【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(jīng)皮冠狀腔內(nèi)血管成形術(shù)(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(shù)之后常會(huì)發(fā)生血管再狹窄。根據(jù)血管再狹窄的病理生理機(jī)制及其發(fā)病過(guò)程可知,血管損傷部位炎癥的發(fā)生以及血管平滑肌細(xì)胞的增殖與遷移是誘發(fā)血管再狹窄的兩個(gè)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(dòng)脈一個(gè)月后,表現(xiàn)出了完整的再內(nèi)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(guò)外科手術(shù)植入藥物涂層支架。因此,本論文探索了雙層納米粒通過(guò)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(duì)如何高效地實(shí)現(xiàn)藥物在血管病灶部位的遞送問(wèn)題,采用便捷簡(jiǎn)單的合成方法制備了兩親性聚合物材料3S-PLGA-PEG,對(duì)其作為藥物載體的性能進(jìn)行了系列的研究。第一部分:制備了內(nèi)核載紫杉醇外殼載質(zhì)粒的雙層納米粒,通過(guò)體外釋放以及細(xì)胞增殖抑制實(shí)驗(yàn)觀察其分步釋放的特性,細(xì)胞轉(zhuǎn)染表明該系統(tǒng)能夠成功的轉(zhuǎn)染并表達(dá)相關(guān)蛋白。構(gòu)建實(shí)驗(yàn)兔動(dòng)脈粥樣硬化模型,通過(guò)球囊灌注的方式,將雙層納米粒遞送到損傷血管。結(jié)果表明雙層納米粒治療組實(shí)驗(yàn)兔表現(xiàn)出完整的內(nèi)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(dòng)脈粥樣硬化的病情。第二部分:為了更好地遞送藥物,通過(guò)開環(huán)聚合法合成了 3S-PLGA,借助草酰氯通過(guò)酯化反應(yīng)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(yīng)步驟提高了產(chǎn)率,各項(xiàng)化學(xué)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(píng)價(jià)了其作為脂溶性藥物遞送載體的性能。結(jié)果表明該材料能夠通過(guò)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(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R943

【相似文獻(xiàn)】

相關(guān)會(huì)議論文 前10條

1 楊菁;苗立夫;宋存先;朱文玲;;雷帕霉素納米粒子用于血管再狹窄治療的研究[A];天津市生物醫(yī)學(xué)工程學(xué)會(huì)第29屆學(xué)術(shù)年會(huì)暨首屆生物醫(yī)學(xué)工程前沿科學(xué)研討會(huì)論文集[C];2009年

2 楊菁;苗立夫;宋存先;朱文玲;;雷帕霉素納米粒子用于血管再狹窄治療的研究[A];天津市生物醫(yī)學(xué)工程學(xué)會(huì)第30次學(xué)術(shù)年會(huì)暨生物醫(yī)學(xué)工程前沿科學(xué)研討會(huì)論文集[C];2010年

3 寧尚秋;;經(jīng)皮腔內(nèi)冠狀動(dòng)脈成形術(shù)后血管再狹窄發(fā)生的機(jī)制[A];中國(guó)病理生理學(xué)會(huì)動(dòng)脈粥樣硬化專業(yè)委員會(huì)五屆一次會(huì)議論文集[C];2002年

4 郭小梅;廖華;;血管平滑肌細(xì)胞增殖信號(hào)轉(zhuǎn)導(dǎo)通路與血管再狹窄防治[A];全國(guó)醫(yī)藥學(xué)術(shù)交流會(huì)暨臨床藥理學(xué)研究進(jìn)展培訓(xùn)班資料匯編[C];2006年

5 鄭雨田;;藥物涂層支架治療小血管再狹窄的研究進(jìn)展[A];天津市生物醫(yī)學(xué)工程學(xué)會(huì)2007年學(xué)術(shù)年會(huì)論文摘要集[C];2007年

6 朱玲玉;蔣麗萍;;縫隙連接蛋白43重構(gòu)在血管再狹窄中的作用[A];中國(guó)藥理學(xué)會(huì)第十次全國(guó)學(xué)術(shù)會(huì)議專刊[C];2009年

7 楊長(zhǎng)春;溫進(jìn)坤;韓梅;;黃芪和當(dāng)歸防治血管再狹窄與抑制粘著斑激酶表達(dá)及活化有關(guān)[A];中國(guó)病理生理學(xué)會(huì)動(dòng)脈粥樣硬化專業(yè)委員會(huì)五屆一次會(huì)議論文集[C];2002年

8 石丹;董少紅;羅林杰;陳科奇;漫峻岷;梁曉萍;;血清C反應(yīng)蛋白及類金屬蛋白酶-9對(duì)PCI后血管再狹窄預(yù)測(cè)價(jià)值的研究[A];中華醫(yī)學(xué)會(huì)心血管病分會(huì)第八次全國(guó)心血管病學(xué)術(shù)會(huì)議匯編[C];2004年

9 沈靂;陳少萍;秦永文;;hVEGF_(165)與嵌合水蛭肽融合基因防治血管再狹窄的研究[A];中華醫(yī)學(xué)會(huì)心血管病學(xué)分會(huì)第八次全國(guó)心血管病學(xué)術(shù)會(huì)議匯編[C];2006年

10 閔e，

本文編號(hào)：2405295