Soluble Urokinase Receptor Conjugated to Carrier Red Blood Cells Binds Latent Pro-urokinase and Alters Its Functional Profile

Overview

Journal J Control Release

Specialty Pharmacology

Date 2009 Jul 21

PMID 19616049

Citations 25

Authors

Juan-Carlos Murciano

Abd Al-Roof Higazi

Douglas B Cines

Vladimir R Muzykantov

Affiliations

Soon will be listed here.

Abstract

Coupling plasminogen activators to carrier red blood cells (RBC) prolongs their life-time in the circulation and restricts extravascular side effects, thereby allowing their utility for short-term thromboprophylaxis. Unlike constitutively active plasminogen activators, single chain urokinase plasminogen activator (scuPA) is activated by plasmin proteolysis or binding to its receptor, uPAR. In this study we conjugated recombinant soluble uPAR (suPAR) to rat RBC, forming RBC/suPAR complex. RBC carrying suPAR circulated in rats similarly to naïve RBC and markedly prolonged the circulation time of suPAR. RBC/suPAR carrying approximately 3x10(4) suPAR molecules per RBC specifically bound up to 2x10(4) molecules of scuPA, retained approximately 75% of scuPA-binding capacity after circulation in rats and markedly altered the functional profile of bound scuPA. RBC carrying directly conjugated scuPA adhered to endothelial cells, while showing no appreciable fibrinolytic activity. In contrast, RBC/suPAR loaded with scuPA did not exhibit increased adhesion to endothelium, while effectively dissolving fibrin clots. This molecular design, capitalizing on unique biological features of the interaction of scuPA with its receptor, provides a promising modality to deliver a pro-drug for prevention of thrombosis.

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