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.
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.
Liu Jin, Weller Gregory E R, Zern Blaine, Ayyaswamy Portonovo S, Eckmann David M, Muzykantov Vladimir R, Radhakrishnan Ravi: Computational model for nanocarrier binding to endothelium validated using in vivo, in vitro, and atomic force microscopy experiments. Proceedings of the National Academy of Sciences of the United States of America 107(38): 16530-5, Sep 2010.
Muzykantov Vladimir R: NO gets a test ride on high-tech transporting nanodevices: A commentary on "Sustained-release nitric oxide from long-lived circulating nanoparticles". Free radical biology & medicine 49(4): 528-9, Aug 2010.
Chorny Michael, Hood Elizabeth, Levy Robert J, Muzykantov Vladimir R: Endothelial delivery of antioxidant enzymes loaded into non-polymeric magnetic nanoparticles. J. Controlled Release 146(1): 144-51, Aug 2010.
Zaitsev Sergei, Spitzer Dirk, Murciano Juan-Carlos, Ding Bi-Sen, Tliba Samira, Kowalska M Anna, Marcos-Contreras Oscar A, Kuo Alice, Stepanova Victoria, Atkinson John P, Poncz Mortimer, Cines Douglas B, Muzykantov Vladimir R: Sustained thromboprophylaxis mediated by an RBC-targeted pro-urokinase zymogen activated at the site of clot formation. Blood 115(25): 5241-8, Jun 2010.
Armstead William M, Ganguly Kumkum, Kiessling J W, Riley John, Chen Xiao-Han, Smith Douglas H, Stein Sherman C, Higazi Abd A R, Cines Douglas B, Bdeir Khalil, Zaitsev Sergei, Muzykantov Vladimir R: Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders. Journal of neurochemistry 113(2): 303-12, Apr 2010.
Muzykantov Vladimir R: Drug delivery by red blood cells: vascular carriers designed by mother nature. Expert opinion on drug delivery 7(4): 403-27, Apr 2010.
Zaitsev Sergei, Zaitzev Sergei, Spitzer Dirk, Murciano Juan-Carlos, Ding Bi-Sen, Tliba Samira, Kowalska M Anna, Bdeir Khalil, Kuo Alice, Stepanova Victoria, Atkinson John P, Poncz Mortimer, Cines Douglas B, Muzykantov Vladimir R: Targeting of a mutant plasminogen activator to circulating red blood cells for prophylactic fibrinolysis. The Journal of pharmacology and experimental therapeutics 332(3): 1022-31, Mar 2010.
Shuvaev Vladimir V, Christofidou-Solomidou Melpo, Bhora Faiz, Laude Karine, Cai Hua, Dikalov Sergei, Arguiri Evguenia, Solomides Charalambos C, Albelda Steven M, Harrison David G, Muzykantov Vladimir R: Targeted detoxification of selected reactive oxygen species in the vascular endothelium. The Journal of pharmacology and experimental therapeutics 331(2): 404-11, Nov 2009.
Murciano Juan-Carlos, Higazi Abd Al-Roof, Cines Douglas B, Muzykantov Vladimir R: Soluble urokinase receptor conjugated to carrier red blood cells binds latent pro-urokinase and alters its functional profile. J Controlled Release 139(3): 190-6, Nov 2009.
Stein Sherman C, Ganguly Kumkum, Belfield Caitlin M, Xu Xiangsheng, Swanson Edward W, Chen Xiao-Han, Browne Kevin D, Johnson Victoria E, Smith Douglas H, LeBold David G, Cines Douglas B, Muzykantov Vladimir R, Muzykhantov Vladimir R: Erythrocyte-bound tissue plasminogen activator is neuroprotective in experimental traumatic brain injury. Journal of neurotrauma 26(9): 1585-92, Sep 2009.
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Last updated: 09/11/2012
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