Sonothrombolysis of Vascular Clots with Targeted Bubbles

描述(由申请人提供)：这项第二阶段SBIR方案的长期目标是开发与超声结合的靶向微泡，用于治疗血管血栓形成(超声溶栓)。充气微泡目前被用作血管超声诊断剂，因为它们具有良好的反射声音的能力。此外，最近的临床前研究表明，超声介导的微泡空化在溶解血小板血栓方面具有实用价值。在第一阶段，我们已经开发了靶向微泡剂，并证明了：1)在小鼠生殖器动脉模型中与血栓结合，2)体外溶栓比非靶向微泡更有效。赠款第二阶段的研究将包括5个部分：1)合成针对活化的血小板血栓的GP IIb/111a受体的生物结合配体，2)开发具有有效溶栓空化力的壳膜微泡制剂，3)进行超声物理研究，以优化微泡的空化，以实现有效的超声介导性溶栓，4)在闭塞的兔股动脉模型中进行临床前研究，以确定靶向微泡和超声的安全性和有效性，使用基于目标2)和3)的参数，5)在猪左前降支(LAD)或左回旋支闭塞模型上进行临床前研究，以检验超声介导靶向微泡溶栓治疗的安全性和有效性；6)进行CMC和稳定性研究。我们推测，超声介导靶向微泡治疗将提供有效、侵入性更小、更安全的替代溶栓剂或紧急血栓摘除术。此外，超声波介导的疗法将提供负担得起的治疗，可以在昂贵治疗令人望而却步的小医院和急诊室使用。

DESCRIPTION (provided by applicant): The long-term objective of this Phase II SBIR proposal is to develop targeted microbubbles in conjunction with ultrasound for the treatment of vascular thrombosis (Sonothrombolysis). Gas-filled microbubbles are currently used as vascular ultrasound diagnostic agents because of their exquisite ability to reflect sound. In addition, recent pre-clinical studies have demonstrated that ultrasound-mediated cavitation of microbubbles has utility in lysing platelet thrombi (clots). During the Phase I period, we have developed targeted microbubble agents and have demonstrated; 1) binding to thrombi in the mouse cremasteric artery model and 2) lysing thrombi in vitro more efficiently than non-targeted microbubbles. The research in the Phase II period of the grant will involve 5 parts: 1) synthesize bioconjugate ligands selective for the GP IIb/llla receptor on activated platelet thrombi, 2) develop microbubble formulations with shell membranes that possess efficient cavitational force for clot lysis, 3) undertake ultrasound physics studies to optimize cavitation of microbubbles for efficient ultrasound-mediated thrombolysis, 4) conduct preclinical studies in the occluded rabbit femoral artery model to determine safety and efficacy of targeted microbubbles and ultrasound using parameters based upon objectives 2) and 3), 5) perform pre-clinical studies in the left anterior descending (LAD) or left circumflex branch occlusion model in pigs examining safety and efficacy of ultrasound-mediated targeted microbubble thrombolysis therapy, and 6) perform CMC and stability studies. We hypothesize that ultrasound-mediated targeted microbubble therapies will offer efficient, less invasive, and safer alternatives to thrombolytic agents or emergency thrombectomies. Furthermore, ultrasound mediated therapies will provide affordable treatments that can be used in small hospitals and emergency rooms where expensive treatment is prohibitive.