Ultrasound-Assisted Thrombolysis for Stroke Therapy

描述（由申请人提供）：超声联合组织型纤溶酶原激活剂（rt-PA）治疗或超声溶栓已被证明可改善急性缺血性卒中患者的再通。加强溶栓的有效方法已被检查，试图减少出血事件的风险。在我们正在进行的研究中，我们已经证明了溶栓的显著增强与稳定空化的存在相关，并且这种温和的气泡活动可以通过间歇输注造影剂来维持。此外，我们已经证明包封和超声波触发释放一氧化氮和其他生物活性气体，以促进血管舒张和神经保护。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，我们提出了三个具体目标：在目标#1中，我们将开发一种双元件环形阵列换能器，以促进体外和体内同时220-kHz脉冲超声暴露和被动空化检测。在整个治疗过程中监测稳定空化的能力将有助于自动控制和优化溶栓增强。在目标#2中，我们将通过猪出血性中风模型的体内研究，证明使用t-ELIP或rt-PA和造影剂的220-kHz超声增强溶栓的有效性。作为Aim #2中的一种新方法，我们还将评估用装载硫化氢（一种神经保护剂）和八氟丙烷的混合物的ELIP治疗脑出血所达到的神经保护程度，并与装载氙气（一种神经保护剂）和少量气泡成核剂的ELIP进行比较。在Aim #3中，我们将研究回声脂质体在猪动脉血栓模型中传递rt-PA和一氧化氮（一种生物活性气体）的潜力。这些研究的成功完成将阐明超声增强溶栓和超声介导的血管扩张或细胞保护气体输送的效用和潜在风险，并将提供重要的新信息，以协助设计靶向药物来改善急性卒中治疗中的溶栓和神经保护。

DESCRIPTION (provided by applicant): Combined ultrasound and tissue plasminogen activator (rt-PA) therapy, or sonothrombolysis, has been shown to improve recanalization in patients with acute ischemic stroke. Effective methods of enhancing thrombolysis have been examined in an attempt to reduce the risk of hemorrhagic events. In our ongoing studies, we have demonstrated that significant enhancement of thrombolysis correlates with the presence of stable cavitation and this type of gentle bubble activity can be sustained using an intermittent infusion of a contrast agent. In addition, we have demonstrated encapsulation and ultrasound-triggered release of nitric oxide and other bioactive gases to promote vasodilation, and neuroprotection. 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 develop a dual-element annular array transducer to facilitate simultaneous 220-kHz pulsed ultrasound exposure and passive cavitation detection in vitro and in vivo. The ability to monitor stable cavitation throughout treatment will aid in the automated control and optimization of thrombolytic enhancement. In Aim #2, we will demonstrate the efficacy of 220-kHz ultrasound- enhanced thrombolysis using t-ELIP or rt-PA and a contrast agent through in vivo studies in a porcine hemorrhagic stroke model. As a novel approach in Aim #2, we will also evaluate the degree of neuroprotection achieved by treating the intracerebral hemorrhage with ELIP loaded with a mixture of hydrogen sulfide, a neuroprotectant, and octofluoropropane to nucleate bubble activity, and compare to ELIP loaded with a mixture of xenon, a neuroprotectant, and with a smaller amount of the bubble nucleation agent. In Aim #3, we will investigate the potential of echogenic liposomes to deliver rt-PA and nitric oxide, a bioactive gas, in a porcine arterial thrombus model. Successful completion of the proposed studies will elucidate the utility and potential risks of ultrasound-enhanced thrombolysis and ultrasound-mediated delivery of vasodilatory or cytoprotective gases and will provide important new information to assist the design of targeted agents to improve thrombolysis and neuroprotection in acute stroke treatment.