Design of biomedical nanodevices for dissolution of blood clots

Currently, tissue plasminogen activator (tPA) is administered intravenously after myocardial infarction and stroke to ensure blood-clot dissolution. One problem associated with such treatment is systemic toxicity of tPA, which can act upon plasminogen both in circulation and at the clot site, generating systemic plasmin and rendering the patient highly vulnerable to hemorrhaging. Here we report the synthesis and in vitro characterization of prototype nanodevices capable of binding to fibrin clots and initiating their dissolution. The devices consist of tPA and antifibrin antibody covalently attached to a 40 nm polystyrene-latex nanoparticles. These nanoscale devices can directly deliver tPA to the clot site through fibrin-specific antibody. In vitro fibrinolysis assay showed that protein–nanoparticle conjugates were only slightly less potent than free tPA. Moreover, tPA activity in the absence of clots was more than 3-fold less than that of the free enzyme. This property can be critical for therapeutic applications because nanoparticles can be expected to dissolve clots at approximately the same rate as free tPA while simultaneously cleaving much less plasminogen in the circulation, lowering the risk of hemorrhage. This system could therefore become a promising agent for thrombolytic treatment.