Sonothrombolysis of Vascular Clots with Targeted Bubbles

描述（由申请人提供）：该II期SBIR提案的长期目标是开发靶向微泡结合超声治疗血管血栓形成（Sonothrombolysis）。充气微泡具有良好的声反射能力，目前被用作血管超声诊断试剂。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（凝块）方面具有实用价值。在第一阶段，我们开发了靶向微泡剂，并证明；1)在小鼠增稠动脉模型中与血栓结合；2)在体外比非靶向微泡更有效地溶解血栓。第二阶段的研究将包括五个部分：1)在活化的血小板血栓上合成选择性GP IIb/llla受体的生物偶联配体；2)开发具有有效空化力的壳膜微泡配方，用于凝块溶解；3)进行超声物理研究，优化微泡空化，用于有效的超声介导溶栓。4)在兔股动脉闭塞模型中进行临床前研究，根据目标2)和目标3)的参数确定靶向微泡和超声的安全性和有效性；5)在猪左前降支（LAD）或左旋支闭塞模型中进行临床前研究，检查超声介导的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。我们假设超声介导的靶向微泡治疗将提供有效、侵入性小、更安全的替代溶栓药物或紧急血栓切除术。此外，超声介导疗法将提供负担得起的治疗，可用于小型医院和急诊室，在那里昂贵的治疗是望而却步的。

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.