Nanomotors for thrombolytic therapy after stroke

用于中风后溶栓治疗的纳米马达

• 批准号: 8700688
• 负责人: Kunlin Jin
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700688
• 关键词: Acute; Address; Alteplase; Arteries; Binding; Blood Platelets; Blood coagulation; Blood flow; Brain; Catheters; Cerebrovascular Circulation; Clinical; Coagulation Process; Coupled; Cytolysis; Devices; Disease; Distal; Dose; Embolism; Environment; Environmental Wind; Enzymes; Erythrocytes; Excision; Failure; Fibrin; Fibrinolysis; Goals; Hemorrhage; Hour; In Vitro; Internal carotid artery structure; Intravenous; Ischemic Stroke; Left; Liquid substance; Magnetism; Mechanics; Mediating; Modeling; Motion; Myocardial Infarction; Outcome; Patients; Penetration; Plasma; Positioning Attribute; Predisposition; Pulmonary Embolism; Rattus; Research; Risk; Role; Site; Speed; Stroke; Surface; System; Technology; Testing; Therapeutic; Thrombolytic Therapy; Thrombosis; Thrombus; Time; United States; Vertebral column; base; crosslink; disability; effective therapy; enzyme activity; improved; in vivo; in vivo Model; iron oxide; magnetic field; middle cerebral artery; novel; novel strategies; post stroke; public health relevance; thrombolysis

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.

描述（由申请人提供）：静脉内组织纤溶酶原激活因子（TPA）的全身性溶栓仍然是改善急性缺血性中风患者临床结果的唯一经过验证的治疗方法。但是由于中风后3小时的出血风险增加，只有某些中风患者（1-2％）可以从TPA中受益。神经保护技术的不幸失败以及与纤维蛋白水解疗法相关的当前风险和复杂性迫使新方法发明了新方法，以重建中风受害者的血流，这些受害者更安全，更易于使用。为了改善TPA诱导的溶栓和再通速率，我们开发了磁氧化铁（FE3O4） - 纳米运动器，可以通过外部磁场在液体环境中执行旋转和正向运动。一旦纳米动物遇到动脉中的血块，它可以机械地通过凝块旋转以使凝块中的开口更大，或者充当搅拌器，使血凝块缠绕，以便可以中断和TH交联的纤维蛋白网（血液凝块的骨架）。在外部磁体的指导下，纳米运动偶联的TPA可以靶向体内缺血部位。因此，随后可以在高浓度的栓塞部位有效地递送结合的TPA，以促进溶栓。 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观察到TPA。为了检验我们的假设，将解决以下特定目标：（1）表征纳米运动在体外和Ex Vivo中的作用。 （2）表征纳米运动在体内大鼠血栓形成模型中的溶栓中的作用。如果成功的话，这种方法不仅可以彻底改变缺血性中风的治疗，而且还会对其他致命的血栓性疾病（例如心肌梗塞和肺栓塞）产生主要影响。