Fibrin-Specific Thrombolytic Nanoparticles for Acute Stroke

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DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States and, for many survivors, often results in functional impairment and long-term disability. Treatment of acute stroke in the United States is primarily with intravenous (IV) tissue-type plasminogen activator (tPA) and nearly 50% of patients treated achieve almost full recovery. However, few patients with stroke arrive within three hours of symptom presentation and receive IV tPA. Moreover, the potential for significant bleeding, particularly intracerebral hemorrhage, induced by traditional thrombolytics diminishes their clinical use. In this project, we will develop and evaluate fibrin-targeted thrombolytic nanoparticles for treatment of acute stroke. We hypothesize that fibrin-targeted thrombolytic nanoparticles will allow site-directed dissolution of acute thrombus using lower dosages of thrombolytic agent which are constrained by particle size to the circulation, even in the presence of "leaky" endothelium. Our intent is to develop an agent that would be safe and effective for immediate administration by emergency technicians or physicians. Rapid initiation of revascularization is the cornerstone to neurologic rescue.. The major goals of this program will be: To organically synthesize, characterize and demonstrate in vitro, a prototype fibrin-targeted thrombolytic perfluorocarbon nanoparticle (Fibrin-Lytic-NP) based surface coupling of urokinase. These agents will evaluate, characterized, and optimized in vitro for biological activities (homing, plasminogen activation, and fibrin degradation), stability until use, and rapid preparation for on-site administration. To demonstrate pharmacokinetics and pharmacodynamics of the homing and thrombolytic bioactivity of Fibrin-Lytic-NPs for intra-arterial thrombosis in dog studied in situ and in circulation. To evaluate the dose dependent safety of Fibrin-Lytic-NP with particular regard to hemorrhagic complications in vivo rodent surgical wound models.