中性粒细胞膜包裹的活性氧敏感型纳米粒用于芍药苷递送系统的制备及其在动脉粥样硬化的疗效研究

It has been well understood that atherosclerosis is often initiated by the endothelial layers’ dysfunction, which leads to the local inflammation where angiogenesis in atherosclerotic plaque and reactive oxygen species are over-expressed. However, only limited efficacy has been observed in clinics when the drugs are administered systemicallys, likely attributed to the rapid drug clearance by the reticuloendothelial system and unsatisfactory accumulation of therapeutic agents at the arterial injury site. Thus, potential Chinese medicine and new therapeutic paradigm or novel delivery strategies are highly desirable in order to circumvent these issues. Previous studies showed that paeoniflorin exhibited significant protective effects in numerous experimental cardio-cerebral vascular system injuries; the protective effects involved multiple mechanisms, such as antiapoptosis, anti-thrombosis, anti-inflammation and pro-angiogenic action. Our team has solid foundations in designing and evaluating novel supramolecular pharmaceutics and smart biomaterials based on self-assembly principles for the purpose of controlled drug and payload delivery, as well as targeted therapy. This investigation will provide a new insight for designing carriers that are able to escape from the reticuloendothelial system, with targeted transportation and selective drug release, which may address all the main challenges in current drug delivery systems. This novel drug delivery system might potentially be applicable to any inflammatory diseases with high expression of ROS.

动脉粥样硬化形成过程中血管内皮功能损伤、炎症反应、氧化应激及斑块内血管新生是其关键环节，然而传统药物制剂包括中药制剂治疗效果并不理想，可能与动脉损伤部位局部药物累积不充分以及对动脉粥样硬化非选择性有关，开发出具有较好抗动脉粥样硬化的中药新成分，以及较高靶向性和可控释放的中药现代化新剂型是研究和临床上亟待解决的问题。. 课题组前期基于自组装原理的新型超分子药剂和智能生物材料，已完成多种敏感性给药系统的开发制备；证实赤芍总苷可抗细胞凋亡、减少炎症反应、抗血栓、促进缺血组织治疗性血管新生。本项目以芍药苷为模型药物，将内源性免疫细胞膜分离出来并包裹在活性氧敏感型载药纳米胶束表面，以实现载药纳米胶束的靶向传递功能，并有利于逃逸网状内皮系统的清除，从而提高载药纳米胶束的仿生靶向递送。在炎症型疾病的治疗及进一步促进中药制剂现代化具有广泛的应用意义和社会价值。

动脉粥样硬化的治疗现有方法主要为降低胆固醇的药物，虽可减缓该病进程，但不能治愈，缺少可直接用于溶解血管斑块的临床药物。基于AS的炎症特性和巨噬细胞的斑块富集趋向性，拟采用超分子主客体作用构建巨噬细胞-脂质体偶连体，用于动脉斑块的“内应式”靶向递送并开发抗AS的新型细胞治疗生物试剂盒。.本项目中修饰巨噬细胞的β-环糊精（CD -MP）一方面作为主体分子用以偶连载药脂质体，另一方面可以特异性结合斑块胆固醇，促进其溶解和外排，从而达到血管斑块的靶向降解作用。同时，负载于脂质体中的槲皮素 (QT-NP)，可改变斑块巨噬细胞的极化状态并降低斑块血管的炎症，缓解动脉粥样进程，从根本上抑制AS。在血液循环过程中，巨噬细胞通过主客体相互作用与 QT-NP “手牵手”靶向斑块炎症部位，提高QT-NP对斑块血管的靶向效率。从机制上讲，MA-QT-NP 通过激活NRF2通路及上调LXR 活性、增加斑块胆固醇外排和抑制炎症水平，从而促进鼠动脉粥样斑块和人颈动脉斑块的消退，显示出MA-QT-NP 的抗AS临床转化潜力。