【摘要】：心血管疾病是全球死亡的主要原因。目前,介入性治療如球囊灌注,經皮冠狀腔內血管成形術(PTCA)以及支架植入等是治療心血管疾病的常規(guī)手段,然而這些手術之后常會發(fā)生血管再狹窄。根據血管再狹窄的病理生理機制及其發(fā)病過程可知,血管損傷部位炎癥的發(fā)生以及血管平滑肌細胞的增殖與遷移是誘發(fā)血管再狹窄的兩個主要原因。本課題組研制的VEGF基因與紫杉醇雙層納米粒涂層支架,植入小豬冠狀動脈一個月后,表現出了完整的再內皮化和再狹窄的抑制。然而,30%-40%的血管病變,如分支血管及小血管,并不能夠通過外科手術植入藥物涂層支架。因此,本論文探索了雙層納米粒通過球囊灌注的形式給藥,能否有效抑制血管再狹窄的發(fā)生。此外,針對如何高效地實現藥物在血管病灶部位的遞送問題,采用便捷簡單的合成方法制備了兩親性聚合物材料3S-PLGA-PEG,對其作為藥物載體的性能進行了系列的研究。第一部分:制備了內核載紫杉醇外殼載質粒的雙層納米粒,通過體外釋放以及細胞增殖抑制實驗觀察其分步釋放的特性,細胞轉染表明該系統(tǒng)能夠成功的轉染并表達相關蛋白。構建實驗兔動脈粥樣硬化模型,通過球囊灌注的方式,將雙層納米粒遞送到損傷血管。結果表明雙層納米粒治療組實驗兔表現出完整的內皮愈合,且有效抑制了血管再狹窄,并在一定程度上控制了動脈粥樣硬化的病情。第二部分:為了更好地遞送藥物,通過開環(huán)聚合法合成了 3S-PLGA,借助草酰氯通過酯化反應將PEG與PLGA各支鏈連接,第一次使用草酰氯作為連接物合成了 3S-PLGA-PEG,縮短了反應步驟提高了產率,各項化學表征也證明了該材料成功合成。使用雷帕霉素作為模型藥物,制備載藥膠束,評價了其作為脂溶性藥物遞送載體的性能。結果表明該材料能夠通過膠束的形式很好的遞送脂溶性藥物,是良好的載體材料。
[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.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R943

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