be carried together The new technique called ldquodrug-polymer blendingrdquo allowed the researchers to hang the drugmolecules like pendants from individual units of the poly-mer before the units assemble into a polymer nanoparticleThey developed nanoparticles with hydrophobic docetaxeland hydrophilic cisplatin After loading the drugs into thenanoparticle the researchers added a tag that binds to amolecule called prostate-specificmembrane antigen (PSMA)which is a type 2 integral membrane glycoprotein presenton the surfaces of most prostate cancer cells This tag allowsthe nanoparticles to bypass healthy tissues and reduce theside effects caused by most chemotherapy drugs As a resultthey go directly to their target region The new techniquefacilitated them to precisely control the ratio of drugs loadedinto the particle They were also able to control release rate ofthe drugs after they entered the tumor cells [85]
7 Overcoming Other Limitations ofConventional Chemotherapy
Lack of solubility is one of the major limitations of mostchemotherapeutic agents Nanoparticles can effectively solvethe solubility problem Hydrophobic drugs can be encap-sulated in micelles to increase their solubility [86 87]Dendrimers contain many binding sites with which bothhydrophobic and hydrophilic molecules can bind Liposomesalso allow encapsulating hydrophobic drugs and transport-ing them to the desired area soon after administration[87] Several approaches have been taken to overcome P-glycoproteinmediated drug resistance P-glycoprotein locatesdrugs which are localized in the plasmamembrane only Onestrategy is to use the inhibiting agents such as verapamil orcyclosporine when concurrently administered with a cyto-toxic drug can restrain P-glycoproteinThus both chemother-apeutic agent and inhibiting agent are incorporated intothe nanoparticles to overcome the problem associated withP-glycoprotein [25 88 89] A new strategy was devel-oped for inhibition of the P-glycoprotein-mediated effluxof vincristine where vincristine-loaded lipid nanoparticlesconjugated to an anti-P-glycoprotein monoclonal antibody(MRK-16) showed greater cytotoxicity in resistant humanmyelogenous leukaemia cell lines than nontargeted particles[90] Danson et al developed SP1049C a nonionic blockcopolymer composed of a hydrophobic core and hydrophilictail that contains doxorubicin which was able to circumventP-glycoprotein mediated drug resistance in a mouse modelof leukaemia and is now under clinical evaluation [9192] In another study folic acid attached to polyethylenel-glycol derivatized distearoyl-phosphatidylethanolamine wasused to target in vitro doxorubicin loaded liposomes to
folate receptor overexpressing tumor cells Folate receptor-mediated cell uptake of targeted liposomal doxorubicin intoa multidrug resistant subline of M109-HiFR cells (M109R-HiFR) was clearly unaffected by P-glycoprotein-mediateddrug efflux in sharp contrast to uptake of free doxorubicin[93]
8 Targeting Agents
Nanocarriers are used as targeting agents for cancer ther-apy comprising anticancer drugs targeting moieties andpolymers There are a variety of nanocarriers such as lipo-somes dendrimers micelles carbon nanotubes nanocap-sules nanospheres and so forth Therapeutic agents canbe entrapped covalently bound encapsulated or adsorbedto the nanoparticles [5 8] Liposomes are composed oflipid bilayers where the core can be either hydrophilic orhydrophobic depending on the number of lipid bilayers[102 103] Liposomes having a single lipid bilayer contain anaqueous core for encapsulating water soluble drugs whereasother liposomes having more than a single bilayer entraplipid soluble drugs [103 104] They are readily cleared by themacrophages and are therefore coated with inert polymersfor stabilization in the physiological conditions Liposomesare commonly coated with polyethylene glycol (PEG) [2125 105ndash107] In vivo study shows that liposomes coated withhyaluronan (HA) improves circulation time and enhancestargeting to HA receptor-expressing tumors [108 109]Bothactive and passive targeting can be achieved with liposomaldrug delivery Liposomal nanoparticles can conjugate witheither antibodies or ligands for selective drug delivery [110111] They possess some advantages that they are biodegrada-tion nonantigenic and have a high transport rate [112] Theycan also be designed for pH sensitive drug delivery or ther-motherapy [113ndash115] Dendrimers are branched three dimen-sional tree-like structures with a multifunctional core Theyare synthesized fromeither synthetic or natural elements suchas amino acids sugars and nucleotides [116] Dendrimers canbe prepared by controlled polymerization of the monomersmaintaining desired shape and size Multiple entities includ-ing both hydrophobic and hydrophilic molecules can beconjugated to dendrimers due to their exclusive branchingpoint [103 117ndash119] They can also be loaded with drugsusing the cavities in their cores through hydrophobic interac-tions hydrogen bonds or chemical linkages Dendrimers arecapable of delivering genes drugs anticancer agents and soforth [103] Micelles are spherical structures where moleculeswith a hydrophobic end aggregate to form the central coreand the hydrophilic ends of other molecules are in contactwith the liquid environment surrounding the core Micellesare effective carrier for the delivery of water insoluble drugscarried in the hydrophobic core [103 118] Nanospheres arespherical in shape that is composed of a matrix system inwhich drug is evenly distributed by entrapment attachmentor encapsulation The surface of these nanoparticles can bemodified by the addition of ligands or antibodies for targetingpurposes On the other hand nanocapsules are like vesiclesthat have a central core where a drug is confined and a core is
8 ISRN Nanotechnology
Table 1 Some formulations of nanoparticles with positive results in the recent investigations
Type ofnanoparticle Anticancer drug Targeting agent Name of the polymers used Outcome Reference
Polymericnanoparticle Cystatin Cytokeratin specific
surrounded by a polymeric membrane Targeting ligands orantibodies can be attached to the surface [25 102] Fullerenes(also called bucky balls) and nanotubes are a family ofmolecules composed of carbon in the form of a hollow sphereor ellipsoid tube Atoms may be trapped inside fullereneswhile antibodies or ligands are bound to the surface fortargeting [103 117] Carbon nanotubes are modified to makethem water-soluble and functionalized as they can be linkedto a variety of active molecules such as peptides proteinsnucleic acids and therapeutic agents [120 121] Nanotubescan be single walled or multiwalled [102] Suitable polymersfor nanoparticle preparation include poly (alkyl cyanoacry-lates) poly(methylidenemalonate) and polyesters such aspoly(lactic acid) poly(glycolic acid) poly(e-caprolactone)and their copolymers poly(120576-caprolactone) poly(lactic acid)(PLA) poly(glycolic acid) (PGA) and their copolymers aremost extensively researched due to their biocompatibility andbiodegradability [83 101] Table 1 illustrates some polymerbased formulations that brought out positive results in recentresearch
9 Conclusion
Nanotechnology has already revolutionized cancer therapyin many aspects and is radically changing the treatmentpattern It hasmade a great impact on selective recognizing ofthe cancerous cells targeted drug delivery and overcominglimitations of the conventional chemotherapies Some nan-otechnology based formulations have already been launchedin the market and many are undergoing research and clinical
trials The side effects of the traditional chemotherapies cangreatly be removed by these novel active or passive targetingwhich can substantially increase the survival rate As canceris one of the most serious lethal diseases the contributionof nanotechnology in precise treatment avoiding the lifethreatening side effects can potentially contribute to a positivemovement in clinical practice for life saving approach
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] D J Bharali and S A Mousa ldquoEmerging nanomedicines forearly cancer detection and improved treatment current per-spective and future promiserdquo Pharmacology and Therapeuticsvol 128 no 2 pp 324ndash335 2010
[2] G Zhao and B L Rodriguez ldquoMolecular targeting of liposomalnanoparticlesto tumor microenvironmentrdquo International Jour-nal of Nanomedicine vol 8 pp 61ndash71 2013
[3] N R Jabir S Tabrez GMAshraf S Shakil G ADamanhouriand M A Kamal ldquoNanotechnology-based approaches in anti-cancer researchrdquo International Journal of Nanomedicine vol 7pp 4391ndash4408 2012
[4] S A Mousa and D J Bharali ldquoNanotechnology-based detec-tion and targeted therapy in cancer nano-bio paradigms andapplicationsrdquo Cancers vol 3 no 3 pp 2888ndash2903 2011
[5] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancer
ISRN Nanotechnology 9
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
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[17] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008
[18] X Guo and F C Szoka Jr ldquoChemical approaches to triggerablelipid vesicles for drug and gene deliveryrdquo Accounts of ChemicalResearch vol 36 no 5 pp 335ndash341 2003
[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
[20] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008
[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
[28] M F Francis M Cristea and F M Winnik ldquoPolymericmicelles for oral drug delivery why and howrdquo Pure and AppliedChemistry vol 76 no 7-8 pp 1321ndash1335 2004
[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
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10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
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apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
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[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
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[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
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[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
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[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
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[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
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[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
it has always been difficult to get the right amount of drugto the tumor Langer and fellows developed a new method todevelop nanoparticles in which they incorporated drugs withdifferent physical properties which had been impossible withprevious drug delivering nanoparticles Earlier generations ofnanoparticles mean encapsulation in a polymer coating bywhich drugs with different charges or different affinity couldnot be carried together The new technique called ldquodrug-polymer blendingrdquo allowed the researchers to hang the drugmolecules like pendants from individual units of the poly-mer before the units assemble into a polymer nanoparticleThey developed nanoparticles with hydrophobic docetaxeland hydrophilic cisplatin After loading the drugs into thenanoparticle the researchers added a tag that binds to amolecule called prostate-specificmembrane antigen (PSMA)which is a type 2 integral membrane glycoprotein presenton the surfaces of most prostate cancer cells This tag allowsthe nanoparticles to bypass healthy tissues and reduce theside effects caused by most chemotherapy drugs As a resultthey go directly to their target region The new techniquefacilitated them to precisely control the ratio of drugs loadedinto the particle They were also able to control release rate ofthe drugs after they entered the tumor cells [85]
7 Overcoming Other Limitations ofConventional Chemotherapy
Lack of solubility is one of the major limitations of mostchemotherapeutic agents Nanoparticles can effectively solvethe solubility problem Hydrophobic drugs can be encap-sulated in micelles to increase their solubility [86 87]Dendrimers contain many binding sites with which bothhydrophobic and hydrophilic molecules can bind Liposomesalso allow encapsulating hydrophobic drugs and transport-ing them to the desired area soon after administration[87] Several approaches have been taken to overcome P-glycoproteinmediated drug resistance P-glycoprotein locatesdrugs which are localized in the plasmamembrane only Onestrategy is to use the inhibiting agents such as verapamil orcyclosporine when concurrently administered with a cyto-toxic drug can restrain P-glycoproteinThus both chemother-apeutic agent and inhibiting agent are incorporated intothe nanoparticles to overcome the problem associated withP-glycoprotein [25 88 89] A new strategy was devel-oped for inhibition of the P-glycoprotein-mediated effluxof vincristine where vincristine-loaded lipid nanoparticlesconjugated to an anti-P-glycoprotein monoclonal antibody(MRK-16) showed greater cytotoxicity in resistant humanmyelogenous leukaemia cell lines than nontargeted particles[90] Danson et al developed SP1049C a nonionic blockcopolymer composed of a hydrophobic core and hydrophilictail that contains doxorubicin which was able to circumventP-glycoprotein mediated drug resistance in a mouse modelof leukaemia and is now under clinical evaluation [9192] In another study folic acid attached to polyethylenel-glycol derivatized distearoyl-phosphatidylethanolamine wasused to target in vitro doxorubicin loaded liposomes to
folate receptor overexpressing tumor cells Folate receptor-mediated cell uptake of targeted liposomal doxorubicin intoa multidrug resistant subline of M109-HiFR cells (M109R-HiFR) was clearly unaffected by P-glycoprotein-mediateddrug efflux in sharp contrast to uptake of free doxorubicin[93]
8 Targeting Agents
Nanocarriers are used as targeting agents for cancer ther-apy comprising anticancer drugs targeting moieties andpolymers There are a variety of nanocarriers such as lipo-somes dendrimers micelles carbon nanotubes nanocap-sules nanospheres and so forth Therapeutic agents canbe entrapped covalently bound encapsulated or adsorbedto the nanoparticles [5 8] Liposomes are composed oflipid bilayers where the core can be either hydrophilic orhydrophobic depending on the number of lipid bilayers[102 103] Liposomes having a single lipid bilayer contain anaqueous core for encapsulating water soluble drugs whereasother liposomes having more than a single bilayer entraplipid soluble drugs [103 104] They are readily cleared by themacrophages and are therefore coated with inert polymersfor stabilization in the physiological conditions Liposomesare commonly coated with polyethylene glycol (PEG) [2125 105ndash107] In vivo study shows that liposomes coated withhyaluronan (HA) improves circulation time and enhancestargeting to HA receptor-expressing tumors [108 109]Bothactive and passive targeting can be achieved with liposomaldrug delivery Liposomal nanoparticles can conjugate witheither antibodies or ligands for selective drug delivery [110111] They possess some advantages that they are biodegrada-tion nonantigenic and have a high transport rate [112] Theycan also be designed for pH sensitive drug delivery or ther-motherapy [113ndash115] Dendrimers are branched three dimen-sional tree-like structures with a multifunctional core Theyare synthesized fromeither synthetic or natural elements suchas amino acids sugars and nucleotides [116] Dendrimers canbe prepared by controlled polymerization of the monomersmaintaining desired shape and size Multiple entities includ-ing both hydrophobic and hydrophilic molecules can beconjugated to dendrimers due to their exclusive branchingpoint [103 117ndash119] They can also be loaded with drugsusing the cavities in their cores through hydrophobic interac-tions hydrogen bonds or chemical linkages Dendrimers arecapable of delivering genes drugs anticancer agents and soforth [103] Micelles are spherical structures where moleculeswith a hydrophobic end aggregate to form the central coreand the hydrophilic ends of other molecules are in contactwith the liquid environment surrounding the core Micellesare effective carrier for the delivery of water insoluble drugscarried in the hydrophobic core [103 118] Nanospheres arespherical in shape that is composed of a matrix system inwhich drug is evenly distributed by entrapment attachmentor encapsulation The surface of these nanoparticles can bemodified by the addition of ligands or antibodies for targetingpurposes On the other hand nanocapsules are like vesiclesthat have a central core where a drug is confined and a core is
8 ISRN Nanotechnology
Table 1 Some formulations of nanoparticles with positive results in the recent investigations
Type ofnanoparticle Anticancer drug Targeting agent Name of the polymers used Outcome Reference
Polymericnanoparticle Cystatin Cytokeratin specific
surrounded by a polymeric membrane Targeting ligands orantibodies can be attached to the surface [25 102] Fullerenes(also called bucky balls) and nanotubes are a family ofmolecules composed of carbon in the form of a hollow sphereor ellipsoid tube Atoms may be trapped inside fullereneswhile antibodies or ligands are bound to the surface fortargeting [103 117] Carbon nanotubes are modified to makethem water-soluble and functionalized as they can be linkedto a variety of active molecules such as peptides proteinsnucleic acids and therapeutic agents [120 121] Nanotubescan be single walled or multiwalled [102] Suitable polymersfor nanoparticle preparation include poly (alkyl cyanoacry-lates) poly(methylidenemalonate) and polyesters such aspoly(lactic acid) poly(glycolic acid) poly(e-caprolactone)and their copolymers poly(120576-caprolactone) poly(lactic acid)(PLA) poly(glycolic acid) (PGA) and their copolymers aremost extensively researched due to their biocompatibility andbiodegradability [83 101] Table 1 illustrates some polymerbased formulations that brought out positive results in recentresearch
9 Conclusion
Nanotechnology has already revolutionized cancer therapyin many aspects and is radically changing the treatmentpattern It hasmade a great impact on selective recognizing ofthe cancerous cells targeted drug delivery and overcominglimitations of the conventional chemotherapies Some nan-otechnology based formulations have already been launchedin the market and many are undergoing research and clinical
trials The side effects of the traditional chemotherapies cangreatly be removed by these novel active or passive targetingwhich can substantially increase the survival rate As canceris one of the most serious lethal diseases the contributionof nanotechnology in precise treatment avoiding the lifethreatening side effects can potentially contribute to a positivemovement in clinical practice for life saving approach
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] D J Bharali and S A Mousa ldquoEmerging nanomedicines forearly cancer detection and improved treatment current per-spective and future promiserdquo Pharmacology and Therapeuticsvol 128 no 2 pp 324ndash335 2010
[2] G Zhao and B L Rodriguez ldquoMolecular targeting of liposomalnanoparticlesto tumor microenvironmentrdquo International Jour-nal of Nanomedicine vol 8 pp 61ndash71 2013
[3] N R Jabir S Tabrez GMAshraf S Shakil G ADamanhouriand M A Kamal ldquoNanotechnology-based approaches in anti-cancer researchrdquo International Journal of Nanomedicine vol 7pp 4391ndash4408 2012
[4] S A Mousa and D J Bharali ldquoNanotechnology-based detec-tion and targeted therapy in cancer nano-bio paradigms andapplicationsrdquo Cancers vol 3 no 3 pp 2888ndash2903 2011
[5] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancer
ISRN Nanotechnology 9
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
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[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
[20] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008
[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
[28] M F Francis M Cristea and F M Winnik ldquoPolymericmicelles for oral drug delivery why and howrdquo Pure and AppliedChemistry vol 76 no 7-8 pp 1321ndash1335 2004
[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
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[33] J F Kukowska-Latallo K A Candido Z Cao et al ldquoNanoparti-cle targeting of anticancer drug improves therapeutic responsein animal model of human epithelial cancerrdquo Cancer Researchvol 65 no 12 pp 5317ndash5324 2005
[34] G Russell-Jones K McTavish J McEwan and B ThurmondldquoIncreasing the tumoricidal activity of daunomycin-pHPMAconjugates using vitamin B12 as a targeting agentrdquo Journal ofCancer Research Updates vol 1 no 2 pp 1ndash6 2012
[35] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 Article ID 18496 3 pages 2012
[36] H S Yoo and T G Park ldquoFolate-receptor-targeted delivery ofdoxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugaterdquo Journal of Controlled Release vol 100 no 2pp 247ndash256 2004
[37] M Kawamoto T Horibe M Kohno and K Kawakami ldquoAnovel transferrin receptor-targeted hybrid peptide disintegratescancer cell membrane to induce rapid killing of cancer cellsrdquoBMC Cancer vol 11 article 359 2011
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[39] N C Bellocq S H Pun G S Jensen and M E DavisldquoTransferrin-containing cyclodextrin polymer-based particlesfor tumor-targeted gene deliveryrdquo Bioconjugate Chemistry vol14 no 6 pp 1122ndash1132 2003
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10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
[41] H K Sun H J Ji H L Soo W K Sung and G P TaeldquoLHRH receptor-mediated delivery of siRNA using polyelec-trolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEIrdquo Bioconjugate Chemistry vol 19 no11 pp 2156ndash2162 2008
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apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
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internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
[47] J DMarksW H Ouwehand J M Bye et al ldquoHuman antibodyfragments specific for human blood group antigens from aphage display libraryrdquo BioTechnology vol 11 no 10 pp 1145ndash1149 1993
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[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
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[53] G N Naumov L A Akslen and J Folkman ldquoRole of angio-genesis in human tumor dormancy animal models of theangiogenic switchrdquoCell Cycle vol 5 no 16 pp 1779ndash1787 2006
[54] M A J Chaplain ldquoMathematical modelling of angiogenesisrdquoJournal of Neuro-Oncology vol 50 no 1-2 pp 37ndash51 2000
[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
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[58] M Dhanabal M Jeffers andW J LaRochelle ldquoAnti-angiogenictherapy as a cancer treatment paradigmrdquo Current MedicinalChemistry vol 5 no 2 pp 115ndash130 2005
[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
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[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
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[67] J H Park S Kwon J-O Nam et al ldquoSelf-assembled nanoparti-cles based on glycol chitosan bearing 5120573-cholanic acid for RGDpeptide deliveryrdquo Journal of Controlled Release vol 95 no 3 pp579ndash588 2004
[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
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[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
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[73] D F Baban and L W Seymour ldquoControl of tumour vascularpermeabilityrdquo Advanced Drug Delivery Reviews vol 34 no 1pp 109ndash119 1998
[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
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[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
surrounded by a polymeric membrane Targeting ligands orantibodies can be attached to the surface [25 102] Fullerenes(also called bucky balls) and nanotubes are a family ofmolecules composed of carbon in the form of a hollow sphereor ellipsoid tube Atoms may be trapped inside fullereneswhile antibodies or ligands are bound to the surface fortargeting [103 117] Carbon nanotubes are modified to makethem water-soluble and functionalized as they can be linkedto a variety of active molecules such as peptides proteinsnucleic acids and therapeutic agents [120 121] Nanotubescan be single walled or multiwalled [102] Suitable polymersfor nanoparticle preparation include poly (alkyl cyanoacry-lates) poly(methylidenemalonate) and polyesters such aspoly(lactic acid) poly(glycolic acid) poly(e-caprolactone)and their copolymers poly(120576-caprolactone) poly(lactic acid)(PLA) poly(glycolic acid) (PGA) and their copolymers aremost extensively researched due to their biocompatibility andbiodegradability [83 101] Table 1 illustrates some polymerbased formulations that brought out positive results in recentresearch
9 Conclusion
Nanotechnology has already revolutionized cancer therapyin many aspects and is radically changing the treatmentpattern It hasmade a great impact on selective recognizing ofthe cancerous cells targeted drug delivery and overcominglimitations of the conventional chemotherapies Some nan-otechnology based formulations have already been launchedin the market and many are undergoing research and clinical
trials The side effects of the traditional chemotherapies cangreatly be removed by these novel active or passive targetingwhich can substantially increase the survival rate As canceris one of the most serious lethal diseases the contributionof nanotechnology in precise treatment avoiding the lifethreatening side effects can potentially contribute to a positivemovement in clinical practice for life saving approach
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] D J Bharali and S A Mousa ldquoEmerging nanomedicines forearly cancer detection and improved treatment current per-spective and future promiserdquo Pharmacology and Therapeuticsvol 128 no 2 pp 324ndash335 2010
[2] G Zhao and B L Rodriguez ldquoMolecular targeting of liposomalnanoparticlesto tumor microenvironmentrdquo International Jour-nal of Nanomedicine vol 8 pp 61ndash71 2013
[3] N R Jabir S Tabrez GMAshraf S Shakil G ADamanhouriand M A Kamal ldquoNanotechnology-based approaches in anti-cancer researchrdquo International Journal of Nanomedicine vol 7pp 4391ndash4408 2012
[4] S A Mousa and D J Bharali ldquoNanotechnology-based detec-tion and targeted therapy in cancer nano-bio paradigms andapplicationsrdquo Cancers vol 3 no 3 pp 2888ndash2903 2011
[5] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancer
ISRN Nanotechnology 9
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
[16] M M Gottesman C A Hrycyna P V Schoenlein U AGermann and I Pastan ldquoGenetic analysis of the multidrugtransporterrdquo Annual Review of Genetics vol 29 pp 607ndash6491995
[17] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008
[18] X Guo and F C Szoka Jr ldquoChemical approaches to triggerablelipid vesicles for drug and gene deliveryrdquo Accounts of ChemicalResearch vol 36 no 5 pp 335ndash341 2003
[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
[20] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008
[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
[28] M F Francis M Cristea and F M Winnik ldquoPolymericmicelles for oral drug delivery why and howrdquo Pure and AppliedChemistry vol 76 no 7-8 pp 1321ndash1335 2004
[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
[32] J Sudimack and R J Lee ldquoTargeted drug delivery via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 41 no 2 pp147ndash162 2000
[33] J F Kukowska-Latallo K A Candido Z Cao et al ldquoNanoparti-cle targeting of anticancer drug improves therapeutic responsein animal model of human epithelial cancerrdquo Cancer Researchvol 65 no 12 pp 5317ndash5324 2005
[34] G Russell-Jones K McTavish J McEwan and B ThurmondldquoIncreasing the tumoricidal activity of daunomycin-pHPMAconjugates using vitamin B12 as a targeting agentrdquo Journal ofCancer Research Updates vol 1 no 2 pp 1ndash6 2012
[35] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 Article ID 18496 3 pages 2012
[36] H S Yoo and T G Park ldquoFolate-receptor-targeted delivery ofdoxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugaterdquo Journal of Controlled Release vol 100 no 2pp 247ndash256 2004
[37] M Kawamoto T Horibe M Kohno and K Kawakami ldquoAnovel transferrin receptor-targeted hybrid peptide disintegratescancer cell membrane to induce rapid killing of cancer cellsrdquoBMC Cancer vol 11 article 359 2011
[38] T R Daniels B Bernabeu J A Rodrıguez et al ldquoTransferrinreceptors and the targeted delivery of therapeutic agents againstcancerrdquo Biochimica et Biophysica Acta vol 1820 no 3 pp 291ndash317 2012
[39] N C Bellocq S H Pun G S Jensen and M E DavisldquoTransferrin-containing cyclodextrin polymer-based particlesfor tumor-targeted gene deliveryrdquo Bioconjugate Chemistry vol14 no 6 pp 1122ndash1132 2003
[40] C R Dass and P F M Choong ldquoTargeting of small moleculeanticancer drugs to the tumour and its vasculature using
10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
[41] H K Sun H J Ji H L Soo W K Sung and G P TaeldquoLHRH receptor-mediated delivery of siRNA using polyelec-trolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEIrdquo Bioconjugate Chemistry vol 19 no11 pp 2156ndash2162 2008
[42] S S Dharap Y Wang P Chandna et al ldquoTumor-specifictargeting of an anticancer drug delivery system by LHRHpeptiderdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 102 no 36 pp 12962ndash12967 2005
[43] httpwebmitedunewsoffice2006prostatehtml[44] T M Allen ldquoLigand-targeted therapeutics in anticancer ther-
apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
therapiesrdquoNature Reviews Cancer vol 1 no 2 pp 118ndash129 2001[46] W H Ouwehand R Finnern B D Gorick et al ldquoSelection of
internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
[47] J DMarksW H Ouwehand J M Bye et al ldquoHuman antibodyfragments specific for human blood group antigens from aphage display libraryrdquo BioTechnology vol 11 no 10 pp 1145ndash1149 1993
[48] B Liu F Conrad M R Cooperberg D B Kirpotin and JD Marks ldquoMapping tumor epitope space by direct selectionof single-chain Fv antibody libraries on prostate cancer cellsrdquoCancer Research vol 64 no 2 pp 704ndash710 2004
[49] D Peer P Zhu C V Carman J Lieberman and M ShimaokaldquoSelective gene silencing in activated leukocytes by target-ing siRNAs to the integrin lymphocyte function-associatedantigen-1rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 10 pp 4095ndash4100 2007
[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
[51] S Sudarshan D H Holman M L Hyer C Voelkel-JohnsonJ-Y Dong and J S Norris ldquoIn vitro efficacy of Fas ligandgene therapy for the treatment of bladder cancerrdquo Cancer GeneTherapy vol 12 no 1 pp 12ndash18 2005
[52] O Micheau E Solary A Hammann F Martin and M-TDimanche-Boitrel ldquoSensitization of cancer cells treated withcytotoxic drugs to fas-mediated cytotoxicityrdquo Journal of theNational Cancer Institute vol 89 no 11 pp 783ndash789 1997
[53] G N Naumov L A Akslen and J Folkman ldquoRole of angio-genesis in human tumor dormancy animal models of theangiogenic switchrdquoCell Cycle vol 5 no 16 pp 1779ndash1787 2006
[54] M A J Chaplain ldquoMathematical modelling of angiogenesisrdquoJournal of Neuro-Oncology vol 50 no 1-2 pp 37ndash51 2000
[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
[56] N Weidner J Folkman F Pozza et al ldquoTumor angiogenesis anew significant and independent prognostic indicator in early-stage breast carcinomardquo Journal of the National Cancer Institutevol 84 no 24 pp 1875ndash1887 1992
[57] D Fukumura and R K Jain ldquoImaging angiogenesis and themicroenvironmentrdquoAPMIS vol 116 no 7-8 pp 695ndash715 2008
[58] M Dhanabal M Jeffers andW J LaRochelle ldquoAnti-angiogenictherapy as a cancer treatment paradigmrdquo Current MedicinalChemistry vol 5 no 2 pp 115ndash130 2005
[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
[61] D Banerjee R Harfouche and S Sengupta ldquoNanotechnology-mediated targeting of tumor angiogenesisrdquoVascular Cell vol 3article 3 2011
[62] N Boudreau and C Myers ldquoBreast cancer-induced angiogen-esis multiple mechanisms and the role of the microenviron-mentrdquo Breast Cancer Research vol 5 no 3 pp 140ndash146 2003
[63] N N Khodarev J Yu E Labay et al ldquoTumour-endotheliuminteractions in co-culture coordinated changes of gene expres-sion profiles and phenotypic properties of endothelial cellsrdquoJournal of Cell Science vol 116 no 6 pp 1013ndash1022 2003
[64] J S Desgrosellier and D A Cheresh ldquoIntegrins in cancerbiological implications and therapeutic opportunitiesrdquo NatureReviews Cancer vol 10 no 1 pp 9ndash22 2010
[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
[66] S A Anderson R K Rader W F Westlin et al ldquoMag-netic resonance contrast enhancement of neovasculature withalpha(v)beta(3)-targeted nanoparticlesrdquoMagnetic Resonance inMedicine vol 44 pp 433ndash439 2000
[67] J H Park S Kwon J-O Nam et al ldquoSelf-assembled nanoparti-cles based on glycol chitosan bearing 5120573-cholanic acid for RGDpeptide deliveryrdquo Journal of Controlled Release vol 95 no 3 pp579ndash588 2004
[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
[70] J Li J Ji L M Holmes et al ldquoFusion protein from RGDpeptide and Fc fragment of mouse immunoglobulin G inhibitsangiogenesis in tumorrdquo Cancer Gene Therapy vol 11 no 5 pp363ndash370 2004
[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
[72] N Ferrara ldquoVEGF as a therapeutic target in cancerrdquo Oncologyvol 69 no 3 pp 11ndash16 2005
[73] D F Baban and L W Seymour ldquoControl of tumour vascularpermeabilityrdquo Advanced Drug Delivery Reviews vol 34 no 1pp 109ndash119 1998
[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
ISRN Nanotechnology 11
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
therapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007
[6] Y Malam M Loizidou and A M Seifalian ldquoLiposomes andnanoparticles nanosized vehicles for drug delivery in cancerrdquoTrends in Pharmacological Sciences vol 30 no 11 pp 592ndash5992009
[7] K B Sutradhar and M L Amin ldquoNanoemulsionsincreasing possibilities in drug deliveryrdquo European Journalof Nanomedicine vol 5 no 2 pp 97ndash110 2013
[8] N P Praetorius and T KMandal ldquoEngineered nanoparticles incancer therapyrdquoRecent Patents onDrugDeliveryampFormulationvol 1 no 1 pp 37ndash51 2007
[9] K Park ldquoNanotechnology what it can do for drug deliveryrdquoJournal of Controlled Release vol 120 no 1-2 pp 1ndash3 2007
[10] L A Nagahara J S H Lee L K Molnar et al ldquoStrategicworkshops on cancer nanotechnologyrdquoCancer Research vol 70no 11 pp 4265ndash4268 2010
[11] K T Nguyen ldquoTargeted nanoparticles for cancer therapypromises and challengesrdquo Journal of NanomedicineampNanotech-nology vol 2 no 5 article 103e 2011
[12] A Coates S Abraham and S B Kaye ldquoOn the receiving endmdashpatient perception of the side-effects of cancer chemotherapyrdquoEuropean Journal of Cancer and Clinical Oncology vol 19 no 2pp 203ndash208 1983
[13] I F Tannock C M Lee J K Tunggal D S M Cowan andM J Egorin ldquoLimited penetration of anticancer drugs throughtumor tissue a potential cause of resistance of solid tumors tochemotherapyrdquo Clinical Cancer Research vol 8 no 3 pp 878ndash884 2002
[14] R Krishna and L D Mayer ldquoMultidrug resistance (MDR) incancerMechanisms reversal using modulators of MDR and therole ofMDRmodulators in influencing the pharmacokinetics ofanticancer drugsrdquo European Journal of Pharmaceutical Sciencesvol 11 no 4 pp 265ndash283 2000
[15] M Links and R Brown ldquoClinical relevance of the molecularmechanisms of resistance to anti-cancer drugsrdquo Expert Reviewsin Molecular Medicine vol 1999 pp 1ndash21 1999
[16] M M Gottesman C A Hrycyna P V Schoenlein U AGermann and I Pastan ldquoGenetic analysis of the multidrugtransporterrdquo Annual Review of Genetics vol 29 pp 607ndash6491995
[17] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008
[18] X Guo and F C Szoka Jr ldquoChemical approaches to triggerablelipid vesicles for drug and gene deliveryrdquo Accounts of ChemicalResearch vol 36 no 5 pp 335ndash341 2003
[19] S Nie Y Xing G J Kim and J W Simons ldquoNanotechnologyapplications in cancerrdquo Annual Review of Biomedical Engineer-ing vol 9 pp 257ndash288 2007
[20] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008
[21] M V Yezhelyev X Gao Y Xing A Al-Hajj S Nie and RM OrsquoRegan ldquoEmerging use of nanoparticles in diagnosis andtreatment of breast cancerrdquo Lancet Oncology vol 7 no 8 pp657ndash667 2006
[22] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006
[23] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005
[24] D A LaVan T McGuire and R Langer ldquoSmall-scale systemsfor in vivo drug deliveryrdquo Nature Biotechnology vol 21 no 10pp 1184ndash1191 2003
[25] I Brigger C Dubernet and P Couvreur ldquoNanoparticles incancer therapy and diagnosisrdquoAdvancedDrugDelivery Reviewsvol 54 no 5 pp 631ndash651 2002
[26] S I Jeon JH Lee J DAndrade andPGDeGennes ldquoProtein-surface interactions in the presence of polyethylene oxide ISimplified theoryrdquo Journal of Colloid and Interface Science vol142 no 1 pp 149ndash158 1991
[27] P Tallury S Kar S Bamrungsap Y-F Huang W Tan andS Santra ldquoUltra-small water-dispersible fluorescent chitosannanoparticles synthesis characterization and specific target-ingrdquo Chemical Communications vol 17 pp 2347ndash2349 2009
[28] M F Francis M Cristea and F M Winnik ldquoPolymericmicelles for oral drug delivery why and howrdquo Pure and AppliedChemistry vol 76 no 7-8 pp 1321ndash1335 2004
[29] G Storm S O Belliot T Daemen and D D Lasic ldquoSurfacemodification of nanoparticles to oppose uptake by themononu-clear phagocyte systemrdquo Advanced Drug Delivery Reviews vol17 no 1 pp 31ndash48 1995
[30] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995
[31] G A Mansoori P Mohazzabi P McCormack and S Jab-bari ldquoNanotechnology in cancer prevention detection andtreatment bright future lies aheadrdquo World Review of ScienceTechnology and Sustainable Development vol 4 no 2-3 pp226ndash257 2007
[32] J Sudimack and R J Lee ldquoTargeted drug delivery via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 41 no 2 pp147ndash162 2000
[33] J F Kukowska-Latallo K A Candido Z Cao et al ldquoNanoparti-cle targeting of anticancer drug improves therapeutic responsein animal model of human epithelial cancerrdquo Cancer Researchvol 65 no 12 pp 5317ndash5324 2005
[34] G Russell-Jones K McTavish J McEwan and B ThurmondldquoIncreasing the tumoricidal activity of daunomycin-pHPMAconjugates using vitamin B12 as a targeting agentrdquo Journal ofCancer Research Updates vol 1 no 2 pp 1ndash6 2012
[35] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 Article ID 18496 3 pages 2012
[36] H S Yoo and T G Park ldquoFolate-receptor-targeted delivery ofdoxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugaterdquo Journal of Controlled Release vol 100 no 2pp 247ndash256 2004
[37] M Kawamoto T Horibe M Kohno and K Kawakami ldquoAnovel transferrin receptor-targeted hybrid peptide disintegratescancer cell membrane to induce rapid killing of cancer cellsrdquoBMC Cancer vol 11 article 359 2011
[38] T R Daniels B Bernabeu J A Rodrıguez et al ldquoTransferrinreceptors and the targeted delivery of therapeutic agents againstcancerrdquo Biochimica et Biophysica Acta vol 1820 no 3 pp 291ndash317 2012
[39] N C Bellocq S H Pun G S Jensen and M E DavisldquoTransferrin-containing cyclodextrin polymer-based particlesfor tumor-targeted gene deliveryrdquo Bioconjugate Chemistry vol14 no 6 pp 1122ndash1132 2003
[40] C R Dass and P F M Choong ldquoTargeting of small moleculeanticancer drugs to the tumour and its vasculature using
10 ISRN Nanotechnology
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
[41] H K Sun H J Ji H L Soo W K Sung and G P TaeldquoLHRH receptor-mediated delivery of siRNA using polyelec-trolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEIrdquo Bioconjugate Chemistry vol 19 no11 pp 2156ndash2162 2008
[42] S S Dharap Y Wang P Chandna et al ldquoTumor-specifictargeting of an anticancer drug delivery system by LHRHpeptiderdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 102 no 36 pp 12962ndash12967 2005
[43] httpwebmitedunewsoffice2006prostatehtml[44] T M Allen ldquoLigand-targeted therapeutics in anticancer ther-
apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
therapiesrdquoNature Reviews Cancer vol 1 no 2 pp 118ndash129 2001[46] W H Ouwehand R Finnern B D Gorick et al ldquoSelection of
internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
[47] J DMarksW H Ouwehand J M Bye et al ldquoHuman antibodyfragments specific for human blood group antigens from aphage display libraryrdquo BioTechnology vol 11 no 10 pp 1145ndash1149 1993
[48] B Liu F Conrad M R Cooperberg D B Kirpotin and JD Marks ldquoMapping tumor epitope space by direct selectionof single-chain Fv antibody libraries on prostate cancer cellsrdquoCancer Research vol 64 no 2 pp 704ndash710 2004
[49] D Peer P Zhu C V Carman J Lieberman and M ShimaokaldquoSelective gene silencing in activated leukocytes by target-ing siRNAs to the integrin lymphocyte function-associatedantigen-1rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 10 pp 4095ndash4100 2007
[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
[51] S Sudarshan D H Holman M L Hyer C Voelkel-JohnsonJ-Y Dong and J S Norris ldquoIn vitro efficacy of Fas ligandgene therapy for the treatment of bladder cancerrdquo Cancer GeneTherapy vol 12 no 1 pp 12ndash18 2005
[52] O Micheau E Solary A Hammann F Martin and M-TDimanche-Boitrel ldquoSensitization of cancer cells treated withcytotoxic drugs to fas-mediated cytotoxicityrdquo Journal of theNational Cancer Institute vol 89 no 11 pp 783ndash789 1997
[53] G N Naumov L A Akslen and J Folkman ldquoRole of angio-genesis in human tumor dormancy animal models of theangiogenic switchrdquoCell Cycle vol 5 no 16 pp 1779ndash1787 2006
[54] M A J Chaplain ldquoMathematical modelling of angiogenesisrdquoJournal of Neuro-Oncology vol 50 no 1-2 pp 37ndash51 2000
[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
[56] N Weidner J Folkman F Pozza et al ldquoTumor angiogenesis anew significant and independent prognostic indicator in early-stage breast carcinomardquo Journal of the National Cancer Institutevol 84 no 24 pp 1875ndash1887 1992
[57] D Fukumura and R K Jain ldquoImaging angiogenesis and themicroenvironmentrdquoAPMIS vol 116 no 7-8 pp 695ndash715 2008
[58] M Dhanabal M Jeffers andW J LaRochelle ldquoAnti-angiogenictherapy as a cancer treatment paradigmrdquo Current MedicinalChemistry vol 5 no 2 pp 115ndash130 2005
[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
[61] D Banerjee R Harfouche and S Sengupta ldquoNanotechnology-mediated targeting of tumor angiogenesisrdquoVascular Cell vol 3article 3 2011
[62] N Boudreau and C Myers ldquoBreast cancer-induced angiogen-esis multiple mechanisms and the role of the microenviron-mentrdquo Breast Cancer Research vol 5 no 3 pp 140ndash146 2003
[63] N N Khodarev J Yu E Labay et al ldquoTumour-endotheliuminteractions in co-culture coordinated changes of gene expres-sion profiles and phenotypic properties of endothelial cellsrdquoJournal of Cell Science vol 116 no 6 pp 1013ndash1022 2003
[64] J S Desgrosellier and D A Cheresh ldquoIntegrins in cancerbiological implications and therapeutic opportunitiesrdquo NatureReviews Cancer vol 10 no 1 pp 9ndash22 2010
[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
[66] S A Anderson R K Rader W F Westlin et al ldquoMag-netic resonance contrast enhancement of neovasculature withalpha(v)beta(3)-targeted nanoparticlesrdquoMagnetic Resonance inMedicine vol 44 pp 433ndash439 2000
[67] J H Park S Kwon J-O Nam et al ldquoSelf-assembled nanoparti-cles based on glycol chitosan bearing 5120573-cholanic acid for RGDpeptide deliveryrdquo Journal of Controlled Release vol 95 no 3 pp579ndash588 2004
[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
[70] J Li J Ji L M Holmes et al ldquoFusion protein from RGDpeptide and Fc fragment of mouse immunoglobulin G inhibitsangiogenesis in tumorrdquo Cancer Gene Therapy vol 11 no 5 pp363ndash370 2004
[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
[72] N Ferrara ldquoVEGF as a therapeutic target in cancerrdquo Oncologyvol 69 no 3 pp 11ndash16 2005
[73] D F Baban and L W Seymour ldquoControl of tumour vascularpermeabilityrdquo Advanced Drug Delivery Reviews vol 34 no 1pp 109ndash119 1998
[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
ISRN Nanotechnology 11
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
cationic liposomes lessons from gene therapyrdquo Cancer CellInternational vol 6 article 17 2006
[41] H K Sun H J Ji H L Soo W K Sung and G P TaeldquoLHRH receptor-mediated delivery of siRNA using polyelec-trolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEIrdquo Bioconjugate Chemistry vol 19 no11 pp 2156ndash2162 2008
[42] S S Dharap Y Wang P Chandna et al ldquoTumor-specifictargeting of an anticancer drug delivery system by LHRHpeptiderdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 102 no 36 pp 12962ndash12967 2005
[43] httpwebmitedunewsoffice2006prostatehtml[44] T M Allen ldquoLigand-targeted therapeutics in anticancer ther-
apyrdquo Nature Reviews Cancer vol 2 no 10 pp 750ndash763 2002[45] P Carter ldquoImproving the efficacy of antibody-based cancer
therapiesrdquoNature Reviews Cancer vol 1 no 2 pp 118ndash129 2001[46] W H Ouwehand R Finnern B D Gorick et al ldquoSelection of
internalizing antibodies for drug deliveryrdquoMethods in Molecu-lar Biology vol 248 pp 201ndash208 2004
[47] J DMarksW H Ouwehand J M Bye et al ldquoHuman antibodyfragments specific for human blood group antigens from aphage display libraryrdquo BioTechnology vol 11 no 10 pp 1145ndash1149 1993
[48] B Liu F Conrad M R Cooperberg D B Kirpotin and JD Marks ldquoMapping tumor epitope space by direct selectionof single-chain Fv antibody libraries on prostate cancer cellsrdquoCancer Research vol 64 no 2 pp 704ndash710 2004
[49] D Peer P Zhu C V Carman J Lieberman and M ShimaokaldquoSelective gene silencing in activated leukocytes by target-ing siRNAs to the integrin lymphocyte function-associatedantigen-1rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 10 pp 4095ndash4100 2007
[50] HWartlick K Michaelis S Balthasar K Strebhardt J Kreuterand K Langer ldquoHighly specific HER2-mediated cellular uptakeof antibody-modified nanoparticles in tumour cellsrdquo Journal ofDrug Targeting vol 12 no 7 pp 461ndash471 2004
[51] S Sudarshan D H Holman M L Hyer C Voelkel-JohnsonJ-Y Dong and J S Norris ldquoIn vitro efficacy of Fas ligandgene therapy for the treatment of bladder cancerrdquo Cancer GeneTherapy vol 12 no 1 pp 12ndash18 2005
[52] O Micheau E Solary A Hammann F Martin and M-TDimanche-Boitrel ldquoSensitization of cancer cells treated withcytotoxic drugs to fas-mediated cytotoxicityrdquo Journal of theNational Cancer Institute vol 89 no 11 pp 783ndash789 1997
[53] G N Naumov L A Akslen and J Folkman ldquoRole of angio-genesis in human tumor dormancy animal models of theangiogenic switchrdquoCell Cycle vol 5 no 16 pp 1779ndash1787 2006
[54] M A J Chaplain ldquoMathematical modelling of angiogenesisrdquoJournal of Neuro-Oncology vol 50 no 1-2 pp 37ndash51 2000
[55] J Folkman ldquoIncipient angiogenesisrdquo Journal of the NationalCancer Institute vol 92 no 2 pp 94ndash95 2000
[56] N Weidner J Folkman F Pozza et al ldquoTumor angiogenesis anew significant and independent prognostic indicator in early-stage breast carcinomardquo Journal of the National Cancer Institutevol 84 no 24 pp 1875ndash1887 1992
[57] D Fukumura and R K Jain ldquoImaging angiogenesis and themicroenvironmentrdquoAPMIS vol 116 no 7-8 pp 695ndash715 2008
[58] M Dhanabal M Jeffers andW J LaRochelle ldquoAnti-angiogenictherapy as a cancer treatment paradigmrdquo Current MedicinalChemistry vol 5 no 2 pp 115ndash130 2005
[59] N Weidner J P Semple W R Welch and J Folkman ldquoTumorangiogenesis and metastasismdashcorrelation in invasive breastcarcinomardquoThe New England Journal of Medicine vol 324 no1 pp 1ndash8 1991
[60] J Folkman ldquoFundamental concepts of the angiogenic processrdquoCurrent Molecular Medicine vol 3 no 7 pp 643ndash651 2003
[61] D Banerjee R Harfouche and S Sengupta ldquoNanotechnology-mediated targeting of tumor angiogenesisrdquoVascular Cell vol 3article 3 2011
[62] N Boudreau and C Myers ldquoBreast cancer-induced angiogen-esis multiple mechanisms and the role of the microenviron-mentrdquo Breast Cancer Research vol 5 no 3 pp 140ndash146 2003
[63] N N Khodarev J Yu E Labay et al ldquoTumour-endotheliuminteractions in co-culture coordinated changes of gene expres-sion profiles and phenotypic properties of endothelial cellsrdquoJournal of Cell Science vol 116 no 6 pp 1013ndash1022 2003
[64] J S Desgrosellier and D A Cheresh ldquoIntegrins in cancerbiological implications and therapeutic opportunitiesrdquo NatureReviews Cancer vol 10 no 1 pp 9ndash22 2010
[65] Y Pan H Ding L Qin X Zhao J Cai and B DuldquoGold nanoparticles induce nanostructural reorganization ofVEGFR2 to repress angiogenesisrdquo Journal of Biomedical Nan-otechnology vol 9 no 10 pp 1746ndash1756 2013
[66] S A Anderson R K Rader W F Westlin et al ldquoMag-netic resonance contrast enhancement of neovasculature withalpha(v)beta(3)-targeted nanoparticlesrdquoMagnetic Resonance inMedicine vol 44 pp 433ndash439 2000
[67] J H Park S Kwon J-O Nam et al ldquoSelf-assembled nanoparti-cles based on glycol chitosan bearing 5120573-cholanic acid for RGDpeptide deliveryrdquo Journal of Controlled Release vol 95 no 3 pp579ndash588 2004
[68] E A Waters J Chen X Yang et al ldquoDetection of targeted per-fluorocarbonnanoparticle binding using 19F diffusionweightedMR spectroscopyrdquoMagnetic Resonance in Medicine vol 60 no5 pp 1232ndash1236 2008
[69] PMWinter AMMorawski S D Caruthers et al ldquoMolecularimaging of angiogenesis in early-stage atherosclerosis with120572v1205733-integrin-targeted nanoparticlesrdquo Circulation vol 108 no18 pp 2270ndash2274 2003
[70] J Li J Ji L M Holmes et al ldquoFusion protein from RGDpeptide and Fc fragment of mouse immunoglobulin G inhibitsangiogenesis in tumorrdquo Cancer Gene Therapy vol 11 no 5 pp363ndash370 2004
[71] E Ruoslahti ldquoCell adhesion and tumor metastasisrdquo PrincessTakamatsu Symposia vol 24 pp 99ndash105 1994
[72] N Ferrara ldquoVEGF as a therapeutic target in cancerrdquo Oncologyvol 69 no 3 pp 11ndash16 2005
[73] D F Baban and L W Seymour ldquoControl of tumour vascularpermeabilityrdquo Advanced Drug Delivery Reviews vol 34 no 1pp 109ndash119 1998
[74] S K Hobbs W L Monsky F Yuan et al ldquoRegulation oftransport pathways in tumor vessels role of tumor type andmicroenvironmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 8 pp 4607ndash4612 1998
[75] P Rubin and G Casarett ldquoMicrocirculation of tumors Part Ianatomy function and necrosisrdquo Clinical Radiology vol 17 no3 pp 220ndash229 1966
[76] P Shubik ldquoVascularization of tumors a reviewrdquo Journal ofCancer Research and Clinical Oncology vol 103 no 3 pp 211ndash226 1982
ISRN Nanotechnology 11
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
[77] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010
[78] S H JangM GWientjes D Lu and J L-S Au ldquoDrug deliveryand transport to solid tumorsrdquoPharmaceutical Research vol 20no 9 pp 1337ndash1350 2003
[79] H Maeda ldquoThe enhanced permeability and retention (EPR)effect in tumor vasculature the key role of tumor-selectivemacromolecular drug targetingrdquo Advances in Enzyme Regula-tion vol 41 pp 189ndash207 2001
[80] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000
[81] F Yuan ldquoTransvascular drug delivery in solid tumorsrdquo Seminarsin Radiation Oncology vol 8 no 3 pp 164ndash175 1998
[86] A K Patri J F Kukowska-Latallo and J R Baker Jr ldquoTargeteddrug delivery with dendrimers comparison of the releasekinetics of covalently conjugated drug and non-covalent druginclusion complexrdquoAdvancedDrugDelivery Reviews vol 57 no15 pp 2203ndash2214 2005
[87] N Desai ldquoChallenges in development of nanoparticle-basedtherapeuticsrdquo The AAPS Journal vol 14 no 2 pp 282ndash2942012
[88] C E Soma C Dubernet D Bentolila S Benita and P Cou-vreur ldquoReversion of multidrug resistance by co-encapsulationof doxorubicin and cyclosporin A in polyalkylcyanoacrylatenanoparticlesrdquo Biomaterials vol 21 no 1 pp 1ndash7 2000
[89] M L Amin ldquoP-glycoprotein inhibition for optimal drug deliv-eryrdquo Drug Target Insights vol 7 pp 27ndash34 2013
[90] H Matsuo M Wakasugi H Takanaga et al ldquoPossibility of thereversal ofmultidrug resistance and the avoidance of side effectsby liposomesmodified withMRK-16 amonoclonal antibody toP-glycoproteinrdquo Journal of Controlled Release vol 77 no 1-2 pp77ndash86 2001
[91] S Danson D Ferry V Alakhov et al ldquoPhase I dose escalationand pharmacokinetic study of pluronic polymer-bound dox-orubicin (SP1049C) in patients with advanced cancerrdquo BritishJournal of Cancer vol 90 no 11 pp 2085ndash2091 2004
[92] E V Batrakova T Y Dorodnych E Y Klinskii et al ldquoAnthra-cycline antibiotics non-covalently incorporated into the blockcopolymer micelles in vivo evaluation of anti-cancer activityrdquoBritish Journal of Cancer vol 74 no 10 pp 1545ndash1552 1996
[93] D Goren A T Horowitz D Tzemach M Tarshish S Zalipskyand A Gabizon ldquoNuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance effluxpumprdquo Clinical Cancer Research vol 6 no 5 pp 1949ndash19572000
[94] J Kos N Obermajer B Doljak P Kocbek and J Kristl ldquoInac-tivation of harmful tumour-associated proteolysis by nanopar-ticulate systemrdquo International Journal of Pharmaceutics vol 381no 2 pp 106ndash112 2009
[95] A Cirstoiu-Hapca F Buchegger L Bossy M Kosinski RGurny and F Delie ldquoNanomedicines for active targetingphysico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies ontarget cellsrdquo European Journal of Pharmaceutical Sciences vol38 no 3 pp 230ndash237 2009
[96] Y B Patil U S Toti A Khdair L Ma and J Panyam ldquoSingle-step surface functionalization of polymeric nanoparticles fortargeted drug deliveryrdquo Biomaterials vol 30 no 5 pp 859ndash8662009
[97] W Yang Y Cheng T Xu X Wang and L-P Wen ldquoTargetingcancer cells with biotin-dendrimer conjugatesrdquo European Jour-nal of Medicinal Chemistry vol 44 no 2 pp 862ndash868 2009
[98] Y Liu K Li J Pan B Liu and S-S Feng ldquoFolic acid conjugatednanoparticles ofmixed lipidmonolayer shell and biodegradablepolymer core for targeted delivery of Docetaxelrdquo Biomaterialsvol 31 no 2 pp 330ndash338 2010
[99] O Taratula O B Garbuzenko P Kirkpatrick et al ldquoSurface-engineered targeted PPI dendrimer for efficient intracellularand intratumoral siRNA deliveryrdquo Journal of Controlled Releasevol 140 no 3 pp 284ndash293 2009
[100] Y Patil T Sadhukha L Ma and J Panyam ldquoNanoparticle-mediated simultaneous and targeted delivery of paclitaxeland tariquidar overcomes tumor drug resistancerdquo Journal ofControlled Release vol 136 no 1 pp 21ndash29 2009
[101] E Brewer J Coleman andA Lowman ldquoEmerging technologiesof polymeric nanoparticles in cancer drug deliveryrdquo Journal ofNanomaterials vol 2011 Article ID 408675 2011
[102] C C Anajwala G K Jani and S M V Swamy ldquoCurrent trendsof nanotechnology for cancer therapyrdquo International Journal ofPharmaceutical Sciences and Nanotechnology vol 3 pp 1043ndash1056 2010
[103] B Haley and E Frenkel ldquoNanoparticles for drug delivery incancer treatmentrdquo Urologic Oncology vol 26 no 1 pp 57ndash642008
[104] D Lasic ldquoDoxorubicin in sterically stabilizedrdquoNature vol 380no 6574 pp 561ndash562 1996
[105] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004
[106] J Kreuter and T Higuchi ldquoImproved delivery of methoxsalenrdquoJournal of Pharmaceutical Sciences vol 68 no 4 pp 451ndash4541979
[107] D Papahadjopoulos T M Allen A Gabizon et al ldquoStericallystabilized liposomes improvements in pharmacokinetics andantitumor therapeutic efficacyrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no24 pp 11460ndash11464 1991
[108] D Peer and R Margalit ldquoLoading mitomycin C inside longcirculating hyaluronan targeted nano-liposomes increases itsantitumor activity in three mice tumor modelsrdquo InternationalJournal of Cancer vol 108 no 5 pp 780ndash789 2004
[109] R E Eliaz and FC Szoka Jr ldquoLiposome-encapsulated doxoru-bicin targeted to CD44 a strategy to kill CD44-overexpressingtumor cellsrdquoCancer Research vol 61 no 6 pp 2592ndash2601 2001
[110] S R Grobmyera G Zhoua L G Gutweina N IwakumabP Sharmac and S N Hochwalda ldquoNanoparticle deliveryfor metastatic breast cancerrdquo Nanomedicine NanotechnologyBiology and Medicine vol 8 pp S21ndashS30 2012
12 ISRN Nanotechnology
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
[111] Y Liu H Miyoshi and M Nakamura ldquoNanomedicine fordrug delivery and imaging a promising avenue for cancertherapy and diagnosis using targeted functional nanoparticlesrdquoInternational Journal of Cancer vol 120 no 12 pp 2527ndash25372007
[112] Y Fukumori and H Ichikawa ldquoNanoparticles for cancer ther-apy and diagnosisrdquo Advanced Powder Technology vol 17 no 1pp 1ndash28 2006
[113] M B Yatvin W Kreutz B A Horwitz and M Shinitzky ldquopH-sensitive liposomes possible clinical implicationsrdquo Science vol210 no 4475 pp 1253ndash1255 1980
[114] S K Huang P R Stauffer K Hong et al ldquoLiposomes andhyperthermia in mice increased tumor uptake and therapeuticefficacy of doxorubicin in sterically stabilized liposomesrdquo Can-cer Research vol 54 no 8 pp 2186ndash2191 1994
[115] E S Kawasaki and A Player ldquoNanotechnology nanomedicineand the development of new effective therapies for cancerrdquoNanomedicine vol 1 no 2 pp 101ndash109 2005
[116] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012
[117] G A Hughes ldquoNanostructure-mediated drug deliveryrdquoNanomedicine Nanotechnology Biology and Medicine vol 1pp 22ndash30 2005
[118] SMMoghimi A C Hunter and J CMurray ldquoNanomedicinecurrent status and future prospectsrdquoThe FASEB Journal vol 19no 3 pp 311ndash330 2005
[119] C Kojima K Kono K Maruyama and T Takagishi ldquoSynthesisof polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugsrdquo Biocon-jugate Chemistry vol 11 no 6 pp 910ndash917 2000
[120] Z Liu K Chen C Davis et al ldquoDrug delivery with carbonnanotubes for in vivo cancer treatmentrdquo Cancer Research vol68 no 16 pp 6652ndash6660 2008
[121] A Bianco K Kostarelos and M Prato ldquoApplications of carbonnanotubes in drug deliveryrdquo Current Opinion in ChemicalBiology vol 9 no 6 pp 674ndash679 2005
