Transcript 1 - NEBM
Results from genomics and proteomics research are revealing the molecular basis for many diseases. However, the development of new medicines that address such diseases has been considerably slow, principally due to the lack of effective drug-delivery systems. Polymer-based pharmaceuticals, and associated nanotechnologies, constitute an interesting new approach to this issue. Polymer-drug conjugates and polymer-protein conjugates are being used in a wide range of applications, as in the treatment of diseases such as cancer and hepatitis C, and judging from the current research, their role will be even more significant in the near future. Polymer-protein conjugation can be seen as an approach to increase the efficiency of protein-, peptide- and antibody- based drugs, given the vast range of these medicines that are being created as a result from recent research.1 Polymer-drug conjugates in current clinical use or development: 3 Polymer-drug conjugates Compound name Status Indications HPMA copolymer-doxorubicin Phase II Various cancers, particularly lung and breast cancer HPMA copolymer-doxorubicin-galactosamine Phase I/II Particularly hepatocellular carcinoma. HPMA copolymer-camptothecin Phase I Various cancers. HPMA copolymer-paclitaxel Phase I Various cancers. HPMA copolymer-carboplatin platinate Phase I/II Various cancers. HPMA copolymer-DACH-platinate Phase I/II Various cancers. PGA-paclitaxel Phase III Various cancers, particularly non-small cell lung cancer; ovarian cancer PGA-camptothecin Phase I/II Various cancers. Dextran-doxorubicin Phase I Various cancers. Modified dextran-camptothecin Phase I Various cancers. PEG-camptothecin Phase II Various cancers. Examples of polymer-drug conjugates: 1 PEGylation a) HPMA-doxorubicin uses a GlyPhe-Leu-Gly tetrapeptide linker, which is cleaved inside lysosomes by the protease cathepsin B. PEGylation is a relatively new technique of polymer-protein conjugation, that consists in the covalent binding of polyethylene glycol (PEG) to substances like enzymes, cytokines and monoclonal antibody fragments. 2 b) HPMA-doxorubicin-galactosamine is the only polymer to bear a targeting ligand to proceed to clinical evaluation. Main advantages: •Increased protein solubility; c) PGA (polyglutamate) is a biodegradable polymer, thus PGApaclitaxel releases drug through hydrolysis during circulation, but most of the drug is released inside lysosomes after cleavage of the polymer backbone by protease chatepsin B. •Reduced immunogenicity; •Increased plasma-half life, thus requiring less frequent dosing, which is of great patient benefit. Polymer-protein conjugates in current clinical use or development: 3 Compound Status PEG-adenosine deaminase Market Indications Hepatocellular carcinoma PEG-L-asparaginase Market Acute lymphoblastic leukaemia PEG-GCSF Market PEG-α-interferon 2a Market / Phase I/II PEG-α-interferon 2b Market / Phase I/II Prevention of neutropaenia associated with cancer chemotherapy Hepatitis B and C / Melanoma, chronic myeloid leukaemia and renal-cell carcinoma Hepatitis C / Melanoma, multiple myeloma and renal-cell carcinoma Hepatocellular carcinoma Phase I PEG-arginine deiminase Chemical Structure Chitosan 4 Polymer-drug conjugation has been explored so far mainly as a means of targeted drug-delivery for anti-cancer drugs. Initially it was thought that the addition of a targeting ligand would be a requirement for conjugation. However, the discovery that the increased molecular weight would lead to passive targeting by the EPR effect paved the way for the first polymer-drug conjugates. 1 Applications Hyaluronic Acid 5 • • • • • • • • • • • • • Mechanism of action Polymer-drug conjugates mechanism of action is based on two main aspects: EPR-mediated targeting and endocellular drug-delivery through the endocytic pathway. 3 Dextran Gellan 6 Antibacterial Anti-tumoural Antioxidant Polymeric carriers on drug delivery systems Viscosurgery Viscoaugmentation Viscoseparation Viscosupplementation Viscoprotection Reduction of inflammation Analgesic Cross-linked hydrogel for drug delivery Decreasing of vascular thrombosis Lubricant agent in some eye drops Increasing blood sugar levels Replacement of blood loss Plasma substitution Volume expansion Rheological improvement Carrier in anticancer therapy Tablet film coating Platform technology for gastric retention Ophthalmic aqueous liquid Spray able wound care Controlled release compositions Natural Polymer's characteristics Biocompatibility EPR effect The Enhanced Permeability and Retention (EPR) effect consists in the passive accumulation of circulating macromolecules in the tumour tissue, believed to be due to two reasons: the increased permeability of the tumour angiogenic vasculature, and the absence of effective lymphatic drainage from the tissue. Lysosomotropic/endosomotropic drug-delivery Lysosomotropic and endosomotropic drug-delivery is the liberation of the drug inside lysosomes and endosomes, respectively. After endocytic uptake of the conjugate from the tumour interstitium, the action of lysosomal proteases (such as chatepsin B) or the decrease in pH inside lysosomes and endosomes would lead to the cleavage of the conjugate linker or the polymer backbone, releasing the drug inside the cell. Biodegradability Low toxicity Clinical trials with polymer-drug conjugates assure the feasibility of the concept as means of anti-cancer drug targeting systems. Although some of the results are satisfactory, polymer-drug conjugation is a concept that allows a lot more of development. New strategies such as combinatorial therapies and/or administration of drugs that increase angiogenic tumor vasculature permeability, for instance, are possibilities for more effective treatments based on polymer conjugation. In addition, new advances in polymer synthesis such as new polymeric architectures could be translated into the field of polymer therapeutics, providing new possibilities for clinical development. Polymer-protein conjugates and natural polymers are also legitimate approaches to healthcare that, if well studied and tested, could boost medical treatments to very important diseases such as cancer or hepatitis C. If further researches clarify some obstacles found in current clinical trials, namely those associated with polymerdrug conjugates, the biomedical applications of polymer-based pharmaceuticals could go beyond some of the therapeutics that are used today. References: 1 Duncan, Stability R. 2003. The dawning era of polymer therapeutics. Nat Rev Drug Discov 2:347-60; 2 Biotechnology. PEGylation. Accessed in November, 26, 2008. Biotechnology: http://www.biology.iupui.edu/biocourses/Biol540/3DrugCaseStudies2k7.htm; 3 Duncan, R. 2006. Polymer conjugates as anticancer nanomedicines. Nat Rev Cancer 6:688-701; 4 Kogan, G., L. Soltes, R. Stern, and P. Gemeiner. 2007. Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications. Biotechnol Lett 29:17-25; 5 Vinsova and E. Vavrikova. 2008. Recent Advances in Drugs and Prodrugs Design of Chitosan. Current Pharmaceutical Design, 14: 1311-1326; 6 Arsenio M. Fialho, Leonilde M. Moreira, Ana Teresa Granja, Alma O. Popescu, Karen Hoffmann and Isabel Sá-Correia. 2008. Occurrence, production, and applications of gellan: current state and perspectives. Appl Microbiol Biotechnol. 79:889–900 Acknowledgements: Prof. Leonilde Moreira