用于超临界技术制备载药胶束的两亲聚合物研究

发布时间：2018-05-17 04:36

本文选题：超临界二氧化碳 + 链转移剂　；参考：《东南大学》2016年硕士论文

【摘要】：研究发现紫杉醇对于多种癌症具有很好的治疗效果,但是紫杉醇药物的水溶性极差,这一缺陷限制了其在临床上的应用。目前发现两亲嵌段聚合物胶束可以增强紫杉醇药物的水溶性。有机溶剂挥发法是制备该胶束的经典方法之一,但采用这一制备法制得的胶束中不可避免残留的有机溶剂可能对人体产生一定的危害。为此,本论文开发出一种新的无污染绿色环保的方法-超临界二氧化碳挥发法制备聚合物胶束,并在两亲嵌段聚合物的合成、聚醋酸乙烯酯在超临界二氧化碳中的相行为、胶束制备、胶束的表征等方面开展了系统的研究工作。本论文合成了三种可逆加成-断裂链转移(RAFT)链转移剂,用红外吸收光谱、核磁共振氢谱确认了产物的结构,用合成出的三种链转移剂诱导醋酸乙烯酯单体的聚合。研究发现：以乙醇、二硫化碳、氢氧化钾和2-溴丙酸乙酯为原料制备的黄原酸盐链转移剂对醋酸乙烯酯单体的聚合起促进作用,并成功制备了聚醋酸乙烯酯。本文对醋酸乙烯酯单体的聚合条件进行优化,探究了反应温度、反应时间、链转移剂与引发剂摩尔比对醋酸乙烯酯聚合的影响。用凝胶色谱(GPC)测试了聚合物的分子量及其分子量分布。测试了所合成的窄分子量分布的聚醋酸乙烯酯在不同温度和压力下二氧化碳中的浊点压力,结果表明聚醋酸乙烯酯具有较强的亲超临界二氧化碳性。利用制得的聚醋酸乙烯酯作为大分子链转移,聚乙二醇甲基丙烯酸酯(PEGMA)为亲水单体,成功制备出两亲嵌段聚合物聚醋酸乙烯酯-b-聚乙二醇甲基丙烯酸酯(PVAc-b-PEGMA),并将制备的两亲嵌段聚合物采用有机溶剂挥发法和超临界二氧化碳挥发法制备聚合物胶束。用芘荧光探针技术测试了聚合物的临界胶束浓度(CMC),其临界胶束浓度值为33.88 mg/L。用透射电镜(TEM)对胶束的形貌进行了观察,两种方法制备的胶束都呈现均一的球状结构。动态光散射(DLS)测试了胶束的粒径及粒径分布,超临界二氧化碳挥发法制备所得胶束的平均粒径要比有机溶剂挥发法制备所得胶束的平均粒径要大,其平均粒径为476 nm。利用紫外-可见见光光谱对胶束的载药能力进行了测试,超临界二氧化碳挥发法制备的胶束载药量和包封率要比有机溶剂挥发法制备所得胶束的载药量和包封率高,其载药量和包封率分别为12.7%和38.1%。通过对胶束性能的表征,说明本文制备的两亲嵌段聚合物可用于超临界二氧化碳挥发法制备胶束,其制备过程中只需超临界二氧化碳和水,对环境无污染,具有较好的发展前景。
[Abstract]:Paclitaxel has been found to be effective in the treatment of many cancers, but the poor water solubility of paclitaxel drugs limits its clinical application. Amphiphilic polymer micelles have been found to enhance the solubility of paclitaxel drugs. The organic solvent volatilization method is one of the classical methods to prepare the micelle, but the residual organic solvent in the micelle prepared by this method may be harmful to the human body. In this paper, a new pollution-free green environmental protection method, supercritical carbon dioxide volatilization method, was developed to prepare polymer micelles, and to synthesize amphiphilic block polymers and the phase behavior of polyvinyl acetate in supercritical carbon dioxide. The preparation of micelles and the characterization of micelles have been studied systematically. In this paper, three reversible addition-break chain transfer agents (RAFTs) were synthesized. The structure of the products was confirmed by IR and NMR spectra, and the polymerization of vinyl acetate monomer was induced by the three chain transfer agents. It was found that the xanthate chain transfer agent prepared from ethanol, carbon disulfide, potassium hydroxide and ethyl 2-bromopropionate played an important role in the polymerization of vinyl acetate monomer, and the polyvinyl acetate was prepared successfully. The polymerization conditions of vinyl acetate monomer were optimized. The effects of reaction temperature, reaction time and molar ratio of chain transfer agent to initiator on the polymerization of vinyl acetate were investigated. The molecular weight and molecular weight distribution of the polymer were measured by gel chromatography (GPC). The cloud point pressure of the synthesized polyvinyl acetate with narrow molecular weight distribution in carbon dioxide at different temperatures and pressures was measured. The results show that the polyvinyl acetate has a strong supercritical carbon dioxide affinity. Poly (vinyl acetate) was used as macromolecular chain transfer and polyethylene glycol methacrylate (PEGMA) as hydrophilic monomer. The amphiphilic block polymer poly (vinyl acetate) -b-polyethylene glycol methacrylate (PVAc-b-PEGMAA) was successfully prepared. The amphiphilic block polymers were prepared by organic solvent volatilization and supercritical carbon dioxide volatilization. The critical micelle concentration (CMC) of the polymer was measured by pyrene fluorescence probe technique. The critical micelle concentration was 33.88 mg 路L ~ (-1) 路L ~ (-1). The morphology of the micelles was observed by TEM and TEM. The micelles prepared by the two methods showed uniform spherical structure. The particle size and particle size distribution of micelles were measured by DLSs. The average particle size of micelles prepared by supercritical carbon dioxide volatilization method was larger than that prepared by organic solvent volatilization method, and the average particle size was 476 nm. The drug loading capacity of micelles prepared by supercritical carbon dioxide volatilization method is higher than that prepared by organic solvent volatilization method, and the drug loading capacity and encapsulation efficiency of micelles prepared by supercritical carbon dioxide volatilization method are higher than those prepared by organic solvent volatilization method. The drug loading and entrapment efficiency were 12.7% and 38.1%, respectively. The amphiphilic block polymers prepared in this paper can be used in the preparation of micelles by supercritical carbon dioxide volatilization method, and only supercritical carbon dioxide and water are required in the preparation process, so there is no pollution to the environment. It has a good development prospect.
【学位授予单位】：东南大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：TQ460.4;O631.5

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