DRUG TARGETING IN NEOPLASTIC DISEASES

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DRUG TARGETING IN NEOPLASTIC DISEASES Vamshi Krishna .J

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2 Treatment options for cancer 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.

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3 Chemotherapy Two basic types of agents are recognized 1. C ell C ycle S pecific A gents 2. C ell C ycle N onspecific A gents C ell C ycle N onspecific A gents: A ctive throughout the cell cycle - Alkylating Agents - Platinum Compounds - Antibiotics C ell C ycle S pecific A gents : A ct 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

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4 Tumor Physiology & EPR Effect Cancerous growth feeds parasitically on the existing supply of blood and nutrients. As the tumor develops, it can develop it’s own blood vessels but cannot form its own lymphatic system. The blood vessels developed, are often leaky and porous within the tumor interstitium. 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.

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Complex Particulate Multicomponent Systems Liposomes Niosomes Nanoparticles Cells as carriers Microspheres Magnetic microspheres Emulsions Implantable drug delivery systems 5

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6 Liposomes

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7 Liposomes

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8 Targeting strategies using liposomes can be designed as: Natural targeting of conventional liposomes. Long circulatory liposomes (Stealth liposomes). Ligand mediated targeting. Use of anti receptor antibodies or antibodies developed against specific surface antigens on the tumor vascular endothelium. Use of stealth liposomes and ligand mediated targeting in combination. Liposomes

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Sterically stabilized liposomes , avoid scavenging through receptor mediated uptake by mononuclear phagocytic cells of reticulo endothelial system 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. PEG can be substituted by, Sialo-glyco conjugates . - Sialoglycoprotein of human erythrocytes. - Sialoglycopeptide derived fetuin. - Sialic acid conjugated cholesterol substituted pullulan. 9

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10

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Mechanisms proposed... For the action of stealth liposomes Attraction of dysopsonins (serum proteins). Steric barrier and hindrance. Shielding of negative charge. Increased surface hydrophilicity. Inhibition of interactions with serum lipoproteins including opsonins. 11

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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. 12 Release of drug from Liposomes… A Constraint ?

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Liposome targeting to tumors using vitamin and growth factor receptors 13 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).

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Targeted Vs Non targeted liposomes ...in Tumor targeting 14 Non-targeted or targeted liposomes: Interaction mediated via non internalizing receptors Diffusion of drug Endocytosis Targeted liposomes: Interaction mediated via internalizing receptors

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Triggered release of liposomes 15 An ideal system may involve some time dependent or other specific inducible changes in the liposome membrane or its coating to produce intelligent liposomes that will change their properties (e.g.. leakage rate, fusogenic activity and interaction with particular cells) upon getting specific stimulus following their application. Triggered release signal sensitive liposomes are of following types. - Thermo sensitive liposomes - P H sensitive liposomes - Magneto liposomes - Photo activated liposomes

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16 Dramatic increase in the permeability of liposomes occurred at a temperature (above physiologic temperature).The fluctuations in temperature insitu trigger the release of the contents delivering them at cellular level. In addition, the temperature of the desired site can be artificially manipulated by applying local heating , that could increase the temperature of the desired site and hence concomitant release of the contents. Incorporation of anti target Mab’s on P H sensitive immunoliposomes possess the ability to specifically deliver cytotoxic drugs (methotrexate) to the cytoplasm of the cell .

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17 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). Target cell recognition by immunoliposomes is influenced by two factors : - The type of the antibody molecule. - The chemistry of conjugation.

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18 Immunoliposomes

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19 Immunoliposomes, make use of use of hyperthermia or magnetic field for the induced release of it’s contents. Liposomal systems appear to be the most promising carrier systems, for photo sensitizers in the photodynamic therapy of tumors. The photo sensitizer(Eosin) coupled to a phospholipid and incorporated into trinitrophenol(TNP) bearing liposomes, inorder to target the photo sensitizer to B-lymphoma cells , that expresses TNP-specific membrane I g G receptors.

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20 Haptenated(TNP)-liposomes with photo sensitizer(Eosin), released upon irradiation following specific interaction of TNP with anti-TNP I g G of tumor cell Photosensitive liposomes Anti-TNP I g G Photo sensitizer Hapten (TNP) Tumor cell Liposome

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Niosomes 21 Niosomes are non-ionic surfactant vesicles obtained on hydration of synthetic nonionic surfactants, with or without incorporation of cholesterol or other lipids. They are similar to liposomes but the bilayer in the case of niosomes is made up of non-ionic surface active agents, rather than phospholipids, as seen in the case of liposomes. Liposomes face problems such as; they are expensive, their ingredients like phospholipids are chemically unstable because of their predisposition to oxidative degradation, they require special storage and handling and purity of natural phospholipids is variable.

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Microspheres 22 Many of the biocompatible polymers can be used as small soluble molecular drug carriers. Therapeutic agents can be incorporated into these assembled polymers (particle size less than 200 µ m). Albumin microspheres, Chitosan microspheres and many other synthetic microspheres are being used as carriers for the delivery of several chemotherapeutic agents. Magnetic Microspheres : To minimize the reticuloendothelial clearance and increase the target specificity . They are composed of denatured serum albumin matrix that serves as the vesicle in which anticancer agent and ultrafine particles of magnetite are entrapped.

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23 Definition: Magnetic microspheres are supramolecular particles that are small enough to circulate through capillaries without producing embolic occlusion (<4 μm) but are sufficiently susceptible (ferromagnetic) to be captured in micro vessels and dragged in to the adjacent tissues by magnetic fields of 0.5-0.8 tesla (T)

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NanoParticles 24 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. Nanoparticles can be prepared using natural hydrophilic polymers ( proteins and polysaccharides ) or synthetic hydrophobic polymers ( PECL, PLA, PLGA, Poly cyanoacrylates, PMMA ). 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.

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Implantable Systems 25 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. Solid Implants :

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26 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. In-situ Forming Implants :

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Complex particulate multicomponent systems reported with anticancer drugs 27

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Intra-tumoral Drug Delivery 28 The concept of administration of drug directly into the tumor arose 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, BCNU-polyanhydride implant, Vinblastine-Collagen matrix, Methotrexate-Polylactide implant, all have resulted in suppression of tumor.

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29 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.

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30 Marketed Products

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31 In the recent past, we have witnessed an explosion in research aimed at creating novel drug delivery systems for various kinds of neoplasms. During the next few decades, the clinical evaluation of many of the new tumor targeting drug delivery systems will be in operation. Progress in immunology, human genomics , liposomes & nanoparticle technology etc. should lead to greater insight into the type of targeting molecules that can be used to achieve site-specific drug delivery. As our understanding of the drug action and pathogenesis of different types of neoplasms becomes vivid, more rational approaches to the design of therapeutic systems , that target the tumors with no or reduced side effects, will emerge. Conclusion

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32 References S. P. Vyas  and   R. K . Khar. Targeted and Controlled Drug Delivery (Novel Carrier Systems) . N.K. Jain. Advances in controlled and Novel Drug Delivery. N.K. Jain. Progress in Controlled and Novel Drug Delivery. World Wide Web. http://www.sysrevpharm.org/article.asp?issn=0975-8453;year=2011;volume=2;issue=2;spage=91;epage=95;aulast=Rajgor http://www.benthamscience.com/ddf/samples/ddf1-1/0004DDF.pdf http://www.mvspacific.com/REAGENTS/Reagents%20Data%20Sheets/M-1001-010.html http://www.liposomes.org/2011/09/immunoliposomes.html http://electronicdesign.com/article/power/medical-technology-motto-live-long-and-proper-5052 http://www.sysrevpharm.org/article.asp?issn=0975-8453;year=2011;volume=2;issue=2;spage=91;epage=95;aulast=Rajgor

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Thank You… 33