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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1999-2006. Prepublished online as a Blood First Edition Paper on November 28, 2007; DOI 10.1182/blood-2007-07-103002. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-07-103002v1 111/4/1999    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ding, B.-S. Articles by Muzykantov, V. R. Search for Related Content PubMed PubMed Citation Articles by Ding, B.-S. Articles by Muzykantov, V. R. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Prophylactic thrombolysis by thrombin-activated latent prourokinase targeted to PECAM-1 in the pulmonary vasculature Bi-Sen Ding1, Nankang Hong2, Juan-Carlos Murciano3, Kumkum Ganguly4, Claudia Gottstein5, Melpo Christofidou-Solomidou6, Steven M. Albelda6, Aron B. Fisher2, Douglas B. Cines7, and Vladimir R. Muzykantov1,2 1 Department of Pharmacology, Institute for Translational Medicine and Therapeutics; 2 Institute for Environmental Medicine, University of Pennsylvania, Philadelphia; 3 Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; 4 Los Alamos National Laboratory, Los Alamos, NM; 5 Department of Chemical Engineering, University of California Santa Barbara, CA; 6 Division of Pulmonary, Allergy, and Critical Care Medicine; 7 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia A recombinant prodrug, single-chain urokinase-type plasminogen activator (scuPA) fused to an anti–PECAM-1 antibody single-chain variable fragment (anti–PECAM scFv/scuPA) targets endothelium and augments thrombolysis in the pulmonary vasculature.1 To avoid premature activation and inactivation and to limit systemic toxicity, we replaced the native plasmin activation site in scFv/low-molecular-weight (lmw)–scuPA with a thrombin activation site, generating anti–PECAM scFv/uPA-T that (1) is latent and activated by thrombin instead of plasmin; (2) binds to PECAM-1; (3) does not consume plasma fibrinogen; (4) accumulates in mouse lungs after intravenous injection; and (5) resists PA inhibitor PAI-1 until activated by thrombin. In mouse models of pulmonary thrombosis caused by thromboplastin and ischemia-reperfusion (I/R), scFv/uPA-T provided more potent thromboprophylaxis and greater lung protection than plasmin-sensitive scFv/uPA. Endothelium-targeted thromboprophylaxis triggered by a prothrombotic enzyme illustrates a novel approach to time- and site-specific regulation of proteolytic reactions that can be modulated for therapeutic benefit. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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