Background and Introduction Cancer Development of abnormal cells that divide uncontrollably which have the ability to infiltrate and destroy normal body tissue Chemotherapy Use of anti-cancer (cytotoxic) drugs to destroy cancer cells. Work by disrupting the growth of cancer cells Nonspecificity Toxicity Adverse side effects Poor solubility
Cancer Nanotechnology interdisciplinary research, cutting across the disciplines of Biology Chemistry Engineering Physics Medicine Nanoparticles Semiconductor quantum dots (QDs) Ion oxide nanocrystals Carbon nanotubes Polymeric nanoparticles Liposomes Unique Properties Structural Optical Magnetic
• 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 selectivityTissues with a leaky endothelial wall contribute to asignificant uptake of NP. In liver, spleen and bonemarrow, NP uptake is also due to the macrophagesresiding in the tissues.
• In tumors the uptake depends on the so-called enhanced permeability and retention effect (EPR).
Schematic of EPR (enhancedpermeability and retention) effect insolid tumors:1- nanovehicles passively target to vasculatureand extravasate through fenestrated tumorvasculature.2- the extended circulation time (stealthfeatures) allows accumulation in tumor tissue3- lack of lymphatic drainage prevents removalof nanoparticles after extravasationThis passive targeting process facilitates tumortissue binding, followed by drug release for cellkilling.Nanovehicles which fail to bind to tumor cellswill reside in the extracellular (interstitial)space, where they eventually becomedestabilized because of enzymatic andphagocytic attack. This results in extracellulardrug release for eventual diffusion to nearbytumor cells and bystander cell.
In vivo distribution of long-circulating radiolabeled liposomes i.v. injected into C26 tumour-bearing miceLiposomes : DPPC ( a saturated lipid)/ 20%GM1 ganglioside ( a stealth Glycolipid)
Molecular Cancer Imaging (QDs) Tumor Targeting and Imaging Emission wavelengths are size tunable (2 nm-7 nm) 4 High molar extinction coefficients Conjugation with copolymer improves size-tunable optical properties of ZnS-capped CdSe QDs biocompatibility, selectivity and decrease cellular toxicity 5
Correlated Optical and X-Ray ImagingHigh resolution sensitivity in detection of smalltumors 6x-rays provides detailed anatomical locations Polymer-encapsulated QDs No chemical or enzymatic degradations QDs cleared from the body by slow filtrationor excretion out of the body
ANTICANCER DRUG•Passive diffusion •Poorly vascolarized tumor PHYSIOLOGICAL BARRIERS•EPR non cellular based mechanisms region •Acidic enviroments in tumors DRUG DRUG RESISTANCE •Biochemical alterations cellular based mechanisms •Endocytosis/phagocytosis by the cells •Overcome MDR DISTRIBUTION, CLEARANCE OF •Large volume of DRUG distribution •Toxic side-effects on normal cells Controlled tumoral interstitial drug release
TUMOR-TISSUE TARGETINGConventional Nanoparticles Long-circulating Nanoparticles• Size > 100 nm. • Size < 100 nm, “Stealth”, invisible to• Delivery to RES tissues. macrophages.• Rapid effect (0.5-3 hr). • Hydrophylic surface to reduce opsonization (e.g. PEG)• For RES localized tumors (hepatocarcinoma, hepatic • Prolonged half-life in blood compartment. metastasis, non-small cell lung • Selective extravasation in pathological cancer, small cell lung site. cancer, myeloma, lymphoma). • For tumors located outside the RES regions. • Gradually absorbed by lymphatic system.
TUMOR-CELL TARGETING MDR Reversion 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 Brigger et al., 2002
V di uscita V didel farmaco(Attività Pgp) ingresso farmaco Conc intracellulare farmaco Diff di conc farmaco esterno/interno
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 beingtreated with a platinum-based chemotherapy drug.•Women with advanced breast cancer who have an increasedrisk of heart damage from other chemotherapy drugs.• Aids-related Kaposi’s sarcoma .Myocet® , another form of liposomal doxorubicin, is used totreat advanced (metastatic) breast cancer| in combination withanother chemotherapy drug, cyclophosphamide| .
Target: enzimi del rilassamento di DNAInibitori 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 alleestremita’ e sui monomeri.Idrolisi di GTP a GDP disassembla microtubulo. Per la stabilitàservono MAP