Nanotechnology in Cancer Treatment

Background and Introduction Cancer

Development of abnormal cells that divide uncontrollably which have the ability to infiltrate and destroy normal body tissue

Chemotherapy

Nonspecificity Toxicity Adverse side effects Poor solubility

Use of anti-cancer (cytotoxic) drugs to destroy cancer cells.

Work by disrupting the growth of cancer cells

interdisciplinary research, cutting across the disciplines of

Biology Chemistry Engineering Physics Medicine

Cancer Nanotechnology

Semiconductor quantum dots (QDs) Ion oxide nanocrystals Carbon nanotubes Polymeric nanoparticlesLiposomes

Structural Optical Magnetic

Nanoparticles

Unique Properties

• Tumors generally can’t grow beyond 2 mm in size without becoming angiogenic (attracting new capillaries) because difficulty in obtaining oxygen and nutrients.

• Tumors produce angiogenic factors to form new capillary structures.

• Tumors also need to recruit macromolecules from the blood stream to form a new extracellular matrix.

• Permeability-enhancing factors such as VEGF (vascular endothelial growth factor) are secreted to increase the permeability of the tumor blood vessels.

Tissue selectivity

Tissues with a leaky endothelial wall contribute to a significant uptake of NP. In liver, spleen and bone marrow, NP uptake is also due to the macrophages residing in the tissues.

• In tumors the uptake depends on the so-called enhanced permeability and retention effect (EPR).

TUMOR-TISSUE TARGETING

Schematic of EPR (enhanced permeability and retention) effect in solid tumors: 1- nanovehicles passively target to vasculature and extravasate through fenestrated tumor vasculature.

2- the extended circulation time (stealth features) allows accumulation in tumor tissue

3- lack of lymphatic drainage prevents removal of nanoparticles after extravasation

This passive targeting process facilitates tumor tissue binding, followed by drug release for cell killing. Nanovehicles which fail to bind to tumor cells will reside in the extracellular (interstitial) space, where they eventually become destabilized because of enzymatic and phagocytic attack. This results in extracellular drug release for eventual diffusion to nearby tumor cells and bystander cell.

In vivo distribution of long-circulating radiolabeled liposomes i.v. injected into C26 tumour-bearing mice

Liposomes : DPPC ( a saturated lipid)/ 20%GM1 ganglioside ( a stealth Glycolipid)

Targeting tumours vasculature

Vascular targetsVascular endothelial GFVascular cell adhesion moleculeMatrix metalloproteinases

Tumour targetsHuman epidermal receptorTransferrin receptorFolate receptor

Affinity-based targeting of tumors.

Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104

© 2010 Ruoslahti et al.

Saturation of receptors affects the specificity of targeting.

Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104

© 2010 Ruoslahti et al.

Treating tumors with cooperative nanoparticles.

Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104

© 2010 Ruoslahti et al.

Molecular Cancer Imaging (QDs)

Tumor Targeting and Imaging

size-tunable optical properties of ZnS-capped CdSe QDs

Emission wavelengths are size tunable (2 nm-7 nm) 4

High molar extinction coefficients

Conjugation with copolymer improves biocompatibility, selectivity and decrease cellular toxicity 5

Correlated Optical and X-Ray Imaging

High resolution sensitivity in detection of small tumors 6

x-rays provides detailed anatomical locations

Polymer-encapsulated QDs

No chemical or enzymatic degradations

QDs cleared from the body by slow filtration or excretion out of the body

ANTICANCER DRUG

PHYSIOLOGICAL BARRIERSnon cellular based mechanisms

DRUG RESISTANCEcellular based mechanisms

DISTRIBUTION, CLEARANCE OF DRUG

•Poorly vascolarized tumor region•Acidic enviroments in tumors

•Biochemical alterations

•Large volume of distribution•Toxic side-effects on normal cells

DRUG

•Passive diffusion•EPR

•Endocytosis/phagocytosis by the cells•Overcome MDR

Controlled tumoral interstitial drug release

TUMOR-TISSUE TARGETINGConventional Nanoparticles

• Size > 100 nm.• Delivery to RES tissues.• Rapid effect (0.5-3 hr).• For RES localized tumors

(hepatocarcinoma, hepatic metastasis, non-small cell lung cancer, small cell lung cancer, myeloma, lymphoma).

Long-circulating Nanoparticles

• Size < 100 nm, “Stealth”, invisible to macrophages.

• Hydrophylic surface to reduce opsonization (e.g. PEG)

• Prolonged half-life in blood compartment.• Selective extravasation in pathological

site.• For tumors located outside the RES

regions.• Gradually absorbed by lymphatic system.

TUMOR-CELL TARGETINGMDR Reversion

Brigger et al., 2002

A) Free doxorubicin enters into the tumor cells by diffusion but is effluxed by Pgp, resulting in the absence of therapeutic efficacy.

B) Doxorubicin-loaded NPs adhere at the tumor cell membrane where they release their drug content, resulting in microconcentration gradient of doxorubicin at the cell membrane, which could saturate Pgp and reverse MDR

V di uscita del farmaco(Attività Pgp)

Conc intracellulare farmaco

V di ingresso farmaco

Diff di conc farmaco esterno/interno

Zhang et al., 2008

Caelyx® is a form of doxorubicin| that is enclosed in liposomes. It is sometimes known as pegylated doxorubicin hydrochloride (PLDH). It is used to treat:•Advanced ovarian cancer that has come back after being treated with a platinum-based chemotherapy drug.•Women with advanced breast cancer who have an increased risk of heart damage from other chemotherapy drugs.• Aids-related Kaposi’s sarcoma .

Myocet® , another form of liposomal doxorubicin, is used to treat advanced (metastatic) breast cancer| in combination with another chemotherapy drug, cyclophosphamide| .

Alexis et al., 2009

Target: enzimi del rilassamento di DNA

Inibitori delle topoisomerasi

Doxorubicina• Induce complesso ternario DNA-farmaco-Topoisomerasi

(filamenti di DNA rotti legati in 5’ a una tirosina dell’enzima)

• Danneggia il filamento formando radicali liberi-

Target: microtubuliAntimitotici inibizione di assemblaggio

stabilizzazione polimeri.

Microtubuli: polimeri di tubulina: crescita richiede GTP alle estremita’ e sui monomeri.Idrolisi di GTP a GDP disassembla microtubulo. Per la stabilità servono MAP