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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 26, 2007; DOI: 10.1124/jpet.107.120535

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*Substance via MeSH


Received for publication January 26, 2007.
Revised March 22, 2007.
Accepted for publication March 22, 2007.

Delivery of anti-PECAM scFv-urokinase fusion protein to the cerebral vasculature lyses arterial clots and attenuates post-ischemic brain edema

Kristina Danielyan 1, Bi-Sen Ding 1, Claudia Gottstein 2, Douglas B Cines 1, Vladimir R Muzykantov 1*

1 University of Pennsylvania 2 UCSB

* Address correspondence to: E-mail: muzykant{at}mail.med.upenn.edu

Abstract

Efficacy and safety of the current means of preventing cerebrovascular thrombosis in patients at high risk of stroke are sub-optimal. In theory, anchoring of fibrinolytic plasminogen activators on the luminal surface of the cerebral endothelium might arrest formation of occlusive clots in this setting. We tested this approach using a recombinant construct anti-PECAM scFv-uPA, fusing low molecular weight single-chain pro-urokinase plasminogen activator (lmw-scuPA) with a single-chain variable fragment (scFv) of an antibody directed to the stably expressed endothelial surface determinant, Platelet-Endothelial Cell Adhesion Molecule-1 (PECAM-1), implicated in inflammation and thrombosis. Studies in mice showed that scFv-uPA, but not unconjugated uPA: i) accumulates in the brain after intravascular injection; ii) lyses clots lodged in the cerebral arterial vasculature without hemorrhagic complications; iii) provides rapid and stable cerebral reperfusion; and, iv) alleviates post-thrombotic brain edema. Effective and safe thromboprophylaxis in the cerebral arterial circulation by anti-PECAM scFv-uPA provides a prototype of a new paradigm to prevent recurrent cerebrovascular thrombosis.


Key words: Drug delivery, Endothelium, Fibrinolysis, PECAM-1, Plasminogen activators, Thrombosis


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[Abstract] [Full Text] [PDF]


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