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NAGAR Credit Seminar (GE 511) 1 Slide 2: 2 FLOW OF PRESENTATION Slide 3: Cancer is a leading cause of death worldwide: it accounted for 7.9 million deaths (around 13% of all deaths) in 2008 Cancer is a term for a large group of different diseases in which cells divide and grow uncontrollably, and invade (metastasis) nearby parts of the body INTRODUCTION The traditional chemotherapy used in cancer has many serious side effects with narrow therapeutic index Because they act by interfering with all rapidly dividing cells Tumor targeting can be achieved by TARGETED THERAPY TARGETED DRUG DELIVERY The side effects can be ameliorated by selectively targeting the cancer cells, sparing the normal cells 3 How to minimize these side effects ??? Slide 4: Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targets which are needed for carcinogenesis and tumor growth. Antibody-mediated signal inhibition 4 TARGETED THERAPY Targeted cancer therapies are more effective than current treatments and less harmful to normal cells. Slide 5: The main categories of targeted therapy are small molecules and monoclonal antibodies are: 5 Contd… Slide 6: 6 How to reduce side effects of existing drugs ??? Slide 7: Passive targeting Active targeting Stimuli responsive drug release Free drug Passive targeting Active targeting Stimli responsive drug release Lammers T et al. Br J Cancer. 2008;99:392 - 397. 7 TARGETED DRUG DELIVERY Advantage of the morphological and physiological differences between tumor and normal tissues Slide 8: Impaired lymphatic drainage Failure of Drug Delivery Systems to drain back into blood from the tumor interstitial fluid (Retention effect) Angiogenesis & Hypervasculature (pore size of 100-780 nm) Drug delivery systems of particle size less than 200 nm have greater tendency to cross tumor vasculature (Enhanced permeability effect) Matthew RD. J Natl Cancer Inst. 2006;98. 8 PASSIVE TARGETING Enhanced Permeability and Retention effect (EPR effect) Slide 9: Clearance of passively targeted drug delivery systems EPR effect can be achieved to the full extent only if the circulation half life of the drug delivery system is sufficiently large Renal clearance Controlled by the molecular weight and size of the drug carriers Molecular weight should be higher than threshold of renal clearence (45 kDa) Reticuloendothelial system (RES) uptake Contorlled by modifying the particle surface with non-immunogenic water soluble polymers and particle size (below 100 nm) PEGylation e.g., sterically stabilized liposomes (SSLs) 9 Sapra P et al. Prog Lipid Res. 2003;42:439-462. Contd… Slide 10: There are two broad classes of tumor targeted drug delivery systems. Macromolecular conjugates Particulate systems 10 EPR effect can only be applied to macromolecular Drug delivery systems, as small molecule drugs leak through the capillary pores of normal vessels too! Lammers T et al. Br J Cancer. 2008;99:392 - 397. Contd… Targeted drug delivery systems Slide 11: 11 Contd… Approved passive tumor targeted drug delivery systems Slide 12: Active targeting of the drugs can be achieved by exploiting the unique features of the tumor cells which are absent in normal cells. Tumor targets (over expressed on tumor cells) Tumor-associated antigens Growth factor receptors Incorporation of biorecognizable moiety into drug delivery systems will lead to actively-targeted drug delivery systems 12 Byrne JD et al. Adv Drug Delivery Rev. 2008;60:1615-1626. ACTIVE TARGETING Active targeting Slide 13: 13 Elements of Active tumor targeted drug delivery systems Contd… Slide 14: Paul Ehrlich (1908) coined phrase, “magic bullets and poisoned arrows”: use of antibodies to specifically target toxic substances to pathogens Monoclonal antibodies recognize the protein (antigen) on the surface of the cancer cell and lock onto it There are two main mechanisms for cancer treatment Acting directly Immunoconjugates 14 Alley SC et al. Curr Opin Chem Biol. 2010;14:529-537. Contd… Monoclonal Antibodies as Active-targeting Moieties Slide 15: Immunoconjugates combine the targeting power of mAbs and cytotoxic activity of drugs 15 Contd… Immunoconjugates Slide 16: Radionuclide attached to antibody Usually ß-emitters, e.g. 131I, 90Y Cytotoxic over a distance from its source depending on path length E.g., 131I anti-IL2R antibody is under phase 1 study for IL2R-expressing lymphomas 16 Hartmann F et al. Cancer Res. 1994;54:4362-4370. Contd… Radioimmunotherapy Scheme for radioimmunotherapy Slide 17: 17 Bagshawe KD. Expert Rev Anticancer Ther. 2006;6:1421-1431. Contd… Antibody directed enzyme prodrug therapy (ADEPT) Slide 18: E.g., Doxorubicin is coupled to anti-lewis Y (LeY) antibody (BR96) Many drug immunoconjugate are prepared and evaluated for their efficacy and cytotoxicity 18 Alley SC et al. Curr Opin Chem Biol. 2010;14:529-537. Contd… Drug immunoconjugates Slide 19: Some of the most exploited targets for antibody targeting are: 19 Contd… Targets for Immunoconjugates Slide 20: Proteins and peptides can be used as potential targeting moieties or ligands for many receptors Targets for proteins 20 Contd… Protein/Peptides as Active Targeting Moieties Slide 21: The folate receptor is significantly upregulated on many cancer cells compared to normal tissue (ovarian, lung, brain, head and neck tumors) Normal cells transport a reduced folate across their membranes but will not transport folate conjugates of any type Malignant cells transport folate conjugates through the folate receptor, which is considered the alternative route 21 Contd… Vitamins as Active Targeting Moieties Slide 22: 22 Confocal microscopic pictures of KB cells incubated with (A) DOX, (B) DOX nano-aggregates, and (C) DOX/FOL nano-aggregates at an equivalent doxorubicin concentration of 50 µM for 3 h at 37OC. E.g., Yoo HS et al, produced doxorubicin nano aggregates from doxorubicin–polyethylene glycol–folate (DOX–PEG–FOL) conjugate, and was found to exhibited more potent cytotoxic effect on KB cells than free doxorubicin Yoo HS et al. J Control Release. 2004;100:247-256. Contd… Slide 23: Advantage of the difference in pH, temperature and presence of enzymes is used to release the drug in the tumor microenvironment The rapid release of the drug form its carrier is key to the therapeutic efficacy of the dosage form. The tumor microenvironment differs form the normal cells microenvinornment 23 STIMULI RESPONSIVE DRUG RELEASE Slide 24: lactic acid production (Warburg effect) Tumor cells Blocks uptake of weakly basic drugs (e.g., Doxorubicin) The mean pH of tumor extacellular fluid – 7.06 (5.7 – 7.8) acid liable linker or Acid destabilising nanoparticles Drug release Acid labile linkers Cis-aconityl Hydrazone Polymers undergoing destabilisation in acidic environment Poly (L-histidine) Poly(β-amino esters) Polymers containing sulfadimethoxine moiety 24 Contd… pH Sensitive Drug Release Ulbrich K et al. Adv Drug Delivery Rev. 2004;56:1023-1050 Slide 25: Thermosensitive liposomes 25 Sharp phase transition in the lipid phase at temperatures a few degrees above 37oC Packing defects observed at the gel-to-liquid crystalline phase transition result in increased permeability to entrapped solutes or drugs Contd… Theromosensitive Drug Release Drummond DC et al. Prog Lipid Res. 2000;39:409-460. Destabilisation of lilpid membrane at mild hyperthermia Slide 26: β-Glucuronidase Commonly found in the necrotic areas of tumors. Acts upon β1 – 4 bonds linking two glucose or glucose-substituted molecules Proteases This enzyme lyses the amino-peptidyl bond of the prodrug resulting in an intracellular conversion to free drug. The amino-peptidyl bond is relatively stable in serum and posses no systemic side effects of the drug HMR1826: This conjugate is activated by β – glucuronidase 26 Contd… Enzyme activated conjugates Huang PS et al. Curr Opin in Genet Dev. 2001;11:104-110. Slide 27: Magnetic nanoparticles (MNPs) can be transported through an external magnetic field gradient, penetrating deep into the human tissue E.g., Tamoxifen-loaded Fe3O4/poly(L-lactic acid) nanoparticles and evaluated its cytotoxicity against MCF-7 breast cancer cells. 27 Contd… External Stimuli Triggered Systems – Magnetic field Hafeli UO et al. Int J Pharm. 2004;277:19-24. Transport of MNPs towards magnetic field Slide 28: 28 An Ideal tumor targeted systems have to be developed using the principles of stimuli, passive and active targeting combined with the advances in fields of tumor biology and biomaterials. And multipurpose systems have to be developed which can be used for treatment, diagnosis and imaging. Till now different targets for active targeting have been identified and tested using different drug delivery systems but still... CONCLUSION Slide 29: Thank you Slide 30: 30 Monoclonal antibody Antibody produced from a single B-lymphocyte Murine monoclonal antibody Monoclonal antibody derived entirely from mice Chimeric antibody Monoclonal antibody constructed from Mouse V-regions and human C-regions Humanized antibody Monoclonal antibody constructed with only antigen binding regions (CDRs) from mouse. Remainder is human Slide 31: Conjugation of antibodies: Random conjugation is commonly carried out by carbodiimide-mediated site-specific binding of antibodies to nanoparticles can be done using maleimide. 3 methods to attach cytotoxic drug to variable regions of mAb Couple drug to lysine moieties in the mAb Generation of aldehyde groups by oxidizing the carbohydrate region and subsequent reaction with amino-containing drugs or drug derivatives Couple drugs to sulfhydryl groups by selectively reducing the interchain disulfides near the Fc region of the mAb 31 Slide 32: Decreased receptor affinity as a result of conjugation methods Circulating free antigen Insufficient tumor penetration Possible changes in the antigen over time Immunogenicity of the conjuagate Lack of sufficient selectivity of the tumor antigens Antigen expression is heterogenous on tumor cells Inner regions of solid tumors poorly vascularized and have low blood flow Causes gastrointestinal toxicity An initial screening of the target antigens in cancer patients is necessary prior to starting a treatment regimen of immunoconjuates 32 Contd… limitations You do not have the permission to view this presentation. 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