Nanomotors for thrombolytic therapy after stroke

描述（由申请方提供）：静脉注射组织型纤溶酶原激活剂（tPA）全身溶栓仍然是改善急性缺血性卒中患者临床结局的唯一经证实的治疗方法。但是，由于卒中后3小时以上出血风险增加，只有某些卒中患者（1-2%）可以从tPA中获益。神经保护技术的不幸失败以及与纤溶治疗相关的当前风险和复杂性迫使发明新的方法来重建中风患者的血流，这些方法使用起来更安全和更简单。为了提高tPA诱导的血栓溶解和再通率，我们开发了磁性氧化铁（Fe 3 O 4）-纳米马达，它可以通过外部磁场在液体环境中进行旋转和向前运动。一旦纳米马达遇到动脉中的血凝块，它可以机械地旋转通过凝块以在凝块中形成更大的开口，或者充当搅拌器以缠绕血凝块，从而可以破坏交联的纤维蛋白网（血凝块的骨架）。结合tPA的纳米马达可以在外部磁体的引导下靶向体内缺血部位;因此，结合的tPA随后可以以高浓度有效地递送到栓塞部位以促进血栓溶解。我们假设1）可生物降解的磁性纳米马达缀合的tPA（纳米马达-tPA）可以在磁性引导下递送到缺血部位，并且2）血液凝块可以在旋转磁场下通过纳米马达机械地穿孔和松动，因此促进tPA和血浆（用于凝块溶解的底物）的槽内递送，并且改善血栓溶解超过目前观察到的tPA的效率。为了验证我们的假设，将解决以下具体目标：（1）表征纳米马达在体外和离体溶栓中的作用。(2)在大鼠体内血栓形成模型中表征纳米马达在血栓溶解中的作用。如果成功，这种方法不仅可以彻底改变缺血性中风的治疗，还可以对心肌梗死和肺栓塞等其他致命血栓性疾病产生重大影响。

DESCRIPTION (provided by applicant): Systemic thrombolysis with intravenous tissue plasminogen activator (tPA) remains the only proven treatment to improve clinical outcome of patients with acute ischemic stroke. But because of an increased risk of hemorrhage beyond 3 hours post stroke, only certain stroke patients (1-2%) can benefit from tPA. The unfortunate failure of neuroprotective technologies and the current risks and complexity associated with fibrinolytic therapy compels invention of new approaches to reestablish blood flow in stroke victims that are safer and simpler to use. To improve tPA-induced thrombolysis and recanalization rates, we have developed magnetic iron oxide (Fe3O4)-nanomotors, which can perform rotary and forward motion in liquid environment by an external magnetic field. Once the nanomotors encounter the blood clot in the artery, it can either mechanically twirl through the clot to make a larger opening in the clot or act as a beater to wind the blood clot, so that and th cross-linked fibrin mesh (the backbone of a blood clot) can be disrupted. The nanomotors conjugated tPA can target to the ischemic site in vivo under the guidance of an external magnet; therefore, bound tPA can subsequently be efficiently delivered at the site of embolism at high concentration to facilitate thrombolysis. We hypothesize that 1) biodegradable magnetic nanomotors conjugated tPA (nanomotor-tPA) can be delivered to ischemic site under magnetic guidance and 2) blood clots can be mechanically pored and loosened by the nanomotors under a rotating magnetic field, therefore promoting intraclot delivery of both tPA and plasma (substrate for clot lysis) and improving thrombolysis beyond the efficiency currently observed for tPA. To test our hypothesis, the following Specific Aims will be addressed: (1) To characterize the role of nanomotors in thrombolysis in vitro and ex vivo. (2) To characterize the role of nanomotors in thrombolysis in the rat thrombotic model in vivo. If successful, this approach could revolutionize not just the treatment of ischemic stroke but also have majorly impact on other deadly thrombotic diseases such as myocardial infarction and pulmonary embolism.