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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4191-4198. Prepublished online as a Blood First Edition Paper on September 6, 2005; DOI 10.1182/blood-2005-05-2002. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-05-2002v1 106/13/4191    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 HighWire 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 Cell Adhesion and Motility Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature Bi-Sen Ding, Claudia Gottstein, Andrea Grunow, Alice Kuo, Kumkum Ganguly, Steven M. Albelda, Douglas B. Cines, and Vladimir R. Muzykantov From the Department of Pharmacology, University of Pennsylvania, Philadelphia, PA; the Department of Internal Medicine I, Experimental Oncology and Vascular Biology, University of Cologne, Germany; the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA; the Department of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania, Philadelphia, PA; and the Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA. Means to prevent thrombus extension and local recurrence remain suboptimal, in part because of the limited effectiveness of existing thrombolytics. In theory, plasminogen activators could be used for this purpose if they could be anchored to the vascular lumen by targeting stably expressed, noninternalized determinants such as platelet-endothelial-cell adhesion molecule 1 (PECAM-1). We designed a recombinant molecule fusing low-molecular-weight single-chain prourokinase plasminogen activator (lmw-scuPA) with a single-chain variable fragment (scFv) of a PECAM-1 antibody to generate the prodrug scFv/lmw-scuPA. Cleavage by plasmin generated fibrinolytically active 2-chain lmw-uPA. This fusion protein (1) bound specifically to PECAM-1-expressing cells; (2) was rapidly cleared from blood after intravenous injection; (3) accumulated in the lungs of wild-type C57BL6/J, but not PECAM-1 null mice; and (4) lysed pulmonary emboli formed subsequently more effectively than lmw-scuPA, thereby providing support for the concept of thromboprophylaxis using recombinant scFv-fibrinolytic fusion proteins that target endothelium. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B.-S. Ding, N. Hong, M. Christofidou-Solomidou, C. Gottstein, S. M. Albelda, D. B. Cines, A. B. Fisher, and V. R. Muzykantov Anchoring Fusion Thrombomodulin to the Endothelial Lumen Protects against Injury-induced Lung Thrombosis and Inflammation Am. J. Respir. Crit. Care Med., August 1, 2009; 180(3): 247 - 256. [Abstract] [Full Text] [PDF] C. Garnacho, V. Shuvaev, A. Thomas, L. McKenna, J. Sun, M. Koval, S. Albelda, V. Muzykantov, and S. Muro RhoA activation and actin reorganization involved in endothelial CAM-mediated endocytosis of anti-PECAM carriers: critical role for tyrosine 686 in the cytoplasmic tail of PECAM-1 Blood, March 15, 2008; 111(6): 3024 - 3033. [Abstract] [Full Text] [PDF] B.-S. Ding, N. Hong, J.-C. Murciano, K. Ganguly, C. Gottstein, M. Christofidou-Solomidou, S. M. Albelda, A. B. Fisher, D. B. Cines, and V. R. Muzykantov Prophylactic thrombolysis by thrombin-activated latent prourokinase targeted to PECAM-1 in the pulmonary vasculature Blood, February 15, 2008; 111(4): 1999 - 2006. [Abstract] [Full Text] [PDF] R. Rossin, S. Muro, M. J. Welch, V. R. Muzykantov, and D. P. Schuster In Vivo Imaging of 64Cu-Labeled Polymer Nanoparticles Targeted to the Lung Endothelium J. Nucl. Med., January 1, 2008; 49(1): 103 - 111. [Abstract] [Full Text] [PDF] K. Danielyan, B.-S. Ding, C. Gottstein, D. B. Cines, and V. R. Muzykantov Delivery of Anti-Platelet-Endothelial Cell Adhesion Molecule Single-Chain Variable Fragment-Urokinase Fusion Protein to the Cerebral Vasculature Lyses Arterial Clots and Attenuates Postischemic Brain Edema J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 947 - 952. [Abstract] [Full Text] [PDF] P. Stoll, N. Bassler, C. E. Hagemeyer, S. U. Eisenhardt, Y. C. Chen, R. Schmidt, M. Schwarz, I. Ahrens, Y. Katagiri, B. Pannen, et al. Targeting Ligand-Induced Binding Sites on GPIIb/IIIa via Single-Chain Antibody Allows Effective Anticoagulation Without Bleeding Time Prolongation Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1206 - 1212. [Abstract] [Full Text] [PDF] B.-S. Ding, T. Dziubla, V. V. Shuvaev, S. Muro, and V. R. Muzykantov Advanced drug delivery systems that target the vascular endothelium. Mol. Interv., April 1, 2006; 6(2): 98 - 112. [Abstract] [Full Text] [PDF]

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