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Vladimir R. Muzykantov, M.D., Ph.D.Assistant Professor of Pharmacology Institute for Environmental Medicine Areas of Interest in Bioengineering Graduate Group: Drug Delivery, Cardiovascular Areas of Interest in Pharmacology Graduate Group: Cardiovascular and Cancer Research Interests: Targeted delivery of therapeutics, enzymes and genes to endothelial cells and other vascular target for treatment of thrombotic and oxidative stresses. Key words: drug targeting, drug delivery, carriers, nano-technology, endothelium, ischemia, endocytosis, lung, erythrocytes, fibrinolysis, oxidative stress, antioxidants, acute lung injury. Description of the research: The more new drugs are designed, the higher interest in two basic questions: i) how to minimize their side effects via a more adequate delivery to therapeutic targets – an affected organ, tissue or cell; and, ii) how to improve their effects by precise addressing into desirable subcellular compartments. We work on novel strategies for targeted delivery of anti-oxidant and anti-thrombotic enzymes and genes encoding these proteins, to endothelial cells (using monoclonal antibodies and other ligands that bind selectively to surface adhesion molecules and other specific endothelial determinants). We characterize subcellular addressing, intracellular traffic, activity and effects of targeted drugs in models including cell cultures, perfused organs and in animal models of acute oxidative and thrombotic stress. These animal models also used to characterize a new approach for intravascular delivery of anti-thrombotic agents using red blood cells as carriers (Trojan horse approach). Methods used in the lab include protein biochemistry, bioconjugation and bioengineering; design of polymer carriers for drug delivery, nano-technologies, cell and molecular biology approaches; animal studies and diverse morphological and imaging techniques. Potential research projects for rotation or Ph.D. thesis students include, but not limited to: 1. Role of endothelial glycocalyx in drug targeting 2. Surface adhesion molecules as therapeutic targets 3. Mechanisms of intracellular addressing via GPI-linked proteins and caveoli 4. Signal transduction and molecular regulation of intracellular traffic of drugs 5. Chemical modifications of proteins and other therapeutics to prolong their life-time in circulation 6. Design of polymer and nano-particle carriers for drug delivery 7. Biocompatible coupling of drugs to red blood cells 8. Testing of the therapeutic effects/limitations of anti-oxidant protection by targeted delivery of anti-oxidant enzymes 9. Testing of anti-thrombotic activities of antibody-coupled and red blood cells coupled plasminogen activators. Selected Key References: V.Muzykantov, E.Atochina, H.Ischiropoulos, S.Danilov and A.Fisher (1996) Immunotargeting of antioxidant enzymes to the pulmonary endothelium. Proc.Natl.Acad.Sci.USA, 93, 5213-5218 E.Atochina, I.Balyasnikova, S.Danilov, D.Granger, A.Fisher and V.Muzykantov (1998) Immunotargeting of catalase to ACE or ICAM-1 protects perfused rat lungs against oxidative stress. Am.J.Physiol.(Lung)., 19:L806-L817 V.Muzykantov, M.Christofidou, I.Balyasnikova, D.Harshaw, L.Schultz, A.Fisher and S.Albelda (1999) Streptavidin facilitates internalization and pulmonary targeting of an anti-endothelial cell antibody (PECAM): a strategy for intraendothelial drug delivery. Proc.Natl.Acad.Sci.USA, 96:2379-2384. A.Scherpereel, R.Wiewrodt, M.Christofidou-Solomidou, R.Gervais, J-C.Murciano, S.M.Albelda and V.R.Muzykantov (2001) Cell-selective intracellular delivery of a foreign enzyme to endothelium in vivo using vascular immunotargeting FASEB.J., 15:416-426. R.Wiewrodt, A.Thomas, L.Cipelletti, M.Christofidou-Solomidou, D.Weitz,
S.I.Feinstein, D.Schaffer, S.M.Albelda, M.Koval and V.Muzykantov
(2002) Size-dependent immunotargeting of cargo materials into endothelial
cells. Blood, 99: 912-922
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