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targeted dds for cancer

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  • 1. TARGETED DRUG DELIVERY SYSTEM FOR CANCER PRESENTED BY Neha singh M.pharm 1 yr. GUIDED BY V.B pokharkar Hod Pharmaceutics 1
  • 2. WHAT IS CANCER? • Division – uncontrolled cell division • Growth – formation of a lump (tumour) or large numbers of abnormal white cells in the blood • Mutation – changes to how the cell is viewed by the immune system • Spread – ability to move within the body and survive in another part
  • 3. TYPES OF CANCER • Carcinomas • Sarcomas • Lymphomas • Leukaemias • Adenomas • Often prefixed by the specific cell
  • 4. CANCEROUS GROWTH
  • 5. Malignant versus benign tumours
  • 6. What Causes Cancer? • External Factors – chemicals, radiation, viruses, and lifestyle • Internal Factors – hormones, immune conditions, and inherited mutations • Theories ▫ Cellular change/mutation theories ▫ Carcinogens ▫ Oncogenes/ protooncogenes
  • 7. Factors Believed to Contribute to Global Causes of Cancer Figure 16.2
  • 8. “Hallmarks of cancer” • Self-sufficiency in growth signals • Insensitivity to anti-growth signals • Evading apoptosis • Limitless reproductive potential • Sustained angiogenesis • Tissue invasion and metastases • Genomic instability
  • 9. What are the differences in the features of normal and cancer cells?
  • 10. Barriers offered by tumor vasculature
  • 11. Barriers to drug acess
  • 12. TUMOR PHYSIOLOGY & EPR EFFECT • Cancerous growth feeds on the existing supply of blood and nutrients. As the tumor develops, it can develop it’s own blood vessels. • The blood vessels developed, are often leaky and porous . • Interstitial pressure inside the tumor is much higher when compared to the normal cell and viscosity of blood in tumor is much higher –- slower drug migration . • Enhanced Permeability and Retention ( EPR ) effect is the property by which certain sizes of molecules (typically liposomes, nanoparticles, and macromolecular drugs) tend to accumulate in tumor tissue much more than they do in normal tissues.
  • 13. Erb-B1 HER1 EGFR Erb-B2 HER2 neu Erb-B3 HER3 The HER Family of Receptors Tyrosine kinase domain Ligand- binding domain Erb-B4 HER4 TGF-α EGF Epiregulin Betacellulin HB-EGF Amphiregulin Heregulin Heregulin (neuregulin- Epiregulin HB-EGF Neuregulins-3, -4 No ligand- binding activity* Ligands *HER2 dimerizes with other members of the HER family. Roskoski. Biochem Biophys Res Commun. 2004;319:1. Rowinsky. Annu Rev Med. 2004;55:433.
  • 14. EGFR inhibitors
  • 15. Cell cycle of normal cell
  • 16. TREATMENT OPTIONS FOR CANCER SURGERY • Surgery: before 1955 • Radiotherapy: 1955-1965 • Hyperthermia: 1958-1967 • Chemotherapy: after 1965 • Immunotherapy and Gene therapy • The design of tumor specific delivery of chemotherapeutic agents is a means, to address the issues of the dose-limiting toxic side effects of these agents, by enhancing the fraction of dose actually reaching the tumor while, reducing the amount of drug that reaching the non- targeted organs.
  • 17. Issues with traditional chemotherapy • Act on all rapidly dividing cells - non-selective - toxic to normal cells - often IV treatments - finite number of cycles
  • 18. Anticancer Drugs and Side Effects
  • 19. Chemotherapy  Two basic types of agents are recognized 1. Cell Cycle Specific Agents 2. Cell Cycle Nonspecific A gents  Cell Cycle Specific Agents : Act during a specific phase of the cell cycle – • S Phase Specific Drug: Anti metabolites, Topoisomerase Inhibitors • M Phase Specific Drug: Vinca Alkaloids, Taxanes – • G2 Phase Specific Drug: Bleomycin  Cell Cycle Nonspecific A gents: Active throughout the cell cycle – • Alkylating Agents • Platinum Compounds • Antibiotics
  • 20. TARGETED THERAPIES • Targeted cancer therapies block the growth and spread of cancer by interfering with specific molecules involved in tumour growth and progression Mechanisms of action of targeted therapies • Interfere with cell growth signalling • Interfere with tumour blood vessel development • Promote specific death of cancer cells • Stimulate the immune system to destroy cancer cells • Deliver toxic drugs to cancer cells
  • 21. MOLECULAR MARKERS Gene Cancer Drug KRAS Colorectal Cetuximab BRAF Melanoma Vemurafenib EGFR NCSLC Gefitinib and erlotinib HER2 Breast Trastuzumab CKIT GIST Imatinib
  • 22. Role of molecular markers • Early detection/diagnosis • Prognosis • Prediction of toxicity, response, relapse
  • 23. Methods developed to enhance specificity of chemotherapeutic agents • First order targeting • Second order targeting • Third order targeting • Passive targeting • Active targeting • Physical targeting
  • 24. Anti neoplastic agents can be formulated as… • Pro-drugs • Simple Soluble Macro Molecular Systems • Soluble Synthetic Polymer Systems • Polymer–Drug Conjugates • Complex Particulate Multicomponent Systems
  • 25. PRODRUG - Challenging factors 1. Requires an activatable version of the drug, and research in its development is comparable in cost to drug development. 2. The technology does not necessarily place the drug where it is needed . • This may be improved by a targeting carrier system.
  • 26. GLYCOPROTEINS • The family of glycoproteins includes many enzymes, acute phase reactant proteins and plasma proteins. • Mannose, galactose and sialic acid are the principle sugars that form the carbohydrate components of this simple macromolecules and tend to confer receptor specificity . • Use of glycoproteins as a delivery system for antineoplastic diseases is attractive conceptually due to the targeting specificity afforded by the ligand - receptor interaction principle.
  • 27. MONOCLONALANTIBODIES • Monoclonal antibodies are very specific to their immunological ligands and are thus very appealing drug carriers. • Monoclonal antibodies have been coupled to cytotoxic anti cancer agents such as doxorubicin and the carrier substrate dextran. The Mabs used in these formulations were directed in theory against epitopes found only on cancer cells . Antibodies tend to be very confirmationally stable and usually retain their binding specificity when combined with other molecules.
  • 28. MONOCLONALANTIBODIES
  • 29. FDA-approved monoclonal antibodies for cancer treatment
  • 30. BISPECIFIC ANTIBODIES • In carcinoma patients the combination treatment of IL-2 and Bis- 1F bispecific antibody directed against epithelial glycoprotein -2 and TcR/CD3 complex on T-Lymphocytes elicited an immune response measured by elevated plasma levels of TNF- α and interferon – γ . Through cross linking of T-cell receptor and CD3 complex on the cytotoxic T-lymphocytes and epithelial glycoprotein-2 on the target cell , the lymphocyte tends to be capable of actively lysing the target cells .
  • 31. ANTIBODY DIRECTED ENZYME- PRO DRUG THERAPY (ADEPT ) • The need for antibody internalization, which is one of the problems associated with immunoconjugates is a addressed in this strategy, known as Antibody directed enzyme- pro drug therapy (ADEPT). • Enzymosomes are liposomal constructs engineered to provide a mini bio environment . Enzymes are covalently immobilized or coupled to the surface of liposomes, therefore, when a non toxic product is administered simultaneously, it is converted by the immobilized enzyme to a potent anti-tumor agent in the vicinity of tumor cell lines.
  • 32. IMMUNOTOXIN CONJUGATE • Toxins are molecules that inactivate Viral cytosolic components of the protein synthesis machinery in catalytic manner. • Reaching cytosol is the major requirement. • Immuno-toxins are the conjugates of antibodies (Mab)/ (Fab) fragments and toxins in which the cell binding moieties of the toxins are replaced by the binding specific chain of Ab.
  • 33. SOLUBLE SYNTHETIC POLYMER SYSTEMS • The synthetic polymeric carriers are large enough to avoid filtration and removal by the kidneys but small enough to avoid trapping by the liver and spleen. • Many natural and synthetic biodegradable polymers have been investigated as implants, microcapsules, micro particles and nanocapsules in order to achieve prolonged release and targeting of a variety of drugs. • Apart from targeting, the backbone of a polymeric carrier molecule provides both controlled, sustained release pattern and a means of protecting the drug form the physiological environment.
  • 34. DESIGN OF POLYMER CONJUGATES POLYMER • Should degrade into non-toxic, non immunogenic, water soluble metabolites that are eliminated easily via renal filtration but be of sufficiently high molecular weight to allow entrapment in the tumor by EPR effect. E.g.: Dextrin (2000-55,000) Poly glutamic acid (30,000 -60,000) • Polymer should possess functional groups which are amenable to conjugation with a drug directly or through a linker. • Polymer should possess high drug carrying capacity.
  • 35. COMPLEX PARTICULATE MULTI- COMPONENT SYSTEMS • Liposomes • Niosomes • Nanoparticles • Cells as carriers • Microspheres • Magnetic microspheres • Emulsions • Implantable drug delivery systems
  • 36. LIPOSOMES • Targeting strategies using liposomes can be designed as: Natural targeting of conventional liposomes. Long circulatory liposomes (Stealth liposomes) Ligand mediated targeting.
  • 37. STERICALLY STABILIZED LIPOSOMES • It avoid scavenging through receptor mediated uptake by mononuclear phagocytic cells of RES rich organs. A fraction of the lipids present, have a polyethylene glycol polymer bound to their head groups. This polymer binds a lot of water creating a water cloud around the liposome, which hides it from the immune system and provide long circulatory behavior . Hence the name, Stealth liposomes.
  • 38. Liposome targeting to tumors using vitamin and growth factor receptors Advances in liposome technology have resulted in the development of ligand targeted liposomes capable of selectively increasing the efficacy of carried agents against receptor bearing tumor cells. Receptors for vitamins and growth factors have become attractive targets for ligand-directed liposomal therapies due to their high expression levels on various forms of tumor and their ability to internalize after binding to the liposomes conjugated to receptors’ natural ligands (vitamins).
  • 39. Release of drug from liposomes…A Constraint ? • The design of liposomes can be such that, they can become leaky a few degrees above the body temperature hence letting the encapsulated material flow out. By tuning the lipid composition to become leaky at a certain temperature above the body temperature. • it is possible to heat the tumor locally by either microwave, ultrasound or radio-frequency radiation resulting in a very fast release of the anti-cancer drug, typically a million times faster than from conventional liposomes.
  • 40. IMMUNOLIPOSOMES • Immunoliposomes are generated by conjugating antibodies either directly to lipid bilayer of liposomes in presence or absence of PEG chains (type I immunoliposomes) or to the distal end of the PEG chain (type II immunoliposomes). • Immunoliposomes, make use of use of hyperthermia. • Liposomal systems appear to be the most promising carrier systems, for photo sensitizers in the photodynamic therapy of tumors agnetic field for the induced release of it’s contents
  • 41. NANOPARTICLES • The loading of drug into ultrafine colloidal particles in the nanometer size range (10-1000nm)is done, for optimization of drug delivery to the desired site with the either the drug encapsulated, dissolved, adsorbed or covalently attached. • They can be prepared using natural hydrophilic polymers. • They can entrap various agents in stable and reproducible fashion. • Stabilizers such as dextran and its derivatives can be incorporated into nanoparticle surface to modify it’s surface characteristics.
  • 42. SOLID IMPLANTS : • Cylindrical monolithic devices of mm or cm dimensions, implanted by a minor surgical incision or injected through a large bore needle into subcutaneous or intra muscular tissue . • The drug in implants may be dissolved or dispersed or embedded in a matrix of polymers. • Implantable drug-delivery systems can detect chemical signals in the body and release appropriate therapeutic dosages for treatment with the help of biosensors . • Improved control of drug levels at the specific site of action is possible, for prolonged duration with significantly small dose.
  • 43. IN-SITU FORMING IMPLANTS : • In-situ gels consists of biodegradable polymers dissolved in a biocompatible carrier ( DMSO or NMP ). When the liquid polymer system is placed in the body, it solidifies upon contact with aqueous body fluids to form a solid implant. The gel- matrix, thus formed will release the incorporated drug slowly over a period of weeks to months, and ultimately biodegrade depending on the composition used
  • 44. INTRA-TUMORAL DRUG DELIVERY • The concept of administration of drug directly into the tumor arise from the non uniform and in adequate accumulation of drug or drug carrier in the tumor. • Prodrug approach has been successfully utilized for intra tumoral chemotherapy for a variety of drugs. Mitomycin C, conjugated with dextran and subcutaneously implanted in B 16 melanoma, resulted in reduction in tumor growth. • It can also be optimized using polymeric implants . Cisplatin-Collagen matrix, Vinblastine-Collagen matrix, Methotrexate-Polylactide implant, all have resulted in suppression of tumor.
  • 45. CHEMOEMBOLIZATION • Embolization is widely acknowledged form of endovascular therapy. • It consists of delivering an embolic material locally through a catheter that has been previously inserted in the vessels supplying the pathological area. • Chemoembolization involves the selective arterial embolization of a tumor together with a simultaneous or subsequent local delivery of chemotherapeutic agents. Microcapsule bound intra-arterial chemotherapy has the greatest potential in treating most of the tumors.
  • 46. Summary of targeted therapy actions Mechanism Drug Interfere with cell growth signalling Erlotinib, Gefitinib, Crizotinib Interfere with tumour blood vessel development Bevacizumab, Pazopanib Promote specific death of cancer cells Olaparib Stimulate the immune system to destroy cancer cells Ipilimumab Deliver toxic drugs to cancer cells Trastuzumab emtansine
  • 47. CANCER VACCINES • Prophylactic vaccines e.g. Gardasil®, Cervarix® • Therapeutic vaccines: - delay or stop cancer cell growth - cause tumour shrinkage - prevent cancer from recurring - eliminate cancer cells not killed by other forms of treatment
  • 48. PROVENGE® VACCINE • Licensed for metastatic prostate cancer in USA • Designed to stimulate an immune response by T-cells to prostatic acid phosphatase, an antigen found on most prostate cancer cells
  • 49. Vaccines in development... • Telo Vac: immune response against the protein telomerase which is widely expressed in pancreatic cancer • IMA901 in combination with sunitinib in renal cell carcinoma to see if overall survival is improved • TroVax stimulates the immune system to destroy cancer cells that express the 5T4 tumour antigen, which is present in approximately 85% of solid tumours
  • 50. IMPACT OF TARGETED THERAPIES • Personalised medicine - given until progression - additional to existing therapy - extending life - improving quality of life
  • 51. Antibodies
  • 52. THANK YOU

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