Sonothrombolysis of Vascular Clots with Targeted Bubbles

描述（由申请人提供）：本II期SBIR提案的长期目标是开发靶向微泡与超声联合治疗血管血栓形成（超声溶栓）。充气微泡由于具有良好的反射声的能力，目前被用作血管超声诊断剂。此外，最近的临床前研究已经证明，超声介导的微泡空化在溶解血小板血栓（凝块）中具有实用性。在I期期间，我们已经开发了靶向微泡剂，并且已经证明：1）在小鼠提睾动脉模型中与血栓结合，以及2）比非靶向微泡更有效地在体外溶解血栓。第二阶段的研究将包括五个部分：1）合成对活化的血小板血栓上的GP IIb/IIIa受体具有选择性的生物缀合物配体，2）开发具有壳膜的微泡制剂，所述壳膜具有用于凝块溶解的有效空化力，3）进行超声物理学研究以优化用于有效超声介导的血栓溶解的微泡的空化，4）在闭塞的兔股动脉模型中进行临床前研究，以使用基于目标2）和3）的参数来确定靶向微泡和超声的安全性和有效性，5）在猪的左前降支（LAD）或左回旋支分支闭塞模型中进行临床前研究，检查超声的安全性和有效性-介导的靶向微泡溶栓治疗，以及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、微创和更安全的溶栓药物或紧急血栓切除术的替代方案。此外，超声介导的治疗将提供负担得起的治疗，可以在昂贵的治疗是禁止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.