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Nanotechnology for 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) Iron 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 of NP 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:
EPR, in principle, is based on passive targetingThis 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.
How EPR works
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
In vivo distribution of long-circulating radiolabeled liposomes i.v. injected into C26 tumour-bearing mice
CPILs: DPPC ( a saturated lipid)/ 20%GM1 ganglioside ( a stealth Glycolipid)
DOXORUBICIN pharmacokinetics
Vascular targetsVascular endothelial GFVascular cell adhesion moleculeMatrix metalloproteinases
Affinity-based targeting of tumors.
Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104
© 2010 Ruoslahti et al.
Tumour targetsHuman epidermal receptorTransferrin receptorFolate receptor
Saturation of receptors affects the specificity of targeting.
Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104
Treating tumors with cooperative nanoparticles.
Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104
Targeting stress-related protein, p32, upregulated upon thermal treatment.
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
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
•Passive diffusion•EPR
•Endocytosis/phagocytosis by the cells•Overcome MDR
Controlled tumoral interstitial drug release
DRUG
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
Differenza 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