Review Article Nanoparticle-Based Drug Delivery...

Hindawi Publishing CorporationJournal of NanomaterialsVolume 2013 Article ID 863951 11 pageshttpdxdoiorg1011552013863951

Review ArticleNanoparticle-Based Drug Delivery for Therapy of Lung CancerProgress and Challenges

Anish Babu12 Amanda K Templeton12 Anupama Munshi23 and Rajagopal Ramesh124

1 Department of Pathology University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA2 Peggy and Charles Stephenson Cancer Center University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA3Department of Radiation Oncology University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA4The Graduate Program in Biomedical Sciences University of Oklahoma Health Sciences Center Oklahoma City OK 73104 USA

Correspondence should be addressed to Rajagopal Ramesh rajagopal-rameshouhscedu

Received 26 August 2013 Accepted 28 October 2013

Academic Editor Haifeng Chen

Copyright copy 2013 Anish Babu et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The last decade has witnessed enormous advances in the development and application of nanotechnology in cancer detectiondiagnosis and therapy culminating in the development of the nascent field of ldquocancer nanomedicinerdquo A nanoparticle as perthe National Institutes of Health (NIH) guidelines is any material that is used in the formulation of a drug resulting in a finalproduct smaller than 1 micron in size Nanoparticle-based therapeutic systems have gained immense popularity due to theirability to overcome biological barriers effectively deliver hydrophobic therapies and preferentially target disease sites Currentlymany formulations of nanocarriers are utilized including lipid-based polymeric and branched polymeric metal-based magneticand mesoporous silica Innovative strategies have been employed to exploit the multicomponent three-dimensional constructsimparting multifunctional capabilities Engineering such designs allows simultaneous drug delivery of chemotherapeutics andanticancer gene therapies to site-specific targets In lung cancer nanoparticle-based therapeutics is paving the way in the diagnosisimaging screening and treatment of primary and metastatic tumors However translating such advances from the bench to thebedside has been severely hampered by challenges encountered in the areas of pharmacology toxicology immunology large-scalemanufacturing and regulatory issuesThis review summarizes current progress and challenges in nanoparticle-based drug deliverysystems citing recent examples targeted at lung cancer treatment

1 Introduction

Worldwide lung cancer is the leading cause of cancer-relateddeathswith a dismal 5-year survival rate of only 15 [1] Everyyear in the United States approximately 220000 individualsare diagnosed with lung cancer of which 85 of the casesare classified as non-small-cell lung carcinoma (NSCLC) [1]while the remaining cases are diagnosed as small-cell lungcarcinoma (SCLC) Current treatment strategies are stronglydependent on the type of malignancy and stage at the timeof diagnosis but often involve a combination of surgerychemotherapy andor radiation therapy

Chemotherapy a first-line treatment option for ad-vanced-stage lung cancer is often administered intravenouslywhere it circulates throughout the body ultimately locat-ing and destroying cancerous and normal tissues Standard

first-line chemotherapy regimens for lung cancer includeplatinum-based drugs such as cisplatin and carboplatinHowever platinum-based chemotherapy is riddled withdose-limiting side effects including nephro- and cardiotox-icity anemia intestinal injury and peripheral neuropathyas well as less serious symptoms of uneasiness nauseaand fatigue To mitigate many of these untoward effectsplatinum drugs are used in combination with other anti-cancer agents Combination therapy involving two to threedrugs increases the therapeutic effectiveness and reducesthe dosage of each individual drug required to producean observable therapeutic response Common chemothera-peutic agents for combination therapy include a platinumdrug with paclitaxel gemcitabine etoposide or vinblastineHowever like monotherapy combination therapy is limitedby dose-dependent side effects and patientrsquos intolerability

2 Journal of Nanomaterials

to the drug combination resulting in cessation of treatment[2] Additionally the hydrophobic nature of the majorityof the cancer chemotherapeutics makes them poorly watersoluble and therefore limits their administration at high doses[3 4] Thus methods to improve tumor-targeted delivery ofchemotherapeutics that will result in increased drug efficacywith improved pharmacological properties and minimaltoxicity to normal tissues remain a priority in cancer therapy

Experimental therapies such as photodynamic therapy(PDT) immunotherapy and gene therapy provide promisingtools to fight lung cancer In PDT a photosensitizer activatedby laser light reacts with molecular oxygen to form reactiveoxygen species that function to annihilate cancer cells [5]PDT is often used in combination with chemotherapy orsurgery Porfimer sodium a first-generation photosensitizerhas been used in the treatment of early as well as advancedlung carcinomasMore improved and efficient PDTagents arecurrently available as a result of the extensive research effortsin the last two decades However many of these photosen-sitizers are poorly water soluble fettering their intravenousadministration [6]

Immunotherapy harnesses the bodyrsquos immune system tofight cancer Biomolecules or antigens are administered toeither trigger the immune system or reduce the immunesuppressing activities of the tumor [7] Administration ofimmunologically active agents disrupts the tumorigeniccascades by directly blocking growth factors or hormonesand their receptors Certain cancers including lung canceroverexpress growth factor receptors such as the epider-mal growth factor receptor (EGFRHer1) Binding of theligand epidermal growth factor (EGF) to EGFR activatescell proliferation and survival signaling pathways resultingin rapid and uncontrolled tumor growth Cetuximab acompetitive anti-EGFR monoclonal antibody counteractsthe cell proliferation signaling mediated by the endogenousEGF ligand culminating in attenuation of the cell survivalsignals and induction of tumor cell death Gene therapy is arelatively new concept with a large number of research teamsworldwide in active pursuit of identifying and deliveringcancer-suppressing genes for clinical applications [8] Deliv-ery vectors are a necessity in order to protect the therapeuticgenes until they reach their target site Historically viralvectors have been used to deliver gene-based therapeutics[9] however viral vector induced host immune responseslimits their therapeutic potential [10] Definitively there is agrowing need for development of safe and efficient deliveryvehicles for photosensitizers chemotherapeutics and tumorsuppressor genes

Nanotechnology is not pervaded by some of the lim-itations of viral vectors providing an avenue of incrediblepotential for development of tumor-targeting drug deliverysystems This continuously expanding niche will revolution-ize cancer treatment and management [11] More preciselynanoscale drug delivery systems hold great promise in suc-cessfully formulating and enhancing the therapeutic efficacyof a large number of anticancer agents [12] Nanoparticlesare known to positively alter biodistribution increasing ther-apeutic efficiency and reducing nonspecific toxicity of potentanticancer drugs Their superior biocompatibility ability to

protect nucleic acids from degradation and ability to delivertherapeutic genes to cancer cells in vivo make nanoparticlesthe ideal delivery vehicle [13 14] While many nanoparticle-based therapies have been developed such as Abraxane analbumin-bound paclitaxel nanoformulation for the treatmentof metastatic NSCLC [15] few have been translated intoclinical success It continues to be a challenge to identify idealdrug delivery systems for several classes of novel drugs withdifferent physicochemical characteristics and varying degreesof therapeutic activities in the physiological environmentThis review summarizes current progress and challengesin nanoparticle-based drug delivery systems citing recentexamples of applying nanomedicine for lung cancer treat-ment

2 Progress in Nanoparticle DrugGeneDelivery Systems

21 Lipid-Based Nanocarriers Liposomes oil dispersions(micelles) and lipid nanoparticles are the major classesof lipid-based nanocarriers for drug and gene deliveryapplications Liposomes are bilayered phospholipid vesiclescommonly used to deliver hydrophobic and hydrophilicdrugs through either incorporation in the lipid bilayer itselfor encapsulation in the inner aqueous core respectivelyReduction of the number of lipid bilayers reduces the size ofthe liposomes to nanosize increasing the circulation time andtumor localization properties of encapsulated drugs [16]

Liposomes are becoming increasingly more populardelivery vehicles for anticancer therapeutics due to theirstrong biocompatibility properties Over the last decadethe liposomal research field has boomed generating manynew liposomal formulations such as cationic liposomes [17]virosomes [18] temperature-sensitive liposomes [19] andarchaeosomes [20] Despite these huge advances at thebench currently there are only two FDA-approved liposomalformulations DOXIL a liposomal doxorubicin injection forovarian cancer andMarqibo a liposomal vincristine sulphateinjection for lymphoblastic leukemia

In lung cancer treatment liposomes may be a promisingdelivery system for drugs and genes The drug of choice forthe treatment of NSCLC for the last two decades cisplatinis implicated in the development of nephrotoxicity in 20of patients receiving high doses [21] In 2004 Boulikasdeveloped a liposome-based cisplatin drug called Lipoplatinto reduce systemic toxicity of cisplatin [22] Furthermorethese researchers also demonstrated that lipoplatin injectioncompared to standard therapy significantly reduced nephro-toxicity to negligible levels in multiple rat tumor models[23] According to a recent report lipoplatin is anticipated tocomplete phase III clinical trial testing in 2013 and 2014 [24]Paclitaxel another chemotherapeutic drug widely used in thetreatment of lung cancer was historically formulated usingCremophore EL to enhance its solubility in physiologicalfluids However this resulted in hypersensitivity reactionscomplicating its systemic delivery In 2010 a phase I clinicaltrial in NSCLC patients with malignant pleural effusionsdemonstrated in all cases investigated that treatment with

Journal of Nanomaterials 3

paclitaxel formulated with a liposomal carrier had enhancedtherapeutic efficacy [25] Moreover a recent preclinical studyhas shown that liposomal-paclitaxel formulation can bemodified to target lung cancer cells to reduce the inci-dence of drug resistance [26] Specifically the liposomalsurface was decorated with the mitochondrial targetingmolecule d-120572-tocopheryl polyethylene glycol 1000 succinate-triphenylphosphine conjugate (TPGS1000-TPP) These tar-geted paclitaxel liposomes could significantly enhance theircellular uptake inducing mitochondria-mediated apoptoticcell death in humanA549 lung cancer cells At present Lipusua paclitaxel-liposome is commercially available with severalother formulations under clinical investigation [27] Table 1lists current examples of liposomal formulations undergoingclinical trials intended for the treatment of cancer In arandomized phase III multicenter trial liposomal formula-tion of cisplatin and paclitaxel combination therapy reachedeffective therapeutic response while reducing nephrotoxicityin NSCLC patients [28] Interestingly this liposomal drugcombination is reported to not only improve the targetingefficiency to the primary tumor but also be effective againstmetastasis

Liposomes have also been used to deliver cancer vaccinesfor the prevention or treatment of existing cancers Studiesusing therapeutic vaccine Biomira Liposomal Protein 25(BLP25) have shown encouraging results in the treatment ofadvanced NSCLC [29] BLP25 uses a liposomal carrier thattargets the tumor-associated antigenMUC1 to prevent tumorgrowth A preclinical study in a human MUC1 transgeniclung cancer mouse model (hMUC1Tg) demonstrated thatpretreatment with a low dose of cyclophosphamide followedby two cycles of liposome BLP25 treatment significantlyreduced the number of tumor foci [30] Importantly phase IIIclinical studies using liposomeBLP25 are currently underway[31]

Studies from our own laboratory have shown thatlipid based nanocarriers can be effectively used for genedelivery in mouse lung cancer models Preclinical studiesusing the nontargeted nanoparticle system 12-dioleoyl-3-Trimethylammonium Propane (DOTAP)cholesterol (Chol)carrying tumor suppressor genes such as p53 TUSC2FUS1ormda-7IL-24 [32] efficiently delivered therapeutic genes tometastatic tumor sites culminating in a significant therapeu-tic effect with increased animal survival Preclinical studiesfrom our laboratory demonstrating efficacy and safety ofthe DOTAPChol nanoparticle system resulted in its clinicaltesting for delivery of the TUSC2FUS1 tumor suppressorgene in NSCLC patients Results from the phase I clinicaltrial demonstrated that intravenous administration ofTUSC2encapsulated in our DOTAPChol nanoparticle system wassafe and well tolerated with no treatment-related toxicityAdditionally study results showed that the nanoparticleswere efficiently taken up by primary and metastatic tumorsexpression of transgene and gene products occurred and spe-cific alterations in TUSC2-regulated signaling pathways wereobserved [32] Results from this trial have led to discussionfor initiating a phase II study for lung cancer Additionalphase I trials testing DOTAPChol-based nanoparticle ther-apy for breast ovarian andpancreatic cancers are anticipated

The therapeutic genes to be deliveredwill vary and depend onthe cancer type

Solid lipid nanocarriers (SLNs) are another class of vehi-cle for drug and gene delivery SLNs are superior to their lipidcounterparts in their enhanced stability high drug loadingimproved biocompatibility and ease of large-scale manufac-turing production Choi et al [33] transfected p53-null H1299lung cancer cells with SLN-carrier p53 The authors were ableto demonstrate efficient p53 protein expression comparedto commercially available Lipofectin suggesting that SLNscould be used as highly efficient gene therapy vehicles inlung cancer In a recent report researchers successfullyloaded SLNs with Bcl-2 siRNA and paclitaxel for synergisticcombination therapy as well as coencapsulated CdSeZnSquantum dots to bestow optical traceability [34] Collectivelythe properties of SLNs are ideally suited for combined chemo-andor gene-therapy and molecular imaging of cancer

22 Polymeric Nanoparticles As the name suggests poly-meric nanoparticles are synthesized from polymers Morerecently biodegradable polymers such as poly(lactic acid)(PLA) poly(lactic-co-glycolic) acid (PLGA) gelatin albu-min chitosan polycaprolactone and poly-alkyl-cyanoacryl-ates have gained popularity in use because of their con-trolled and sustained release properties subcellular size andbiocompatibility For instance Abraxane an FDA-approvedalbumin-based nanoparticle carrying paclitaxel is indicatedfor first-line treatment of locally advanced or metastaticNSCLC in combination with carboplatin in patients whoare not candidates for curative surgery or radiation ther-apy Polymer nanoparticles have been shown to enhancethe chemo- and radio-therapeutic efficacy of anticanceragents [35] Chemoradiation therapy involves the concurrentadministration of chemotherapy and radiotherapy for thetreatment of many cancers including lung cancer Chemora-diation therapy is known to improve the local tumor controland patient survival Polyethylene glycol- (PEG-) modifiedpolylactic acid nanoparticles loaded with taxanes have sig-nificantly improved the efficacy of chemoradiation therapyin both in vitro and in an A549 lung tumor xenograft model[36] Other research groups have developed a cremophor-free nanoformulation of paclitaxel and cisplatin using blockcopolymers of PEG and polylactic acid for the treatment oflung cancer [37] This nanoformulation called Genexol-PMhas entered phase II clinical trials in patients with advancedNSCLC A separate phase II clinical trial is awaiting resultsfor the same nanocarrier modified to deliver gemcitabineto untreated patients diagnosed with metastatic lung cancer[38]

Traditional anticancer agents are loathed for their repug-nant side effects including the discomfort and pain associatedwith their administration Historically oral drug deliverymethods have not been feasible for the treatment of lungcancer due to the inability of the therapeutic to penetratelung tumor sites and achieve efficient therapeutic concentra-tion even at high administered doses The size shape andsurface charge of nanoparticles provide an avenue for thedevelopment of novel routes of administration for anticanceragents Recently Jiang et al [39] investigated three different


Table 1 Ongoing or recently completed clinical trials of a few liposomal nanoformulations used for cancer chemotherapylowast

Trade namecomposition Indication Phase StagePEGylated Liposomal Doxorubicin AIDS-associated non-Hodgkinrsquos lymphoma I Completed

DoxilCAELYX Liposomal Doxorubicin Malignant female reproductive system neoplasm Ovariancancer I Active

Doxil Liposomal Doxorubicin Resistant solid malignancies I Completed

Liposomal Cytarabine Central nervous system malignanciesStage IV breast cancer II Active

Liposomal Entrapped Paclitaxel Easy toUse (LEP-ETU) Advanced cancer I Completed

Liposomal Daunorubicin

Hematologic cancerChronic myelomonocytic leukemiapreviously treated Myelodysplastic syndromes andrecurrent adult Acute myeloid leukemia

II Completed

BLP25 Liposome Vaccine Lung neoplasmsNon-small-cell lung carcinoma II Completed

CPX-351Liposomal Cytarabine-Daunorubicin Acute myeloid leukemia I Active

Liposomal Vincristine Acute lymphoblastic leukemia II ActiveLiposomal LE-SN38 Advanced cancer I CompletedIHL-305Irinotecan Liposome Injection Advanced solid tumours I Active

Liposome Encapsulated Mitoxantrone(LEM) Advanced cancer I Completed

Liposomal Encapsulated Docetaxel(LE-DT) Advanced solid tumours I CompletedlowastData retrieved from US National Institutes of Health website (httpclinicaltrialsgov) on August 21 2013

polymer-based nanoparticles composed of polycaprolactone(PCL) that were surface modified with chitosan polymerfor oral administration of chemotherapy in lung cancer Themucoadhesive properties of the polymer increased the ther-apeutic effect of anticancer drugs by selectively interactingwith the increased levels of mucin expressed in cancer cellscompared to normal cells Similarly another study reportedthe use of PCL-based diblock copolymer nanoparticles fortreating lung cancer via oral administration [40] Interest-ingly this nanoparticle showed advantages over the com-mercially available Taxotere an injectable docetaxel in termsof cytotoxicity against lung cancer cells Another researchgroup designed a chitosan-based controlled drug deliverysystem to deliver the potent antineoplastic agent lomustineThe lomustine-loaded chitosan nanoparticles demonstratedexcellent control over drug release and enhanced its invitro cytotoxicity against the lung cancer cell line L132 [41]Recently attention has turned towards polymer nanoparticleswith expansile properties for the treatment of lung cancerA Lewis lung carcinoma mouse model demonstrated thatfollowing surgical intervention paclitaxel-loaded expansilenanoparticles delayed the local recurrence of subcutaneouslesions as well as modestly improved the overall survivabilityof the tumor-bearing animals [42]

The advantage of combining PLA or PLGA nanoparticleswith chitosan has recently materialized Chitosan modifica-tion of drug- or gene-loaded PLGA nanoparticles impartsa positive charge to the nanoparticle surface which aids

in cellular uptake and cytotoxicity towards lung cancercells [43 44] Identifying the potential of chitosan-modifiednanoparticles as drug or gene delivery vehicles providesan opportunity for combined chemo- and gene-therapeuticapproaches with same or similar kinds of nanoparticlesystems Currently our lab is developing a chitosanPLA-hybrid-based nanoparticle system for combined delivery ofchemotherapeutics and tumor suppressor genes for lungcancer The nanoparticles are designed such that the rigidPLA polymer matrix containing the chemotherapeutic drugforms the inner core and is surface coated with siRNAor DNA containing chitosan and decorated with tumor-targeting moieties The nanoparticle is less than 200 nm insize and is physicochemically stable for at least 10 days insolution as well as having a drug encapsulation efficiencygreater than 90 (data unpublished) The ultrastructure ofthis drug-loaded nanoparticle system is shown in Figure 1

Polymer nanoparticles have been extensively used instudies aimed at delivering targeted chemotherapeutics tolung cancer Tseng et al [45] developed a gelatin nanopar-ticle system decorated with EGFR-targeted biotinylated EGF(bEGF)These nanoparticles demonstrated enhanced cellularuptake in EGFR overexpressing cancer cell lines holdingpromise for targeted lung cancer therapy Building on thisstrategy the same group reported an aerosol-targeted therapyin a mouse model for lung cancer using bEGF-gelatinnanoparticles loaded with cisplatin [46] The aerosol-basedtargeted drug delivery system resulted in enhanced drug


Figure 1 Transmission electron microscopy of cationic polymercoated poly (lactic acid) nanoparticle carrying the anticancer drugcisplatin

concentrations in tumor tissues contributing to anticanceractivity while direct tumor injection with the nanoparticlesyielded high therapeutic efficacy and reduced systemic toxi-city of cisplatin Additionally gelatin nanoparticles have alsobeen used for the delivery of the hydrophobic drug resveratroltowards NSCLC cells [47]

Dendrimers are branched polymers with a large numberof functional groups that radiate from a central core pro-viding the opportunity to link multiple bioactive moleculesA recent study illustrated the use of dendrimer-targetingpeptide conjugates as a carrier for drugs towardsNSCLC [48]These dendrimer-peptide conjugates when administered toa lung tumor-bearing athymic mouse model were efficientlytaken up by the cancer cells demonstrating their potential as adrug carrier for the treatment of lung cancer [48] In a relatedstudy a newly designed PEGylated dendrimer nanoparticleshowed promising application as an aerosol-inhaled drugdelivery modality [49] The smaller dendrimer particles arereported to enter the blood stream via inhalation while largerparticles are sequestered in the lung for an extended periodof time In the future this method of controlled drug deliveryto the lungs could provide an alternative to injectable drugsystems Starpharma Holdings Ltd Australia released theprimary data of a study utilizing delivery of dendrimer-baseddoxorubicin to rats burdened with metastatic breast cancerin the lungs [50] The authors concluded that there wassubstantial improvement in the efficacy of doxorubicin whendelivered using dendrimers

Hybrid polymer nanoparticles composed of PLGA andchitosan demonstrated enhanced tumor uptake and cytotoxi-city compared to unmodified nanoparticles in A549 cells [51]More importantly the modified nanoparticles administeredto a lung metastatic mouse model demonstrated a lung-specific increase in biodistribution [51] PLGA nanoparticleshave also successfully been used to codeliver paclitaxel andSTAT3 siRNA to the drug-resistant A549 cell line [52] Inanother study paclitaxel-loaded PLGA nanoparticles dec-orated with anti-EGFR demonstrated high binding affinity

to EGFR expressing cells in a mouse lung tumor modelindicating the potential of these nanoparticles for targetedlung cancer therapy [53]

23 Metal-Based Nanoparticles Noble metals such as goldand silver have been extensively investigated for clinical appli-cations including their use in sensitive diagnostic imagingdetecting and classifying of lung cancer [54] Peng et al[55] developed a gold nanoparticle-based biosensor systemwith the capacity to detect lung cancer by analyzing anindividualrsquos exhaled breathThe sensor uses a combination ofan array of chemiresistors based on gold nanoparticles andpattern recognition methods Additionally another researchgroup reported the detection of picograms of enolase 1(ENO1) an immunogenic antigen associatedwithNSCLC byusing an immunosensor that detects electrochemical signalprobes of gold nanoparticle congregates [56] Recently goldnanoparticles have also successfully been tested as sensors fordiscriminating and classifying different lung cancer histolo-gies The sensor was able to distinguish between normal andcancerous cells SCLCandNSCLC andbetween two subtypesof NSCLCs [57]

Additionally gold nanoparticles have been used to deliveranticancer drugs for enhanced therapeutic effectiveness Forexample methotrexate (MTX) has poor tumor retentionability due to its high water solubility which likely con-tributes to its slow or poor therapeutic response in patientsHowever gold nanoparticle conjugates of MTX have hightumor retention and enhanced therapeutic efficacy in aLewis lung carcinoma mouse model [58] Previously wehave shown in NSCLC cells that anti-EGFR antibody (Clone225) conjugated hybrid plasmonic magnetic nanoparticlesexhibited significant enhancement in anticancer activity byinducing autophagy and apoptosis [59] Other studies havedeveloped goldiron oxide nanoclusters surface decoratedwith fluorescently labeled antibodies for targeting EGFRexpressing epidermoid carcinoma cells [60] Such design pro-vides promising applications of gold-based nanoparticles insimultaneous use in magnetic resonance imaging (MRI) andtherapy Recently gold nanoparticles have been applied inPDT for delivery of the water soluble PDT agent purpurin-18-N-methyl-D-glucamine (Pu-18-NMGA) towards A549 cells[61] PDT using Pu-18-NMGA-gold nanoparticle resultedin higher photodynamic activity than free Pu-18-NMGASimilarly silver nanoparticles have demonstrated antipro-liferative effects in cancer cells [62 63] However in vitroexposure of human lung cancer cells to silver nanoparticlesresulted in reactive oxygen species-induced genotoxicityraising concerns of an unfavorable risk to benefit ratio [64]

24 Other Nanoparticle Systems Magnetic nanoparticleshave been extensively investigated and applied in diagnosisand treatment of various cancers Theranostic nanoparticlesconcurrently facilitate imaging and delivery of therapeuticagents Magnetic hyperthermia is a noninvasive therapeuticapproach for lung cancer that entails the heat-induced abla-tion of desired tumor tissue When subjected to alternatingcurrents the magnetic material such as superparamagnetic


iron oxide (SPIO) nanoparticles generate sublethal heatthat causes local tissue damage Sadhukha et al [65] evalu-ated in a mouse model the effectiveness of tumor-targetedSPIO nanoparticles for hyperthermic destruction of NSCLCThe EGFR-targeted SPIO nanoparticles showed enhancedtumor retention and significantly inhibited lung tumorgrowth

Wang et al [66] developed magnetic nanoparticlescapable of detecting micrometastasis in lung cancer Mag-netic nanoparticles conjugated with the epithelial tumorcell marker pan-cytokeratin efficiently isolated circulatingtumor cells (CTCs) from patients diagnosed with lung can-cer The cells were further identified using quantum dots(Qdots) coupled to theNSCLCmicrometastasismarker lung-specific X protein (LUNX) and surfactant protein-A(SP-A)antibody This is the first study that reported the detec-tion of micrometastasis in peripheral blood of lung cancerpatients Magnetic nanoparticles have also been used to over-come drug resistance A cisplatin-resistant A549 lung tumorxenograft model was chemosensitized with cisplatin loadedmagnetic nanoparticles Molecular studies demonstratedthat cisplatin-loaded magnetic nanoparticle-treated tumorshad a significant reduction in localization of lung resis-tance related proteins and enhanced cytotoxicity of cisplatin[67]

Mesoporous silica nanoparticles (MSNs) have beenincreasingly used in anticancer drug delivery research dueto their dynamic capacity for drug loading controlleddrug release property and multifunctional ability Humanlung cancer cells primarily take up MSNs by endocytosis[68] MSNs have also been developed as a carrier forradionuclide isotope holmium-165 (Ho165) and tested in axenograft tumor model [69] In this model MSNs wereable to hold the radionuclide without release and withstandlong irradiation times Additionally Ho165-carrying MSNspredominantly accumulated in the tumor tissue follow-ing intraperitoneal administration in tumor-bearing miceImportantly MSNs enhanced the radio-therapeutic efficacyof Ho165 and demonstrated their potential in managingovarian cancer metastasis MSNs have also been developedfor inhalation treatment of lung cancer [70] The elegantnanoparticle system design fully exploited the dynamic drugloading capabilities and multifunctionalization of MSNs Itwas designed to simultaneously carry cisplatin doxorubicinand two different siRNAs targeted to MRP1 and Bcl-2Moreover it was surface decorated with luteinizing hor-mone releasing hormone (LHRH) peptide for targeted lungcancer therapy The nanoparticle system carrying siRNAinhibited targeted mRNA causing suppression of cellu-lar resistance to the chemotherapeutics accomplishing anenhanced therapeutic efficacy of cisplatin and doxorubicinMSNs were also explored in targeted EGFR-based therapiesMSNsmodifiedwith the cationic polymer polyethyleneimine(PEI) and surface attached with EGFR ligands selectivelytargeted EGFR overexpressing NSCLC cells [71] Moreoverthese nanoparticles when loaded with the anticancer agentpyrrolidine-2 had enhanced targeting and therapeutic effi-ciencies compared to free drug in a subcutaneous lung cancermodel

3 Challenges for Nanoparticle-Based DrugDelivery in Lung Cancer Therapy

Thepast decade has witnessed tremendous growth and devel-opment of drug delivery technology utilizing nanoparticlesystems It is expected that the ongoing research effortsin nanomedicine will continue to lead towards safe effi-cient and feasible drug delivery and highly sensitive andimproved imaging agents for diagnostic and diseasemonitor-ing applications However nanomedicine research is facingnumerous challenges in bridging rapidly developing novelideas and translating them into clinical practice Synthesizingnanoparticle drug delivery systems has always been com-plicated by designing an appropriate size to carry effectivedruggene payload and ability to target to the right placeInappropriate size distribution undefined structureshapepoor biocompatibility and improper surface chemistry arepossible risk factors in the biological environment It hasbeen operose to devise the ideal nanoparticle system fordrug delivery to the lungs due to the variability in thephysicochemical properties and biological behavior of theparticles A number of obstacles including immune reactionrate of clearance from circulation efficiency in targetingand ability to cross biological barriers will follow whenthese nanoparticle systems enter the preclinical and clinicaltesting arenas Having a solid understanding of the biologicalbehavior of nanoparticles is imperative to achieve the highestdrug delivery efficiency

Identification of Physicochemical parameters are abso-lutely critical in determining the particle-particle interactionwithin a biological environment aggregation tendenciesadsorption of proteins on nanoparticle surface and intracel-lular trafficking of nanoparticles A substantial variation inany of these factors can contribute to poor drug delivery lossof therapeutic efficiency andor toxicity Thus the efficacy-toxicity balance of nanoparticle systems largely dependson their physicochemical properties Particles larger than500 nmare not recommended for intravenous administrationsince these particles are rapidly eliminated from the cir-culation The ideal nanoparticle for delivering conventionaltherapeutics to solid tumors is less than 200 nm in size witha spherical shape and a smooth texture in order to easilytransport through tumor vasculature and into tumor cellsSuch physical characteristics are likely advantageous to thenanoparticles in exploiting the enhanced permeation andretention (EPR) effect associated with solid tumors Passivelytargeted nanoparticles enter through leaky vasculature ofthe solid tumors and are retained in the tumor tissue forextended periods of time due to impaired lymphatic flowThis unique microphysiology of tumors is exploited bymany FDA-approved nanoformulations such as Doxil andAbraxane In solid tumors such as lung cancer the EPReffect plays an important role in determining the efficacyof the nanoparticle-based drug delivery system [72] Thepresence of a highly fenestrated blood vasculature in thetumor facilitates the EPR effect allowing the enhancedentry of colloidal nanoparticles into the tumor (Figure 2)Additionally the poor lymphatic flow in the tumor tissueadds to this effect and results in enhanced retention of


Nanoparticle

Blood flow

Lymph flow

Normal tissue

Tumor cell

Normal tissue

Figure 2 A schematic representation of the EPR effect The leakyvasculature and dysfunctional lymphatics of solid tumors allow thepreferential accumulation and retention of colloidal nanoparticlesin contrast to the tight vasculature of normal tissue which excludesnanoparticles

nanoparticles within the tumor site In contrast to tumortissues the blood vasculature in normal tissues is intact andless permeable attenuating the uptake of nanoparticles bynormal tissues Furthermore the size shape and surfaceproperties of nanoparticles are critically important for passivetargeting of solid tumors The EPR effect usually applies toparticles that are less than 200 nm in size However particlesless than 50 nm in size frequently undergo extravasationfrom the tumor through the fenestrations and are thusless likely to be retained in the tumor tissue for extendedperiods of time Moreover active targeting of nanoparticlesis accomplished by decorating the surface of the nanoparticlewith specific ligands to promote the binding and interactionwith overexpressed protein receptors on cancer cell surfacesThis approach leads to preferential binding uptake andintracellular accumulation of the drug or gene in the targetedcells However the overall tumor accumulation and ther-apeutic effect of targeted nanoparticles may be principallycontrolled by the EPR effect [73]

Fabrication of polymeric nanoparticles with uniformand sub-200 nm size requires critical control over eachand every step in the synthesis procedure which is alwayschallenging The size distribution of liposomes or vesicularnanoparticles can be narrowed using common extrusionprocedures However burst release of the drug and poorstability layer additional challenges in the development ofsuch nanoparticles

Surface charge determines the fate of nanoparticles invivo Particle-particle interactions and aggregation tend-encies are largely dependent on the zeta potential ofthe nanoparticles Positively charged nanoparticles havean increased affinity for the negatively charged cellularmembranes of all cells in the body Most nanoparti-cles designed for gene delivery applications use positivelycharged polymers or lipids to achieve enhanced DNA to

nanoparticle interaction Unfortunately some cationic na-noparticles have enhanced hemolytic properties incitingconcern for their safe use in gene delivery For examplecationic lipid composition of N [1-(23-dioleyloxy) propyl]-NNN-trimethylammonium chloride and dioleoylphosphat-idylethanolamine (DOTMADOPE) are reported to behighly hemolytic while 3 beta-[N-(N1015840N1015840-dimethylaminoet-hane)-carbamoyl]-cholesterol (DC-chol)DOPE liposomesare moderately hemolytic [74]

Biocompatible polymer nanoparticles are an alternativeto cationic lipids for the charge-specific delivery of drugsandor genes However little is known in lung tumor modelsabout the effect of surface charge on biodistribution ofnanoparticles PEGylation is routinely used to mask thesurface charge effectively camouflaging the nanoparticle fromopsonin proteins and significantly extending the half-life ofthe nanoparticle in the circulation Another important issuein drug delivery is nanoparticle stability Poor stability ofnanoparticle systems has been attributed to their aggregationtendencies in the physiological environment Once aggre-gated it is virtually impossible to redisperse the particles intotheir original distribution pattern While shear forces can beused to redisperse the particles this may lead to enhanceddrug leaching from the particles andultimately affect the drugloading and therapeutic efficiencies

Additionally further consideration must be given to thecomplexity of nanoparticles and how thismay have a negativeimpact on drug delivery Multifunctional nanoparticles arehot topics in the field of nanomedicine [75] A nanoparticlewith a large number of surface functional groups provides anavenue for the attachment of multiple kinds of biomoleculesfor targeted drug delivery and diagnostic applications forlung cancer A careful analysis of these nanoparticle systemshowever is necessary prior to testing in an in vivo systemMultifunctionalization generally increases the complexity ofthe nanoparticle While a large number of multifunctionalnanoparticles such as theranostic systems targeted to lungcancer are under development Aurimune (CYT-6091) is cur-rently the only known multifunctional nanoparticle systemwith diagnostic and therapeutic properties that has enteredthe clinical setting [76] Aurimune consists of tumor necrosisfactor (TNF) a tumor growth inhibiting agent bound tocolloidal gold nanoparticles for simultaneous imaging andtherapy

Interestingly increased scientific contributions to thefield of nanomedicine have resulted in the emergence ofa new area of research nanotoxicology [77] Even thoughnanoparticles of various compositions have displayed strongtherapeutic properties towards various types of cancer inpreclinical studies they also carry the risk of inducing toxicityto normal cells Emphases in particular towards inorganic-and metal-based nanoparticles have demonstrated that somenanoparticles induce toxicity to normal cells For exam-ple silica nanoparticles in their amorphous state have thepotential to cause inflammatory reactions on target organsresulting in apoptotic cell death [78] Thus the use of silica-based nanoparticles for cancer therapy is limited to low con-centrations (01mgmL) in vitro [78]The toxicity of titaniumoxide (TiO

2) nanoparticles towards healthy cells is also a


matter of concern considering its biological applications [79]Carbon nanotubes (CNTs) have also been reported to exhibittoxicity to normal cells CNTs upon interaction with livecells generate reactive oxygen species causing mitochondrialdysfunction and lipid peroxidation [80] Therefore stringentin vitro and in vivo toxicity studies for each of the novelnanoparticle systems must be conducted to ensure safetyprior to their application in humans

4 Conclusion and Future Perspectives

Nanoparticle-based medicine has infinite potential withnovel applications continuously being developed for use incancer diagnosis detection imaging and treatment Thesesystems are already helping to address key issues withtraditional anticancer agents such as nonspecific targetinglow therapeutic efficiencies untoward side effects and drugresistance as well as surpassing their predecessors with theability to detect early metastasis The ability of nanoparticlesto be tailored for a personalized medicine strategy makesthem ideal vehicles for the treatment of lung cancer Numer-ous nanoparticle-based experimental therapeutics for lungcancer utilize a combinatorial approach balancing the designwith targeting and tracking moieties and anticancer agentsIn general nanoparticles with multicomponent structuresallow design flexibility in drug delivery of poorly watersolublemolecules as well as imparting the ability to overcomebiological barriers and selectively target desired sites withinthe body

However many challenges must be overcome in orderto expedite the translation of nanoparticle-based therapiesfrom the bench to the bedside Nanomedicines are three-dimensional structures of multiple components with pre-ferred spatial arrangement to impart their function Subtlechanges in the synthesis process or composition of thecomplex that alter the physical andor chemical proper-ties can have adverse effects resulting in pharmacologicaland immunological challenges Pharmacokinetics (PK) andbiodistribution are known to be effected by small composi-tional differences in nanoparticles [81] Moreover nanoparti-cles oftentimes require higher bioavailability than traditionalsmall molecules since they are routinely designed for novelroutes of delivery such as by nasal or oral administrationIn vivo clearance of nanoparticles and release kinetics ofthe active drug are also complicated by their physical andchemical properties PEGylation is oftentimes used to maskthe nanoparticle to evade detection by macrophages andavoid opsonization and destruction This strategy effectivelyincreases the circulation time enhancing the distribution andaccumulation of nanoparticles at the intended target siteUltimately small molecules are cleared by the kidney whilelarger particles are cleared by Kupffer cells and macrophagesin the liver and spleen [82] Researches are also challengedwith nanoparticle induced immune responses which canbe elicited by the nanocarrier the payload or both [83]These findings enumerate the importance for identifying keycharacteristics of each component and developing a thoroughunderstanding of the physicochemical properties to ensure

high reproducibility throughout the formulation process andminimize pharmacological and immunological challenges

Aside from the difficulty of nanoparticle design anddiscovery scientists must also battle the lack of standards inthe examination of nanomedicines including manufactur-ing processes functional testing and safety measurementsConceptually nanoparticle-based therapy must overcomethe same hurdles faced by any new drug optimal designof components and properties reproducible manufacturingprocesses institution of analysis methods for sufficient char-acterization favorable pharmacology and toxicity profilesand demonstration of safety and efficacy in clinical trialsStandard drugs are usually composed of a single active agentNanoparticles are complex in nature with multiple activecomponents that can affect the pharmacological behaviorSuch complexity necessitates the modification of standardtesting of pharmacokinetic bioequivalence and safety mea-surements There is an immediate need for regulatory agen-cies to develop an exhaustive list of tests and a streamlinedapproval process to proactively address the emergence ofnew products based on new technologies and facilitatenanomedicine delivery to the clinic

References

[1] S S Ramalingam T K Owonikoko and F R Khuri ldquoLung can-cer new biological insights and recent therapeutic advancesrdquoCA Cancer Journal for Clinicians vol 61 no 2 pp 91ndash112 2011

[2] L C Pronk G Stoter and J Verweij ldquoDocetaxel (Taxotere)single agent activity development of combination treatmentand reducing side-effectsrdquo Cancer Treatment Reviews vol 21no 5 pp 463ndash478 1995

[3] J Lu M Liong J I Zink and F Tamanoi ldquoMesoporous silicananoparticles as a delivery system for hydrophobic anticancerdrugsrdquo Small vol 3 no 8 pp 1341ndash1346 2007

[4] A Kumar S K Sahoo K Padhee et al ldquoReview on solubilityenhancement techniques for hydrophobic drugsrdquo InternationalJournal of Comprehensive Pharmacy vol 3 no 3 pp 1ndash7 2011

[5] P Agostinis K Berg KA Cengel et al ldquoPhotodynamic therapyof cancer an updaterdquo CA Cancer Journal for Clinicians vol 61no 4 pp 250ndash281 2011

[6] A Babu J Periasamy A Gunasekaran et al ldquoPolyethy-lene glycol-modified gelatinpolylactic acid nanoparticles forenhanced photodynamic efficacy of a hypocrellin derivative invitrordquo Journal of Biomedical Nanotechnology vol 9 no 2 pp177ndash192 2013

[7] M Dougan and G Dranoff ldquoImmune therapy for cancerrdquoAnnual Review of Immunology vol 27 pp 83ndash117 2009

[8] M A Kay ldquoState-of-the-art gene-based therapies the roadaheadrdquoNature Reviews Genetics vol 12 no 5 pp 316ndash328 2011

[9] M Giacca and S Zacchigna ldquoVirus-mediated gene delivery forhuman gene therapyrdquo Journal of Controlled Release vol 161 no2 pp 377ndash388 2012

[10] S Nayak and R W Herzog ldquoProgress and prospects immuneresponses to viral vectorsrdquo GeneTherapy vol 17 no 3 pp 295ndash304 2010

[11] J H Grossman and S E McNeil ldquoNanotechnology in cancermedicinerdquo Physics Today vol 65 pp 38ndash42 2012


[12] A Z Wang R Langer and O C Farokhzad ldquoNanoparticledelivery of cancer drugsrdquo Annual Review of Medicine vol 63pp 185ndash198 2012

[13] K Ahmad ldquoGene delivery by nanoparticles offers cancer hoperdquoThe Lancet Oncology vol 3 no 8 p 451 2002

[14] R Ramesh ldquoNanoparticle-mediated gene delivery to the lungrdquoMethods in Molecular Biology vol 434 pp 301ndash331 2008

[15] D Yuan Y Lv Y Yao et al ldquoEfficacy and safety of Abraxanein treatment of progressive and recurrent non-small cell lungcancer patients a retrospective clinical studyrdquoThoracic Cancervol 3 no 4 pp 341ndash347 2012

[16] R M Schiffelers J M Metselaar M H A M Fens A P CA Janssen G Molema and G Storm ldquoLiposome-encapsulatedprednisolone phosphate inhibits growth of established tumorsin micerdquo Neoplasia vol 7 no 2 pp 118ndash127 2005

[17] S Simoes A Filipe H Faneca et al ldquoCationic liposomes forgene deliveryrdquo Expert Opinion on Drug Delivery vol 2 no 2pp 237ndash254 2005

[18] M Adamina U Guller L Bracci M Heberer G C Spagnoliand R Schumacher ldquoClinical applications of virosomes incancer immunotherapyrdquo Expert Opinion on Biological Therapyvol 6 no 11 pp 1113ndash1121 2006

[19] L H Lindner M E Eichhorn H Eibl et al ldquoNoveltemperature-sensitive liposomes with prolonged circulationtimerdquo Clinical Cancer Research vol 10 no 6 pp 2168ndash21782004

[20] L Krishnan L Deschatelets F C Stark K Gurnani and G DSprott ldquoArchaeosome adjuvant overcomes tolerance to tumor-associated melanoma antigens inducing protective CD8+ T cellresponsesrdquo Clinical and Developmental Immunology vol 2010Article ID 578432 13 pages 2010

[21] X Yao K Panichpisal N Kurtzman and K Nugent ldquoCisplatinnephrotoxicity a reviewrdquo American Journal of the MedicalSciences vol 334 no 2 pp 115ndash124 2007

[22] T Boulikas ldquoLow toxicity and anticancer activity of a novelliposomal cisplatin (Lipoplatin) inmouse xenograftsrdquoOncologyReports vol 12 no 1 pp 3ndash12 2004

[23] P Devarajan R Tarabishi J Mishra et al ldquoLow renal toxicityof lipoplatin compared to cisplatin in animalsrdquo AnticancerResearch vol 24 no 4 pp 2193ndash2200 2004

[24] ldquoLiposomal cisplatin (Nanoplatin) for advanced non-smallcell lung cancermdashfirst line (2012)rdquo httpwwwhscnihracuktopicsliposomal-cisplatin-nanoplatin-for-advanced-non-sm

[25] X Wang J Zhou Y Wang et al ldquoA phase I clinical andpharmacokinetic study of paclitaxel liposome infused in non-small cell lung cancer patientswithmalignant pleural effusionsrdquoEuropean Journal of Cancer vol 46 no 8 pp 1474ndash1480 2010

[26] J Zhou W Y Zhao X Ma et al ldquoThe anticancer efficacyof paclitaxel liposomes modified with mitochondrial targetingconjugate in resistant lung cancerrdquo Biomaterials vol 34 no 14pp 3626ndash3638 2013

[27] S Koudelka and J Turanek ldquoLiposomal paclitaxel formula-tionsrdquo Journal of Control Release vol 163 no 3 pp 322ndash3342012

[28] G P Stathopoulos D Antoniou J Dimitroulis et al ldquoLipo-somal cisplatin combined with paclitaxel versus cisplatin andpaclitaxel in non-small-cell lung cancer a randomized phase IIImulticenter trialrdquo Annals of Oncology vol 21 no 11 pp 2227ndash2232 2010

[29] S North and C Butts ldquoVaccination with BLP25 liposomevaccine to treat non-small cell lung andprostate cancersrdquoExpertReview of Vaccines vol 4 no 3 pp 249ndash257 2005

[30] G T Wurz A M Gutierrez B E Greenberg et al ldquoAntitumoreffects of L-BLP25 Antigen-Specific tumor immunotherapy ina novel human MUC1 transgenic lung cancer mouse modelrdquoJournal of Translational Medicine vol 11 no 1 pp 64ndash77 2013

[31] Y-LWu K Park R A Soo et al ldquoINSPIRE a phase III study ofthe BLP25 liposome vaccine (L-BLP25) in Asian patients withunresectable stage III non-small cell lung cancerrdquo BMC Cancervol 11 article 430 2011

[32] C Lu D J Stewart J J Lee et al ldquoPhase I clinical trial ofsystemically administered TUSC2(FUS1)-nanoparticles medi-ating functional gene transfer in humansrdquo Plos One vol 7 no4 Article ID e34833 2012

[33] S H Choi S-E Jin M-K Lee et al ldquoNovel cationic solid lipidnanoparticles enhanced p53 gene transfer to lung cancer cellsrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol68 no 3 pp 545ndash554 2008

[34] K H Bae J Y Lee S H Lee T G Park and Y S Nam ldquoOpti-cally traceable solid lipid nanoparticles loaded with siRNA andpaclitaxel for synergistic chemotherapy with in situ imagingrdquoAdvanced Healthcare Materials vol 2 no 4 pp 576ndash584 2013

[35] A ZWang K Yuet L Zhang et al ldquoChemoRad nanoparticlesa novel multifunctional nanoparticle platform for targeteddelivery of concurrent chemoradiationrdquo Nanomedicine vol 5no 3 pp 361ndash368 2010

[36] J Jung S J Park H K Chung et al ldquoPolymeric nanoparticlescontaining taxanes enhance chemoradiotherapeutic efficacy innon-small cell lung cancerrdquo International Journal of RadiationOncololgy Biology Physics vol 84 pp e77ndashe83 2012

[37] D-W Kim S-Y Kim H-K Kim et al ldquoMulticenter phaseII trial of Genexol-PM a novel Cremophor-free polymericmicelle formulation of paclitaxel with cisplatin in patients withadvanced non-small-cell lung cancerrdquo Annals of Oncology vol18 no 12 pp 2009ndash2014 2007

[38] ldquoA Phase II Trial of Genexol-PM and Gemcitabine in PatientsWith Advanced Non-small-cell Lung Cancerrdquo 2013 httpclinicaltrialsgovshowNCT01770795

[39] L Jiang X Li L Liu and Q Zhang ldquoThiolated chitosan-modified PLA-PCL-TPGS nanoparticles for oral chemotherapyof lung cancerrdquo Nanoscale Research Letters vol 8 no 1 p 662013

[40] T Zhao H Chen L Yang et al ldquoDDAB-modified TPGS-b-(PCL-ran-PGA) Nanoparticles as oral anticancer drug carrierfor lung cancer chemotherapyrdquo Nano vol 8 no 2 Article ID1350014 10 pages 2013

[41] A Mehrotra R C Nagarwal and J K Pandit ldquoLomustineloaded chitosan nanoparticles characterization and in-vitrocytotoxicity on human lung cancer cell line L132rdquo Chemical andPharmaceutical Bulletin vol 59 no 3 pp 315ndash320 2011

[42] R Liu O V Khullar A P Griset et al ldquoThe pax-eNP placed atthe time of surgical resection delayed local tumor recurrenceand modestly prolonged survival in a murine Lewis lungcarcinoma recurrencemodelrdquoAnnals ofThoracic Surger vol 91no 4 pp 1077ndash1083 2011

[43] R Yang S-G YangW-S Shim et al ldquoLung-specific delivery ofpaclitaxel by chitosan-modified PLGA nanoparticles via tran-sient formation of microaggregatesrdquo Journal of PharmaceuticalSciences vol 98 no 3 pp 970ndash984 2009

[44] K Tahara H Yamamoto N Hirashima and Y KawashimaldquoChitosan-modified poly(dl-lactide-co-glycolide) nanospheresfor improving siRNA delivery and gene-silencing effectsrdquo Euro-pean Journal of Pharmaceutics andBiopharmaceutics vol 74 no3 pp 421ndash426 2010


[45] C-L Tseng T-W Wang G-C Dong et al ldquoDevelopment ofgelatin nanoparticles with biotinylated EGF conjugation forlung cancer targetingrdquo Biomaterials vol 28 no 27 pp 3996ndash4005 2007

[46] C-L Tseng W-Y Su K-C Yen K-C Yang and F-H LinldquoThe use of biotinylated-EGF-modified gelatin nanoparticlecarrier to enhance cisplatin accumulation in cancerous lungs viainhalationrdquo Biomaterials vol 30 no 20 pp 3476ndash3485 2009

[47] S Karthikeyan N R Prasad A Ganamani and E Bala-murugan ldquoAnticancer activity of resveratrol-loaded gelatinnanoparticles on NCI-H460 non-small cell lung cancer cellsrdquoBiomedicine and Preventve Nutrition vol 3 no 1 pp 64ndash732013

[48] J Liu J Liu L Chu et al ldquoNovel peptide-dendrimer conjugatesas drug carriers for targeting nonsmall cell lung cancerrdquoInternational Journal of Nanomedicine vol 6 no 1 pp 59ndash692010

[49] G M Ryan L M Kaminskas B D Kelly D J Owen M PMcIntosh and C J H Porter ldquoPulmonary administration ofPEGylated polylysine dendrimers absorption from the lungversus retention within the lung is highly size-dependentrdquoMolecular Pharmaceutics vol 10 no 8 pp 2986ndash2995 2013

[50] ldquoDendrimers improve anticancer efficacy in lung metastasismodelrdquo 2013 httpwwwstarpharmacomnews150


[52] W P Su F Y Cheng D B Shieh C S Yeh andW C Su ldquoPLGAnanoparticles codeliver paclitaxel and Stat3 siRNA to overcomecellular resistance in lung cancer cellsrdquo International Journal ofNanomedicine vol 7 pp 4269ndash4283 2012

[53] N Karra T Nassar A N Ripin et al ldquoAntibody conjugatedPLGA nanoparticles for targeted delivery of paclitaxel palmi-tate efficacy and biofate in a lung cancer mouse modelrdquo Small2013

[54] J Conde G Doria and P Baptista ldquoNoble metal nanoparticlesapplications in cancerrdquo Journal of Drug Delivery vol 2012Article ID 751075 12 pages 2012

[55] G Peng U Tisch O Adams et al ldquoDiagnosing lung cancer inexhaled breath using gold nanoparticlesrdquo Nature Nanotechnol-ogy vol 4 no 10 pp 669ndash673 2009

[56] J-A A Ho H-C Chang N-Y Shih et al ldquoDiagnostic detec-tion of human lung cancer-associated antigen using a goldnanoparticle-based electrochemical immunosensorrdquoAnalyticalChemistry vol 82 no 14 pp 5944ndash5950 2010

[57] O Barash N Peled U Tisch P A Bunn Jr F R Hirschand H Haick ldquoClassification of lung cancer histology by goldnanoparticle sensorsrdquo Nanomedicine Nanotechnology Biologyand Medicine vol 8 no 5 pp 580ndash589 2012

[58] Y-H Chen C-Y Tsai P-Y Huang et al ldquoMethotrexateconjugated to gold nanoparticles inhibits tumor growth in asyngeneic lung tumor modelrdquoMolecular Pharmaceutics vol 4no 5 pp 713ndash722 2007

[59] T Yokoyama J Tam S Kuroda et al ldquoEgfr-targeted hybrid plas-monicmagnetic nanoparticles synergistically induce autophagyand apoptosis in non-small cell lung cancer cellsrdquo PLoS ONEvol 6 no 11 Article ID e25507 2011

[60] L L Ma J O Tam B W Willsey et al ldquoSelective targeting ofantibody conjugated multifunctional nanoclusters (nanoroses)to epidermal growth factor receptors in cancer cellsrdquo Langmuirvol 27 no 12 pp 7681ndash7690 2011

[61] B Lkhagvadulam J H Kim I Yoon and Y K Shim ldquoSize-dependent photodynamic activity of gold nanoparticles con-jugate of water soluble purpurin-18-N-methyl-D-glucaminerdquoBioMed Research International vol 2013 Article ID 720579 10pages 2013

[62] R Govender A Phulukdaree R M Gengan K Anand and AA Chuturgoon ldquoSilver nanoparticles of Albizia adianthifoliathe induction of apoptosis in human lung carcinoma cell linerdquoJournal of Nanobiotechnology vol 11 no 5 pp 1477ndash3155 2013

[63] W G Zhou andWWang ldquoSynthesis of silver nanoparticles andtheir antiproliferationrdquo The Oriental Journal of Chemistry vol28 no 2 pp 651ndash655 2012

[64] R Foldbjerg D A Dang and H Autrup ldquoCytotoxicity andgenotoxicity of silver nanoparticles in the human lung cancercell line A549rdquo Archives of Toxicology vol 85 no 7 pp 743ndash750 2011

[65] T Sadhukha T S Wiedmann and J Panyam ldquoInhalable mag-netic nanoparticles for targeted hyperthermia in lung cancertherapyrdquo Biomaterials vol 34 no 21 pp 5163ndash5171 2013

[66] Y Wang Y Zhang Z Du M Wu and G Zhang ldquoDetectionof micrometastases in lung cancer with magnetic nanoparticlesand quantum dotsrdquo International Journal of Nanomedicine vol7 pp 2315ndash2324 2012

[67] K Li B Chen L Xu et al ldquoReversal of multidrug resistance bycisplatin-loaded magnetic Fe

3O4nanoparticles in A549DDP

lung cancer cells in vitro and in vivordquo International Journal ofNanomedicine vol 8 pp 1867ndash1877 2013

[68] W Sun N Fang B G Trewyn et al ldquoEndocytosis of asinglemesoporous silica nanoparticle into a human lung cancercell observed by differential interference contrast microscopyrdquoAnalytical and Bioanalytical Chemistry vol 391 no 6 pp 2119ndash2125 2008

[69] A J Di Pasqua M L Miller X Lu L Peng and MJay ldquoTumor accumulation of neutron-activatable holmium-containing mesoporous silica nanoparticles in an orthotopicnon-small cell lung cancerrdquo Inorgica Chimca Acta vol 393 no1 pp 334ndash336 2012

[70] O Taratula O B Garbuzenko A M Chen and T MinkoldquoInnovative strategy for treatment of lung cancer targetednanotechnology-based inhalation co-delivery of anticancerdrugs and siRNArdquo Journal of Drug Targeting vol 19 no 10 pp900ndash914 2011

[71] S Sundarraj ldquoEGFR antibody conjugated mesoporous silicananoparticles for cytosolic phospholipase A2120572 targeted nons-mall lung cancer therapyrdquo Journal of Cell Science and Therapyvol 3 no 7 2012

[72] 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

[73] N Dinauer S Balthasar C Weber J Kreuter K Langer andH Von Briesen ldquoSelective targeting of antibody-conjugatednanoparticles to leukemic cells and primary T-lymphocytesrdquoBiomaterials vol 26 no 29 pp 5898ndash5906 2005

[74] H Schreier L Gagne T Bock et al ldquoPhysicochemical proper-ties and in vitro toxicity of cationic liposome cDNA complexesrdquoPharmaceutica Acta Helvetiae vol 72 no 4 pp 215ndash223 1997

[75] G Bao S Mitragotri and S Tong ldquoMultifunctional nanoparti-cles for drug delivery and molecular imagingrdquo Annual Reviewof Biomedical Engineering vol 15 pp 253ndash282 2013

[76] R Wang P S Billone and W M Mullet ldquoNanomedicine inaction an overview of cancer nanomedicine on the market and


in clinical trialsrdquo Journal of Nanomaterials vol 2013 Article ID629681 12 pages 2013

[77] A F Hubbs R R Mercer S A Benkovic et al ldquoNanotoxicol-ogymdasha pathologistrsquos perspectiverdquo Toxicologic Pathology vol 39no 2 pp 301ndash324 2011

[78] J McCarthy I Inkielewicz-Stepmiak J J Corbalan and MW Radomski ldquoMechanisms of toxicity of amorphous silicananoparticles on human using submucosal cells in vitro pro-tective effects of fisetinrdquo Chemical Research in Toxicology vol25 no 10 pp 2227ndash2235 2012

[79] B Trouiller R Reliene A Westbrook P Solaimani and R HSchiestl ldquoTitanium dioxide nanoparticles induce DNA damageand genetic instability in vivo in micerdquo Cancer Research vol 69no 22 pp 8784ndash8789 2009

[80] A Make L Wang and Y Rojanasakul ldquoMechanisms of nano-particle-induced oxidative stress and toxicityrdquo BioMed ResearchInternational vol 2013 Article ID 942916 15 pages 2013

[81] D F Emerich and C G Thanos ldquoThe pinpoint promise ofnanoparticle-based drug delivery and molecular diagnosisrdquoBiomolecular Engineering vol 23 no 4 pp 171ndash184 2006

[82] S M Moghimi A C Hunter and J C Murray ldquoLong-circulating and target-specific nanoparticles theory to prac-ticerdquo Pharmacological Reviews vol 53 no 2 pp 283ndash318 2001

[83] M A Dobrovolskaia P Aggarwal J B Hall and S E McNeilldquoPreclinical studies to understand nanoparticle interactionwiththe immune system and its potential effects on nanoparticlebiodistributionrdquoMolecular Pharmaceutics vol 5 no 4 pp 487ndash495 2008

Submit your manuscripts athttpwwwhindawicom

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Polymer ScienceInternational Journal of



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CompositesJournal of

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Biomaterials


NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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CrystallographyJournal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


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Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Nano

materials


Journal ofNanomaterials


to the drug combination resulting in cessation of treatment[2] Additionally the hydrophobic nature of the majorityof the cancer chemotherapeutics makes them poorly watersoluble and therefore limits their administration at high doses[3 4] Thus methods to improve tumor-targeted delivery ofchemotherapeutics that will result in increased drug efficacywith improved pharmacological properties and minimaltoxicity to normal tissues remain a priority in cancer therapy

Experimental therapies such as photodynamic therapy(PDT) immunotherapy and gene therapy provide promisingtools to fight lung cancer In PDT a photosensitizer activatedby laser light reacts with molecular oxygen to form reactiveoxygen species that function to annihilate cancer cells [5]PDT is often used in combination with chemotherapy orsurgery Porfimer sodium a first-generation photosensitizerhas been used in the treatment of early as well as advancedlung carcinomasMore improved and efficient PDTagents arecurrently available as a result of the extensive research effortsin the last two decades However many of these photosen-sitizers are poorly water soluble fettering their intravenousadministration [6]

Immunotherapy harnesses the bodyrsquos immune system tofight cancer Biomolecules or antigens are administered toeither trigger the immune system or reduce the immunesuppressing activities of the tumor [7] Administration ofimmunologically active agents disrupts the tumorigeniccascades by directly blocking growth factors or hormonesand their receptors Certain cancers including lung canceroverexpress growth factor receptors such as the epider-mal growth factor receptor (EGFRHer1) Binding of theligand epidermal growth factor (EGF) to EGFR activatescell proliferation and survival signaling pathways resultingin rapid and uncontrolled tumor growth Cetuximab acompetitive anti-EGFR monoclonal antibody counteractsthe cell proliferation signaling mediated by the endogenousEGF ligand culminating in attenuation of the cell survivalsignals and induction of tumor cell death Gene therapy is arelatively new concept with a large number of research teamsworldwide in active pursuit of identifying and deliveringcancer-suppressing genes for clinical applications [8] Deliv-ery vectors are a necessity in order to protect the therapeuticgenes until they reach their target site Historically viralvectors have been used to deliver gene-based therapeutics[9] however viral vector induced host immune responseslimits their therapeutic potential [10] Definitively there is agrowing need for development of safe and efficient deliveryvehicles for photosensitizers chemotherapeutics and tumorsuppressor genes

Nanotechnology is not pervaded by some of the lim-itations of viral vectors providing an avenue of incrediblepotential for development of tumor-targeting drug deliverysystems This continuously expanding niche will revolution-ize cancer treatment and management [11] More preciselynanoscale drug delivery systems hold great promise in suc-cessfully formulating and enhancing the therapeutic efficacyof a large number of anticancer agents [12] Nanoparticlesare known to positively alter biodistribution increasing ther-apeutic efficiency and reducing nonspecific toxicity of potentanticancer drugs Their superior biocompatibility ability to

protect nucleic acids from degradation and ability to delivertherapeutic genes to cancer cells in vivo make nanoparticlesthe ideal delivery vehicle [13 14] While many nanoparticle-based therapies have been developed such as Abraxane analbumin-bound paclitaxel nanoformulation for the treatmentof metastatic NSCLC [15] few have been translated intoclinical success It continues to be a challenge to identify idealdrug delivery systems for several classes of novel drugs withdifferent physicochemical characteristics and varying degreesof therapeutic activities in the physiological environmentThis review summarizes current progress and challengesin nanoparticle-based drug delivery systems citing recentexamples of applying nanomedicine for lung cancer treat-ment

2 Progress in Nanoparticle DrugGeneDelivery Systems

21 Lipid-Based Nanocarriers Liposomes oil dispersions(micelles) and lipid nanoparticles are the major classesof lipid-based nanocarriers for drug and gene deliveryapplications Liposomes are bilayered phospholipid vesiclescommonly used to deliver hydrophobic and hydrophilicdrugs through either incorporation in the lipid bilayer itselfor encapsulation in the inner aqueous core respectivelyReduction of the number of lipid bilayers reduces the size ofthe liposomes to nanosize increasing the circulation time andtumor localization properties of encapsulated drugs [16]

Liposomes are becoming increasingly more populardelivery vehicles for anticancer therapeutics due to theirstrong biocompatibility properties Over the last decadethe liposomal research field has boomed generating manynew liposomal formulations such as cationic liposomes [17]virosomes [18] temperature-sensitive liposomes [19] andarchaeosomes [20] Despite these huge advances at thebench currently there are only two FDA-approved liposomalformulations DOXIL a liposomal doxorubicin injection forovarian cancer andMarqibo a liposomal vincristine sulphateinjection for lymphoblastic leukemia

In lung cancer treatment liposomes may be a promisingdelivery system for drugs and genes The drug of choice forthe treatment of NSCLC for the last two decades cisplatinis implicated in the development of nephrotoxicity in 20of patients receiving high doses [21] In 2004 Boulikasdeveloped a liposome-based cisplatin drug called Lipoplatinto reduce systemic toxicity of cisplatin [22] Furthermorethese researchers also demonstrated that lipoplatin injectioncompared to standard therapy significantly reduced nephro-toxicity to negligible levels in multiple rat tumor models[23] According to a recent report lipoplatin is anticipated tocomplete phase III clinical trial testing in 2013 and 2014 [24]Paclitaxel another chemotherapeutic drug widely used in thetreatment of lung cancer was historically formulated usingCremophore EL to enhance its solubility in physiologicalfluids However this resulted in hypersensitivity reactionscomplicating its systemic delivery In 2010 a phase I clinicaltrial in NSCLC patients with malignant pleural effusionsdemonstrated in all cases investigated that treatment with


















II Completed



























Nanoparticle

Blood flow

Lymph flow

Normal tissue

Tumor cell

Normal tissue

















References

































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




















II Completed



























Nanoparticle

Blood flow

Lymph flow

Normal tissue

Tumor cell

Normal tissue

















References

































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials












II Completed



























Nanoparticle

Blood flow

Lymph flow

Normal tissue

Tumor cell

Normal tissue

















References

































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




















Nanoparticle

Blood flow

Lymph flow

Normal tissue

Tumor cell

Normal tissue

















References

































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials











Nanoparticle

Blood flow

Lymph flow

Normal tissue

Tumor cell

Normal tissue

















References

































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Nanoparticle

Blood flow

Lymph flow

Normal tissue

Tumor cell

Normal tissue

















References

































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials










References

































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials
























































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials






















































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



















CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials










CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



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Category:	Documents
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Review Article Nanoparticle-Based Drug Delivery...

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