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Plasminogen Activators as Prophylactic Fibrinolytics: Overcoming Free Protein Shortcomings

David A. Christian1, Kumkum Ganguly2, Younghoon Kim1, Shenshen Cai1, Vladimir R. Muzykantov2, and Dennis E. Discher1. (1) Chemical & Biomolecular Engineering, University of Pennsylvania, Room 129 Towne Building, 220 South 33rd Street, Philadelphia, PA 19104-6393, (2) Institute for Environmental Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104

Plasminogen activators (PAs) are proteins native to the body that are responsible for the dissolution of pre-existing fibrin clots. While PAs are used to dissolve clots in the treatment of acute cases of thrombosis (i.e. stroke, heart attack), their side effects prevent their use as thromboprophylactics. PAs such as tissue-type plaminogen activator (tPA) are cleared quickly from the body, unselectively dissolve both preexisting and nascent (pathological) clots, and have been shown to cause neuronal death and remodeling of the vascular matrix. In previous studies, it has been shown that the coupling of tPA to erythrocytes provides a natural, long-circulating carrier that overcomes the negative side effects of the free protein. Here, we investigate the use of degradable, long-circulating worm micelles as a synthetic carrier of PAs. Worm micelles are formed after blending two different degradable copolymers (4kD PEG-PCL and 10kD NHS-PEG-PCL). A difference in copolymer molecular weights has been previously shown to be effective in presenting the functional site of the copolymer. In this study, direct attachment of PAs to worm micelles is compared to the use of streptavidin as a linker between biotinylated worm micelles and biotinylated tPA.