Vladimir R. Muzykantov, MD, PhD

faculty photo
Founders Professor in Nanoparticle Research
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: Systems Pharmacology and Translational Therapeutics

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

John C Greenwood 1, Fatima M Talebi 2, David H Jang 2, Audrey E Spelde 3, Emily K Gordon 3, Jiri Horak 3, Michael A Acker 4, Todd J Kilbaugh 5, Frances S Shofer 6, John G T Augoustides 3, Jan Bakker 7, Jacob S Brenner 8, Vladimir R Muzykantov 9, Benjamin S Abella 2: Low postoperative perfused vessel density is associated with increased soluble endothelial cell adhesion molecules during circulatory shock after cardiac surgery. Microvasc Res. 150, Nov 2023.

Oscar A. Marcos-Contreras, Jacob W. Myerson, Jia Nong, Jacob Samuel Brenner, Vladimir R. Muzykantov, and Patrick M. Glassman: Effective Prevention of Arterial Thrombosis with Albumin-Thrombin Inhibitor Conjugates. Mol Pharm 20(11): 5243-5946, Oct 2023.

Riera-Domingo C, Leite-Gomes E, Charatsidou I, Zhao P, Carrá G, Cappellesso F, Mourao L, De Schepper M, Liu D, Serneels J, Alameh MG, Shuvaev VV, Geukens T, Isnaldi E, Prenen H, Weissman D, Muzykantov VR, Soenen S, Desmedt C, Scheele CLGJ, Sablina A, Di Matteo M, Martín-Pérez R, Mazzone M.: Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding. Sci Adv 9: eadd5028, Mar 2023.

Reyes-Esteves S, Nong J, Glassman PM, Omo-Lamai S, Ohashi S, Myerson JW, Zamora ME, Ma X, Kasner SE, Sansing L, Muzykantov VR, Marcos-Contreras OA, Brenner JS.: Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage. J Control Release Mar 2023.

Greenwood JC, Talebi FM, Jang DH, Spelde AE, Tonna JE, Gutsche JT, Horak J, Acker MA, Kilbaugh TJ, Shofer FS, Augoustides JGT, Bakker J, Brenner JS, Muzykantov VR, Abella BS.: Topical nitroglycerin to detect reversible microcirculatory dysfunction in patients with circulatory shock after cardiovascular surgery: an observational study. Sci Rep 12: 15257, Sep 2022.

Greenwood JC, Talebi FM, Jang DH, Spelde AE, Kilbaugh TJ, Shofer FS, Acker MA, Augoustides JGT, Bakker J, Meyer NJ, Brenner JS, Muzykantov VR, Abella BS.: Protocol for the MicroRESUS study: The impact of circulatory shock and resuscitation on microcirculatory function and mitochondrial respiration after cardiovascular surgery. PLoS One 17: e0273349, Aug 2022.

Glassman PM, Villa CH, Marcos-Contreras OA, Hood ED, Walsh LR, Greineder CF, Myerson JW, Shuvaeva T, Puentes L, Brenner JS, Siegel DL, Muzykantov VR.: Targeted In Vivo Loading of Red Blood Cells Markedly Prolongs Nanocarrier Circulation. Bioconjug Chem 33: 1286-1294, Jul 2022.

Glassman PM, Villa CH, Marcos-Contreras OA, Hood ED, Walsh LR, Greineder CF, Myerson JW, Shuvaeva T, Puentes L, Brenner JS, Siegel DL, Muzykantov VR.: Targeted In Vivo Loading of Red Blood Cells Markedly Prolongs Nanocarrier Circulation. Bioconjug Chem. June 2022.

Parhiz H, Brenner JS, Patel PN, Papp TE, Shahnawaz H, Li Q, Shi R, Zamora ME, Yadegari A, Marcos-Contreras OA, Natesan A, Pardi N, Shuvaev VV, Kiseleva R, Myerson JW, Uhler T, Riley RS, Han X, Mitchell MJ, Lam K, Heyes J, Weissman D, Muzykantov VR.: Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE). J Control Release(344), 50-61, Apr 2022.

Ferguson LT, Hood ED, Shuvaeva T, Shuvaev VV, Basil MC, Wang Z, Nong J, Ma X, Wu J, Myerson JW, Marcos-Contreras OA, Katzen J, Carl JM, Morrisey EE, Cantu E, Villa CH, Mitragotri S, Muzykantov VR, Brenner JS.: Dual Affinity to RBCs and Target Cells (DART) Enhances Both Organ- and Cell Type-Targeting of Intravascular Nanocarriers. ACS Nano 16: 4666-4683, Mar 2022.

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Last updated: 12/11/2023
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