工程化纳米血小板载带组织纤溶酶原激活物用于血栓治疗

With characteristic of thrombosis formulation, cardiovascular-associated diseases and ischemic stroke are still the major cause of morbidity and mortality worldwide. Clinically, in order to realize rapid thrombus removal and recanalization of the occluded vessel in emergency, surgical intervention and pharmacologic thrombolysis are usually considered as the first choice. However, surgical operation is much expensive and largely depends on hospital settings. Thus, the application of thrombolytic drugs continues to be a popular medical practice for thrombosis-related disease treatment. However, systemic drug administration brings indiscriminate consumption of coagulation factors and subsequently leads to high risk of unexpected bleeding complication. In addition, short half-life of most thrombolytic drugs requires repeated administration within short period which further brings much risk to patients. Therefore, it is especially important to search new strategies to realize targeting delivery of thrombolytic drug and prolong its blood circulation time. A large number of studies have showed that activated platelets are one of the major components in thrombus, indicating that activated platelets targeting is an efficient approach to target thrombus. In this project, we developed a platelet membrane cloaking polymeric nanoparticles simultaneously conjugated with tPA on the surface to achieve clot targets，prolonged half-life and thrombolytic therapy.

心血管相关疾病及缺血性中风的主要特点是血栓形成，严重的威胁了人类的健康和生命。临床上，面对急性血栓病人，最有效的手段就是手术干预或注射溶栓药物。但是，手术介入取出血栓的技术难度大，对医院的设备要求高。因此，溶栓药物成为可以被大部分医院接受的首选疗法。但是，全身性注射溶栓药物会导致全身性的凝血因子消耗，引起严重的出血并发症。此外，溶栓药物半衰期比较短，这就需要我们在短时间内反复注射溶栓药物，这样给病人带来的出血风险显著增加。因此，寻求可以将溶栓药物靶向递送到血栓部分，增加溶栓药物半衰期的新策略，就显的尤为重要。大量的研究都表明，活化血小板是构成血栓的主要成分之一，因此，靶向活化血小板成为靶向血栓的有效手段。在本项目设计中，我们构建一种血小板膜修饰的聚合物纳米载体，并在其表面偶联溶栓药物组织纤溶酶原激活物, 实现将溶栓药物靶向递送到血栓局部和延长其半衰期的目的，进而实验高效安全溶解血栓的目的。

针对已经形成的血栓，溶栓是临床重要的治疗策略。本项目针对现有溶栓药物的半衰期短，治疗时间窗窄，溶栓效率有限且存在很高的出血风险等关键科学问题，构建了一种血小板膜修饰的聚合物纳米载体，并在其表面偶联溶栓药物组织纤溶酶原激活物tPA。主要研究内容包括：血小板膜仿生纳米载体的设计、合成及表征、纳米载体的体外血栓靶向性及活力验证、对多种血栓模型的靶向性，代谢动力学及治疗效果的研究、生物安全性评价及出血风险评估等。实验结果表明，通过血小板膜的仿生设计，实现将溶栓药物靶向递送到血栓局部，达到延长tPA血液半衰期, 扩展治疗时间窗和高效安全溶栓的目的。该策略为临床溶栓治疗提供新的理论指导，具有潜在的临床应用价值，相关成果发表在国际知名学术期刊Advanced Materials上。同时，在本项目的支持下，研究者还开发了一种具有广谱抗血小板药物药效逆转功能的血小板膜纳米海绵，相关成果发表在Circulation Research上，并申请应用专利。