心血管基因、药物纳米递送系统的构建及在血管再狭窄治疗中的应用

发布时间：2019-01-09 07:13

【摘要】：心血管疾病是全球死亡的主要原因。目前,介入性治疗如球囊灌注,经皮冠状腔内血管成形术(PTCA)以及支架植入等是治疗心血管疾病的常规手段,然而这些手术之后常会发生血管再狭窄。根据血管再狭窄的病理生理机制及其发病过程可知,血管损伤部位炎症的发生以及血管平滑肌细胞的增殖与迁移是诱发血管再狭窄的两个主要原因。本课题组研制的VEGF基因与紫杉醇双层纳米粒涂层支架,植入小猪冠状动脉一个月后,表现出了完整的再内皮化和再狭窄的抑制。然而,30%-40%的血管病变,如分支血管及小血管,并不能够通过外科手术植入药物涂层支架。因此,本论文探索了双层纳米粒通过球囊灌注的形式给药,能否有效抑制血管再狭窄的发生。此外,针对如何高效地实现药物在血管病灶部位的递送问题,采用便捷简单的合成方法制备了两亲性聚合物材料3S-PLGA-PEG,对其作为药物载体的性能进行了系列的研究。第一部分:制备了内核载紫杉醇外壳载质粒的双层纳米粒,通过体外释放以及细胞增殖抑制实验观察其分步释放的特性,细胞转染表明该系统能够成功的转染并表达相关蛋白。构建实验兔动脉粥样硬化模型,通过球囊灌注的方式,将双层纳米粒递送到损伤血管。结果表明双层纳米粒治疗组实验兔表现出完整的内皮愈合,且有效抑制了血管再狭窄,并在一定程度上控制了动脉粥样硬化的病情。第二部分:为了更好地递送药物,通过开环聚合法合成了 3S-PLGA,借助草酰氯通过酯化反应将PEG与PLGA各支链连接,第一次使用草酰氯作为连接物合成了 3S-PLGA-PEG,缩短了反应步骤提高了产率,各项化学表征也证明了该材料成功合成。使用雷帕霉素作为模型药物,制备载药胶束,评价了其作为脂溶性药物递送载体的性能。结果表明该材料能够通过胶束的形式很好的递送脂溶性药物,是良好的载体材料。
[Abstract]:Cardiovascular disease is the leading cause of death worldwide. At present, interventional therapy such as balloon perfusion, percutaneous transluminal angioplasty (PTCA) and stent implantation are routine methods for the treatment of cardiovascular diseases. However, restenosis often occurs after these operations. According to the pathophysiological mechanism of vascular restenosis and its pathogenesis, inflammation and proliferation and migration of vascular smooth muscle cells are two main causes of vascular restenosis. The VEGF gene and paclitaxel coated scaffold were implanted into porcine coronary artery for one month and showed complete inhibition of restenosis and restenosis. However, 30-40% of vascular lesions, such as branched and small vessels, cannot be surgically implanted with drug-coated stents. In this paper, we explored whether the double-layer nanoparticles could effectively inhibit the occurrence of restenosis by balloon perfusion. In addition, the amphiphilic polymer 3S-PLGA-PEG was prepared by a convenient and simple synthesis method, and its performance as a drug carrier was studied. Part one: the double-layer nanoparticles carrying paclitaxel capsid plasmid were prepared. The characteristics of step release were observed by in vitro release and inhibition of cell proliferation. Cell transfection showed that the system was able to successfully transfect and express related proteins. A rabbit model of atherosclerosis was constructed, and the double-layer nanoparticles were delivered to the injured vessels by balloon perfusion. The results showed that the experimental rabbits in the double layer nanoparticles group showed complete endothelial healing, effectively inhibited the restenosis of blood vessels, and controlled the condition of atherosclerosis to a certain extent. The second part: in order to better deliver drugs, 3S-PLGA was synthesized by ring-opening polymerization. The PEG was linked to each branch of PLGA by esterification with oxaloyl chloride. 3S-PLGA-PEG was synthesized by using oxaloyl chloride for the first time. The reaction step was shortened and the yield was increased. The chemical characterization also proved that the material was successfully synthesized. Rapamycin was used as a model drug to prepare drug carrier micelles and its performance as liposoluble drug delivery carrier was evaluated. The results show that this material can deliver liposoluble drugs in the form of micelles and is a good carrier material.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

【相似文献】