Vladimir R. Muzykantov

faculty photo
Professor of Pharmacology
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
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 (CT3N) , 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

Farokhirad Samaneh, Ranganathan Abhay, Myerson Jacob, Muzykantov Vladimir R, Ayyaswamy Portonovo S, Eckmann David M, Radhakrishnan Ravi: Stiffness can mediate balance between hydrodynamic forces and avidity to impact the targeting of flexible polymeric nanoparticles in flow. Nanoscale Mar 2019.

Marcos-Contreras Oscar A, Brenner Jacob S, Kiseleva Raisa Y, Zuluaga-Ramirez Viviana, Greineder Colin F, Villa Carlos H, Hood Elizabeth D, Myerson Jacob W, Muro Silvia, Persidsky Yuri, Muzykantov Vladimir R: Combining vascular targeting and the local first pass provides 100-fold higher uptake of ICAM-1-targeted vs untargeted nanocarriers in the inflamed brain. J Control Release 301: 54-61, Mar 2019.

Parhiz Hamideh, Shuvaev Vladimir V, Pardi Norbert, Khoshnejad Makan, Kiseleva Raisa Yu, Brenner Jacob S, Uhler Thomas, Tuyishime Steven, Mui Barbara L, Tam Ying K, Madden Thomas D, Hope Michael J, Weissman Drew, Muzykantov Vladimir R: PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake. J Cont Release 291: 106-115, Dec 2018.

Shuvaev Vladimir V, Khoshnejad Makan, Pulsipher Katherine W, Kiseleva Raisa Yu, Arguiri Evguenia, Cheung-Lau Jasmina C, LeFort Kathleen M, Christofidou-Solomidou Melpo, Stan Radu V, Dmochowski Ivan J, Muzykantov Vladimir R: Spatially controlled assembly of affinity ligand and enzyme cargo enables targeting ferritin nanocarriers to caveolae. Biomaterials 185: 348-359, Dec 2018.

Hood Elizabeth D, Greineder Colin F, Shuvaeva Tea, Walsh Landis, Villa Carlos H, Muzykantov Vladimir R: Vascular Targeting of Radiolabeled Liposomes with Bio-Orthogonally Conjugated Ligands: Single Chain Fragments Provide Higher Specificity than Antibodies. Bioconjug Chem 29(11): 3626-3637, Nov 2018.

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. Nat Commun 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. Adv Mater 30(32): 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. Bioconjug Chem 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. J Control Release 272: 1-8, Feb 2018.

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Last updated: 04/09/2019
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