Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, UK.
School of Chemical Engineering, Chonnam National University, Gwangju, Republic of Korea.
Sci Adv. 2021 Jun 2;7(23). doi: 10.1126/sciadv.abf9033. Print 2021 Jun.
Clinical use of tissue plasminogen activator (tPA) in thrombolytic therapy is limited by its short circulation time and hemorrhagic side effects. Inspired by fibrinogen binding to activated platelets, we report a fibrinogen-mimicking, multiarm nanovesicle for thrombus-specific tPA delivery and targeted thrombolysis. This biomimetic system is based on the lipid nanovesicle coated with polyethylene glycol (PEG) terminally conjugated with a cyclic RGD (cRGD) peptide. Our experiments with human blood demonstrated its highly selective binding to activated platelets and efficient tPA release at a thrombus site under both static and physiological flow conditions. Its clot dissolution time in a microfluidic system was comparable to that of free tPA. Furthermore, we report a purpose-built computational model capable of simulating targeted thrombolysis of the tPA-loaded nanovesicle and with a potential in predicting the dynamics of thrombolysis in physiologically realistic scenarios. This combined experimental and computational work presents a promising platform for development of thrombolytic nanomedicines.
组织型纤溶酶原激活物（tPA）在溶栓治疗中的临床应用受到其循环时间短和出血副作用的限制。受纤维蛋白原与活化血小板结合的启发，我们报告了一种纤维蛋白原模拟的、多臂纳米囊泡，用于血栓特异性 tPA 传递和靶向溶栓。这种仿生系统基于脂质纳米囊泡，表面涂有聚乙二醇（PEG），末端连接环精氨酸-甘氨酸-天冬氨酸（cRGD）肽。我们用人体血液进行的实验表明，它在静态和生理流动条件下对活化血小板具有高度选择性结合，并能在血栓部位有效释放 tPA。在微流控系统中，其溶解血栓的时间与游离 tPA 相当。此外，我们还报告了一种专门设计的计算模型，能够模拟载 tPA 的纳米囊泡的靶向溶栓，并有可能预测生理现实场景中溶栓的动力学。这项结合实验和计算的工作为开发溶栓纳米药物提供了一个有前景的平台。
