Ultrasound-Assisted Thrombolysis for Stroke Therapy

超声辅助溶栓治疗中风

• 批准号: 6911454
• 负责人: CHRISTY K. HOLLAND
• 金额: $ 58.87万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911454
• 关键词: blood vessel occlusion; cerebrovascular occlusions; contrast media; disease /disorder model; disease /therapy duration; drug delivery systems; fibrinolysis; fibrinolytic agents; injection /infusion; juvenile animal; liposomes; nonhuman therapy evaluation; plasminogen activator; stroke therapy; swine; temperature; ultrasound; ultrasound biological effect

DESCRIPTION (provided by applicant):Stroke is the third leading cause of death and the leading cause of disability in the United States. For patients with ischemic stroke, the thrombolytic drug recombinant tissue plasminogen activator (rt-PA) is the only FDAapproved treatment. Systemic or peripheral administration of rt-PA has been used in the treatment of stroke with limited success as it is difficult to control delivery ofrt-PA to the target clot through a peripheral injection. Direct administration of rt-PA into the clot through a catheter shows promise, but to date has been limited by technical demands and availability of expertise in its administration. In addition, rt-PA has a significant risk to induce intracerebral hemorrhage. Therefore, to improve the efficacy of rt-PA-induced clot lysis and to reduce the administered rt-PA dose, we have investigated the synergistic effect of rt-PA and 120-KHz ultrasound on thrombolysis in an in vitro porcine clot model. These preliminary data strongly support the central hypothesis of our proposal that ultrasound enhances thrombolysis, primarily via mechanical mechanisms. To test this hypothesis we propose to investigate three Specific Aims: In Aim #1, we will expand the knowledge base of mechanisms of ultrasound-mediated thrombolysis.in a series of in vitro experiments with a porcine clot model. Using a 30-MHz active cavitation detector (or 15-MHz passive...Constantin?), we will determine the relationship between cavitational activity and accelerated thrombolysis from exposure to pulsed ultrasound. Thermocouple measurements of the clot temperature during the quiescent period of pulsed ultrasound will elucidate the contribution of thermal effects to ultrasound-enhanced thrombolysis. As a novel approach in Aim #2, we will investigate the potential of echogenic liposomes (ELIP), or submicron-sized phospholipid bilayer vesicles enclosing gas and fluid developed by McPherson and MacDonald at Northwestern University, to deliver rt-PA near the intravascular clot causing the ischemic stroke. Furthermore, ELIP can be targeted to clot by conjugating anti-fibrin antibodies to the liposome surface. Diagnostic ultrasound (low MI) will be used in vitro to identify the t-PA-loaded liposomes and to assess the targeting efficiency. The threshold of liposome destruction and drug delivery will be determined using a clinical ultrasound scanner (ATL HDI 5000). Lastly, in Aim #3, we will conduct in vivo studies in porcine hemorrhagic and ischemic stroke models to demonstrate the efficacy of ultrasound-enhanced thrombolysis and to clarify the potential risks for therapeutic ultrasound on brain tissue and in the presence of an echo contrast agent. We expect that successful completion of these studies will contribute significantly to our long-term goal to develop an ultrasound-assisted thrombolysis system that delivers and enhances thrombolytic therapy in the cerebral vasculature and rapidly restores perfusion after ischemic stroke.

描述（由申请人提供）：中风是美国第三大死亡原因和残疾的主要原因。对于缺血性卒中患者，溶栓药物重组组织纤溶酶原激活剂（rt-PA）是FDA批准的唯一治疗方法。rt-PA的全身或外周给药已用于治疗中风，但成功率有限，因为难以通过外周注射控制rt-PA向靶凝块的递送。通过导管直接将rt-PA施用到凝块中显示出前景，但迄今为止受到技术要求和施用专业知识的限制。此外，rt-PA具有诱发脑出血的显著风险。因此，为了提高rt-PA诱导的凝块溶解的功效并减少给予的rt-PA剂量，我们在体外猪凝块模型中研究了rt-PA和120-KHz超声对血栓溶解的协同作用。这些初步的数据有力地支持了我们提出的中心假设，即超声主要通过机械机制促进血栓溶解。为了检验这一假设，我们提出研究三个具体目标：在目标#1中，我们将扩展超声介导的机制的知识基础thrombolysis.in一系列使用猪凝块模型的体外实验。使用30 MHz主动空化探测器（或15 MHz被动空化探测器），康斯坦丁？），我们将确定空化活性和暴露于脉冲超声的加速血栓溶解之间的关系。热电偶测量的血块温度在静止期间的脉冲超声将阐明热效应超声增强溶栓的贡献。作为目标#2中的一种新方法，我们将研究回声脂质体（ELIP）或西北大学麦克弗森和MacDonald开发的封闭气体和液体的亚微米级磷脂双层囊泡在血管内凝块附近递送rt-PA引起缺血性卒中的潜力。此外，ELIP可以通过将抗纤维蛋白抗体缀合至脂质体表面而靶向凝块。将在体外使用诊断超声（低MI）来鉴定负载t-PA的脂质体并评估靶向效率。将使用临床超声扫描仪（ATL HDI 5000）确定脂质体破坏和药物递送的阈值。最后，在目标3中，我们将在猪出血性和缺血性卒中模型中进行体内研究，以证明超声增强溶栓的有效性，并阐明治疗性超声对脑组织和存在超声造影剂的潜在风险。我们希望这些研究的成功完成将大大有助于我们的长期目标，即开发一种超声辅助溶栓系统，在脑血管系统中提供和增强溶栓治疗，并在缺血性卒中后快速恢复灌注。