Ultrasound-Assisted Thrombolysis for Stroke Therapy

超声辅助溶栓治疗中风

• 批准号: 7081275
• 负责人: CHRISTY K. HOLLAND
• 金额: $ 58.53万
• 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/7081275
• 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导致残疾的主要原因。对于缺血性中风患者，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，但效果有限，因为很难通过外周注射控制 rt-PA 向目标凝块的递送。通过导管将 rt-PA 直接注射到血凝块中显示出良好的前景，但迄今为止，其注射仍受到技术要求和专业知识的限制。此外，rt-PA具有诱发脑出血的显着风险。因此，为了提高rt-PA诱导的血栓溶解的功效并减少rt-PA的给药剂量，我们在体外猪血栓模型中研究了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提议的中心假设，即超声主要通过机械机制增强血栓溶解。为了检验这一假设，我们建议研究三个具体目标：在目标#1中，我们将通过猪血凝块模型进行一系列体外实验，扩展超声介导的溶栓机制的知识库。使用 30 MHz 主动空化检测器（或 15 MHz 被动...Constantin？），我们将确定空化活动与暴露于脉冲超声导致的加速溶栓之间的关系。在脉冲超声静止期间热电偶测量凝块温度将阐明热效应对超声增强溶栓的贡献。作为目标 2 中的一种新方法，我们将研究西北大学 McPherson 和 MacDonald 开发的回声脂质体 (ELIP) 或亚微米大小的磷脂双层囊泡，其内含气体和液体，在引起缺血性中风的血管内凝块附近传递 rt-PA 的潜力。此外，ELIP 可以通过将抗纤维蛋白抗体缀合到脂质体表面来靶向凝结。将在体外使用诊断超声（低 MI）来识别负载 t-PA 的脂质体并评估靶向效率。脂质体破坏和药物输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功效，并澄清治疗性超声对脑组织和存在回声造影剂的潜在风险。我们预计这些研究的成功完成将为我们的长期目标做出重大贡献，即开发超声辅助溶栓系统，在脑血管系统中提供和增强溶栓治疗，并在缺血性中风后快速恢复灌注。