Vladimir R. Muzykantov, MD, PhD

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.

Selected Publications

Kiseleva, R Yu; Glassman, P G; LeForte, K M; Walsh, L R; Villa, C H; Shuvaev, V V; Myerson, J W; Aprelev, P A; Marcos‐Contreras, O A; Muzykantov, V R; Greineder, C F: Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo FASEB journal 34(9): 11577-11593, August 2020.

Anvay Ukidve, Zongmin Zhao, Alexandra Fehnela, Vinu Krishnana,b, Daniel C. Pan, Yongsheng Gaoa, Abhirup Mandal, Vladimir Muzykantov, and Samir Mitragotri: Erythrocyte-driven immunization via biomimicry of their natural antigen-presenting function PNAS Jul 2020 Notes: 2020 Jul 14;202002880. doi: 10.1073/pnas.2002880117.

Marcos-Contreras Oscar A, Greineder Colin F, Kiseleva Raisa Yu, Parhiz Hamideh, Walsh Landis R, Zuluaga-Ramirez Viviana, Myerson Jacob W, Hood Elizabeth D, Villa Carlos H, Tombacz Istvan, Pardi Norbert, Seliga Alecia, Mui Barbara L, Tam Ying K, Glassman Patrick M, Shuvaev Vladimir V, Nong Jia, Brenner Jacob S, Khoshnejad Makan, Madden Tom, Weissmann Drew, Persidsky Yuri, Muzykantov Vladimir R: Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood-brain barrier. Proceedings of the National Academy of Sciences of the United States of America 117(7): 3405-3414, Feb 2020.

Ji Weihang, Smith Paige N, Koepsel Richard R, Andersen Jill D, Baker Stefanie L, Zhang Libin, Carmali Sheiliza, Myerson Jacob W, Muzykantov Vladimir, Russell Alan J: Erythrocytes as carriers of immunoglobulin-based therapeutics. Acta biomaterialia 101: 422-435, Jan 2020.

Peghaire C, Dufton N P, Lang M, Salles-Crawley I I, Ahnström J, Kalna V, Raimondi C, Pericleous C, Inuabasi L, Kiseleva R, Muzykantov V R, Mason J C, Birdsey G M, Randi A M: The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature. Nature communications 10(1): 5014, Nov 2019.

Myerson Jacob Wheatley, McPherson Olivia, DeFrates Kelsey G, Towslee Jenna H, Marcos-Contreras Oscar A, Shuvaev Vladimir V, Braender Bruce, Composto Russell J, Muzykantov Vladimir R, Eckmann David M: Cross-linker-Modulated Nanogel Flexibility Correlates with Tunable Targeting to a Sterically Impeded Endothelial Marker. ACS nano 13(10): 11409-11421, Oct 2019.

Paek Jungwook, Park Sunghee E, Lu Qiaozhi, Park Kyu-Tae, Cho Minseon, Oh Jeong Min, Kwon Keon Woo, Yi Yoon-Suk, Song Joseph W, Edelstein Hailey I, Ishibashi Jeff, Yang Wenli, Myerson Jacob W, Kiseleva Raisa Y, Aprelev Pavel, Hood Elizabeth D, Stambolian Dwight, Seale Patrick, Muzykantov Vladimir R, Huh Dongeun: Microphysiological Engineering of Self-Assembled and Perfusable Microvascular Beds for the Production of Vascularized Three-Dimensional Human Microtissues. ACS nano 13(7): 7627-7643, Jun 2019.

Lutton Evan M, Farney S Katie, Andrews Allison M, Shuvaev Vladimir V, Chuang Gwo-Yu, Muzykantov Vladimir R, Ramirez Servio H: Endothelial Targeted Strategies to Combat Oxidative Stress: Improving Outcomes in Traumatic Brain Injury. Frontiers in neurology 10: 582, Jun 2019.

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 11(14): 6916-6928, 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.

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Last updated: 08/31/2020
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