Fibrin-Specific Thrombolytic Nanoparticles for Acute Stroke

描述（由申请人提供）：中风是美国第三大死亡原因，对于许多幸存者来说，通常会导致功能障碍和长期残疾。在美国，急性卒中的治疗主要是静脉注射（IV）组织型纤溶酶原激活剂（tPA），近50%的患者几乎完全康复。然而，很少有中风患者在出现症状后3小时内到达并接受IV tPA治疗。此外，由传统溶栓剂引起的显著出血，特别是脑内出血的可能性减少了它们的临床应用。在本项目中，我们将开发和评估用于治疗急性脑卒中的纤维蛋白靶向溶栓纳米颗粒。我们假设，纤维蛋白靶向的溶栓纳米颗粒将允许使用较低剂量的溶栓剂，即使在存在“渗漏”内皮的情况下，也可以通过循环的颗粒大小限制急性血栓的定点溶解。我们的目的是开发一种安全有效的药物，供紧急技术人员或医生立即使用。快速启动血运重建是神经系统抢救的基石。该计划的主要目标将是：有机合成，表征和体外演示，原型纤维蛋白靶向溶栓全氟化碳纳米颗粒（Fibrin-Lytic-NP）基于尿激酶的表面偶联。这些试剂将在体外评价、表征和优化生物活性（归巢、纤溶酶原活化和纤维蛋白降解）、使用前稳定性和现场给药快速制备。证明在原位和循环中研究的溶纤蛋白纳米粒对犬动脉内血栓形成的归巢和溶栓生物活性的药代动力学和药效学。评价溶纤蛋白-NP的剂量依赖性安全性，特别是在体内啮齿动物手术伤口模型中的出血性并发症。

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.