Thrombus-targeted complexes of plasminogen activator and fibrin fragments

Abstract

Thrombolytic hybrids are formed as covalent or non-covalent complexes of fibrin fragments and plasminogen activator molecules. Native plasmin degradation fragments of fibrin or non-native fibrin fragments are covalently or non-covalently linked to plasminogen activators such as t-PA, scu-PA, urokinase, streptokinase, and the like. Useful native fibrin fragments which may be utilized to form complexes with plasminogen activators include fragments E.sub.1, E.sub.2, E.sub.3, D and DD, and (DD)E complex. The fibrin fragment component targets the hybrid to vascular thrombi, immobilizing the plasminogen activator molecule onto the fibrin surface of the thrombus. Once localized on a thrombus surface, the plasminogen activator component of the hybrid activates only the clot-surface bound plasminogen transported by the fibrin fragment vehicle, without significant systemic activation of plasminogen. The hybrids are strong potentiators of plasminogen activator activity, generating more plasmin from fibrin-surface bound plasminogen than the plasminogen activator molecule alone. The hybrids have a longer half-life in circulation than the corresponding unprotected plasminogen activator molecules.

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