温度控释溶栓药物纳米制剂的构建与过热溶栓研究

Most thrombolytic drugs are protease with drawbacks of being inactivation in vivo and short blood circulation time. It’s a dilemmatic state that over-dosages of drugs induced bleeding, while limited dosages have little thrombolytic effect. So, it’s great significance in the academic to fabricate a smart controlled thrombolytic drugs release nano-pharmaceutics, which possess a targeted and on-demand drug dosed mode for clinical thrombolysis. To aim at the research status of thrombolytic drugs delivery system, drug conjugated system with sustained release and controlled release system via endogenous signal, a thrombolytic drugs delivery system based on temperature-responsive magnetic liposomes, which could achieve magnetic targeted drug delivery, remote controlled drug release via magnetic hyperthermia signal with an additional effect of hyperthermia assistant thrombolysis, was present in this project. A blood vessel model was fabricated via 3D printing technology and the thrombolytic effect of nano-pharmaceutics was evaluated in static and dynamic statement in vitro and in animal model. On this basis, the change of thrombus microenvironment in the localized hyperthermia was observed and the mechanism of hyperthermia enhanced thrombolysis would be illuminated. The study would supply scientific reasons for illumination of mechanism, and lay a solid foundation for exploring a new nano-pharmaceutics in clinical thrombolysis.

溶栓药物多为蛋白酶类药物，体内易失活、循环周期短；临床用药常陷入量过多易诱导出血，量过少则无溶栓效果的两难局面。因此，构建具有智能可控特性的溶栓药物纳米制剂，实现定向按需的给药方式对临床溶栓治疗具有重要意义。针对目前的溶栓药物输送体系多为药物偶联的缓释系统及内源性信号控释系统的研究现状，本项目提出构建基于温度响应性磁性脂质体的溶栓药物纳米制剂，通过外界磁场将纳米制剂输送至血栓发生处，在利用磁热响应刺激信号对溶栓药物控释的同时，还实现了热信号辅助溶栓的双重效应。本项目拟利用3D打印技术构建血管模型，分别在体外静态、动态环境和动物体内水平，研究纳米制剂对血栓溶解的影响规律。并在此基础上，考察原位过热溶栓期间血栓微环境所发生的变化，深度探讨过热促进血栓溶解的作用机制。本研究将为阐明过热促进血栓溶解的科学内涵提供理论依据，同时为开发适用于临床的溶栓药物纳米制剂打下坚实的基础。

临床使用溶栓药物常面临少则无效，多则出血等副作用。鉴于这一临床问题，我们基于局部过热可促进血栓溶解，构建了一系列通过光热促发温度响应性溶栓药物递送系统。相关研究涉及递送系统的设计与构建、药物释放规律、递送系统的体内外生物学评价以及小动物体内溶栓评价。另外，本项目还拓展研究了抗肿瘤药物智能递送体系和不同色温光的生理学上影响。具体研究内容包括：（1）光热响应性溶栓药物递送系统的构建；（2）递送系统的溶栓增强效率研究；（3）局部过热对血栓溶解的影响；（4）氧化还原响应性抗肿瘤药物递送系统；（5）不同色温光对褪黑素、伤口愈合及生发的影响。本项目成功构建了几种温度响应性溶栓药物控释系统，并验证了局部过热可直接加强药物溶栓效率。. 总体上讲，项目进展顺利，完成情况良好，在Nanoscale Horizons、ACS Applied Materials & Interfaces、Journal of Materials Chemistry B、ACS Biomaterials-Science & Engineering等杂志发表论文9篇，申请国家发明专利1项；培养硕士研究生4名。完成了该项目的既定目标。已取得的“温度控释溶栓药物纳米制剂的构建与过热溶栓研究”研究成果，为今后光热溶栓治疗提供理论依据。