Ultrasound-Assisted Thrombolysis for Stroke Therapy

超声辅助溶栓治疗中风

• 批准号: 7032852
• 负责人: CHRISTY K. HOLLAND
• 金额: $ 1.76万
• 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/7032852
• 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致残原因。对于缺血性卒中患者，溶栓药物重组组织型纤溶酶原激活剂（rt-PA）是唯一获fda批准的治疗药物。全身或外周给药rt-PA已被用于治疗中风，但成功有限，因为很难控制rt-PA通过外周注射输送到目标凝块。通过导管将rt-PA直接给药到血栓中显示出希望，但迄今为止，由于技术要求和在给药方面的专业知识的可用性而受到限制。此外，rt-PA有诱发脑出血的显著风险。因此，为了提高rt-PA诱导的溶栓效果，减少rt-PA给药剂量，我们在体外猪血块模型中研究了rt-PA和120 khz超声对溶栓的协同作用。这些初步数据有力地支持了我们建议的中心假设，即超声主要通过机械机制增强溶栓。为了验证这一假设，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溶栓机制的知识库。在猪血块模型的一系列体外实验中。使用30 mhz主动空化检测器（或15 mhz被动…Constantin?），我们将确定空化活性与暴露于脉冲超声加速溶栓之间的关系。热电偶测量在脉冲超声静止期间的凝块温度将阐明热效应对超声增强溶栓的贡献。作为Aim #2的一种新方法，我们将研究回声脂质体（ELIP）的潜力，或亚微米大小的磷脂双层囊泡包裹气体和液体，由西北大学的McPherson和MacDonald开发，在引起缺血性中风的血管内凝块附近传递rt-PA。此外，ELIP可以通过结合抗纤维蛋白抗体到脂质体表面来靶向凝块。诊断超声（低MI）将用于体外鉴定载t- pa脂质体并评估靶向效率。脂质体破坏和药物递送的阈值将使用临床超声扫描仪（ATL HDI 5000）确定。最后，在目标#3中，我们将在猪出血性和缺血性中风模型中进行体内研究，以证明超声增强溶栓的有效性，并阐明超声治疗对脑组织和回声造影剂存在的潜在风险。我们期望这些研究的成功完成将对我们开发超声辅助溶栓系统的长期目标做出重大贡献，该系统可在缺血性卒中后提供并增强脑血管溶栓治疗并快速恢复灌注。