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，急性中风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的三小时内到达并接受静脉注射tPA。此外，传统的溶栓药物可能导致严重出血，特别是脑出血，这减少了它们的临床应用。在这个项目中，我们将开发和评估用于治疗急性中风的纤维蛋白靶向溶栓纳米颗粒。我们假设，纤维蛋白靶向溶栓纳米颗粒将允许急性血栓定向溶解，使用低剂量的溶栓剂，即使在存在“渗漏”的内皮细胞的情况下，也受颗粒大小的限制。我们的目的是开发一种安全有效的药剂，可以立即由急救技术人员或医生使用。快速启动血运重建是神经系统抢救的基石。本项目的主要目标是：有机合成、表征和体外证明基于纤维蛋白靶向溶栓的全氟碳纳米颗粒（Fibrin-Lytic-NP）尿激酶表面偶联的原型。这些药物将在体外对生物活性（归巢、纤溶酶原激活和纤维蛋白降解）、使用前的稳定性和现场给药的快速制备进行评估、表征和优化。在原位和循环中研究纤维蛋白溶解- nps对狗动脉血栓形成的归家和溶栓生物活性的药物动力学和药效学。评估纤维蛋白溶解- np的剂量依赖性安全性，特别是关于体内啮齿动物手术伤口模型的出血性并发症。

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.