Vladimir R. Muzykantov

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Professor of Pharmacology
Senior Investigator, Institute for Environmental Medicine, University of Pennsylvania School of Medicine
Member, Institute of Medical Engineering, University of Pennsylvania School of Medicine
Member, Center for Cancer Pharmacology, University of Pennsylvania School of Medicine
Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine
Member, Center for Environmental Toxicology, University of Pennsylvania School of Medicine
Member, Cardiovascular Institute, University of Pennsylvania School of Medicine
Associate Director for Professional Development, NRSA in Lung Biology, Institute for Environmental Medicine
Vice-Chair for Faculty Development, Department of Pharmacology, University of Pennsylvania
Founding Co-Director of the PSOM/SEAS Center for Targeted Therapeutics and Translational Nanomedicine , University of Pennsylvania
Department: Pharmacology

Contact information
10-105 Smilow Center for Translational Research
3400 Civic Center Blvd
Philadelphia, PA 19104-5158
Office: 215-898-9823
Fax: 215-898-0868
Graduate Group Affiliations
Education:
M.D. (Internal Medicine)
First School of Medicine, Moscow, Russia, 1980.
Ph.D. (Biochemistry)
National Cardiology Research Center, Moscow, Russia, 1985.
M.A. (Honoris Causa)
University of Pennsylvania, 2004.
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Description of Research Expertise

Research Interests:
Drug/gene targeting and vascular biology

Particular areas of interest/expertise include the recognition of surface antigens on normal or pathologically altered endothelial cells; vascular inflammation and leukocytes adhesion; mechanisms of oxidative stress and antioxidant protection of the endothelium; evaluation of specific markers of endothelial injury; immunotargeting of antioxidant enzymes, fibrinolytics and genes to the pulmonary endothelium; pulmonary pathophysiology; lung ischemia/reperfusion; prolongation of enzymes life-time in the bloodstream; controlled elimination of radiolabeled antibodies or pathogens from the bloodstream; exploration of red blood cells as carriers for prolonged circulation and site-specific delivery of drugs (fibrinolytics and anticoagulants); regulation of fibrinolysis and complement; mechanisms and regulation of intracellular targeting/trafficking of drugs.

Research Summary
The laboratory is focused on several projects. First is the targeting of drugs (enzymes either degrading or generating oxidants, fibrinolytics, interferon, antisense oligos and genes) to the pulmonary vascular endothelium. The purpose is to develop strategies for controlled site-specific delivery of a drug to the defined subcellular compartments of the pulmonary endothelium. For example, genetic material must be delivered into the nucleus, antioxidants must accumulate in the cytoplasm, and fibrinolytics must avoid internalization. We therefore study how carrier antibodies and their derivatives recognize endothelium, and characterize cellular trafficking and local effects of the targeted agents in cell cultures, perfused animal lungs and in intact animals. Our research includes identification of the molecules localized on the surface of endothelium useful as targets for drug delivery to either normal or pathologically challenged endothelium. Endothelium-specific antigens may serve as such targets. Affinity carriers that are currently explored in our laboratory include monoclonal antibodies (and their fragments) to: angiotensin-converting enzyme (ACE), thrombomodulin and surface adhesion molecules, ICAM, PECAM, P- and E-selectins. We have characterized carriers and their modifications providing: i) a drug with an affinity to endothelium (recognition and targeting) and, ii) drug delivery in a proper cellular compartment (sub-cellular addressing). Targeting to either surface (by non-internalizable carriers) or intracellularly has been documented in cell culture, perfused lungs and in rodents in vivo.

Secondly, we explore red blood cells (RBC) as natural carriers for drugs. We have developed an original methodology for effective conjugation of large amounts of a drug (e.g., fibrinoytic enzymes or receptors for plasminogen activators) on RBC, without loss of biocompatibility of the complex. Conjugation provides prolongation of half-life of plasminogen activators in vivo by orders of magnitude and offers specific transfer of the conjugated protein (tPA, uPA-receptor) to the pulmonary endothelium. Both mechanism of the transfer (tentatively via exchange of GPI-anchored membrane proteins between RBC and endothelium) and potential therapeutic applications of RBC-conjugated fibrinolytics (treatment/prevention of pulmonary embolism/deep vein thrombosis) are in the focus of the research. We also explore RBC as carriers for intracellular drug delivery in phagocyte cells in the reticuloendothelial tissue (liver and spleen) and endothelial cells.

Description of Itmat Expertise

Dr. Muzykantov is interested in targeted drug delivery.

Selected Publications

Brenner Jacob S, Pan Daniel C, Myerson Jacob W, Marcos-Contreras Oscar A, Villa Carlos H, Patel Priyal, Hekierski Hugh, Chatterjee Shampa, Tao Jian-Qin, Parhiz Hamideh, Bhamidipati Kartik, Uhler Thomas G, Hood Elizabeth D, Kiseleva Raisa Yu, Shuvaev Vladimir S, Shuvaeva Tea, Khoshnejad Makan, Johnston Ian, Gregory Jason V, Lahann Joerg, Wang Tao, Cantu Edward, Armstead William M, Mitragotri Samir, Muzykantov Vladimir: Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude. Nature communications 9(1): 2684, Jul 2018.

Myerson Jacob W, Braender Bruce, Mcpherson Olivia, Glassman Patrick M, Kiseleva Raisa Y, Shuvaev Vladimir V, Marcos-Contreras Oscar, Grady Martha E, Lee Hyun-Su, Greineder Colin F, Stan Radu V, Composto Russell J, Eckmann David M, Muzykantov Vladimir R: Flexible Nanoparticles Reach Sterically Obscured Endothelial Targets Inaccessible to Rigid Nanoparticles. Advanced materials (Deerfield Beach, Fla.) Page: e1802373, Jun 2018.

Khoshnejad Makan, Greineder Colin F, Pulsipher Katherine W, Villa Carlos H, Altun Burcin, Pan Daniel C, Tsourkas Andrew, Dmochowski Ivan J, Muzykantov Vladimir R: Ferritin Nanocages with Biologically Orthogonal Conjugation for Vascular Targeting and Imaging. Bioconjugate chemistry 29(4): 1209-1218, Apr 2018.

Villa Carlos H, Pan Daniel C, Johnston Ian H, Greineder Colin F, Walsh Landis R, Hood Elizabeth D, Cines Douglas B, Poncz Mortimer, Siegel Don L, Muzykantov Vladimir R: Biocompatible coupling of therapeutic fusion proteins to human erythrocytes. Blood advances 2(3): 165-176, Feb 2018.

Shuvaev Vladimir V, Kiseleva Raisa Yu, Arguiri Evguenia, Villa Carlos H, Muro Silvia, Christofidou-Solomidou Melpo, Stan Radu V, Muzykantov Vladimir R: Targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin. Journal of controlled release : official journal of the Controlled Release Society 272: 1-8, Feb 2018.

Khoshnejad Makan, Brenner Jacob S, Motley William, Parhiz Hamideh, Greineder Colin F, Villa Carlos H, Marcos-Contreras Oscar A, Tsourkas Andrew, Muzykantov Vladimir R: Molecular engineering of antibodies for site-specific covalent conjugation using CRISPR/Cas9. Scientific reports 8(1): 1760, Jan 2018.

Greineder Colin F, Villa Carlos H, Walsh Landis R, Kiseleva Raisa Y, Hood Elizabeth D, Khoshnejad Makan, Warden-Rothman Robert, Tsourkas Andrew, Muzykantov Vladimir R: Site-Specific Modification of Single-Chain Antibody Fragments for Bioconjugation and Vascular Immunotargeting. Bioconjugate chemistry 29(1): 56-66, Jan 2018.

Kiseleva Raisa Yu, Greineder C F, Villa C H, Marcos-Contreras O A, Hood E D, Shuvaev V V, DeLisser H M, Muzykantov V R: Vascular endothelial effects of collaborative binding to platelet/endothelial cell adhesion molecule-1 (PECAM-1). Scientific reports 8(1): 1510, Jan 2018.

Pan Daniel C, Myerson Jacob W, Brenner Jacob S, Patel Priyal N, Anselmo Aaron C, Mitragotri Samir, Muzykantov Vladimir: Nanoparticle Properties Modulate Their Attachment and Effect on Carrier Red Blood Cells. Scientific reports 8(1): 1615, Jan 2018.

Kartha Sonia, Yan Lesan, Weisshaar Christine L, Ita Meagan E, Shuvaev Vladimir V, Muzykantov Vladimir R, Tsourkas Andrew, Winkelstein Beth A, Cheng Zhiliang: Superoxide Dismutase-Loaded Porous Polymersomes as Highly Efficient Antioxidants for Treating Neuropathic Pain. Advanced healthcare materials 6(17), Sep 2017.

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Last updated: 06/20/2018
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