叶酸靶向的还原敏感星形共聚物胶束作为抗癌药物载体的应用研究

发布时间：2018-06-24 21:26

本文选题：还原响应 + 星形共聚物　；参考：《西南交通大学》2014年硕士论文

【摘要】：基于高分子聚合物的药物载体,可以结合细胞特点和胞内微环境进行设计,如响应刺激型载体或载体的靶向性修饰等。开发出智能型的药物传递系统,也是近年来的研究热点。在癌症治疗的药物载体中,星型共聚物的载体相比线型的共聚物展现出一些独特的优点,例如更好的稳定性,较小的粒径分布和更高的载药量等。本文中,我们构建了一种基于星型共聚物的具有靶向功能和还原敏感性的多功能胶束。其特点在于,该材料选用生物相容性良好的聚乙二醇和聚己内酯,由二硫键连接,以季戊四醇为核,形成星形的两亲嵌段共聚物,再接枝処酸作为靶向基团,制备出星形共聚物(star-PECLss-FA),并且经过了HNMR、FT-IR和GPC等表征,证明了聚合物的成功合成。采用溶剂挥发法制备胶束,测定了临界胶束浓度(CMC),胶束具有良好的稳定性和耐稀释性,考察了胶束的粒径和形貌,呈现均匀球形。模拟细胞内的10mM GSH作用于胶束,胶束对于谷胱甘肽的还原性响应,在粒径、形貌和分子量的变化上都有所表现。证明了具有还原敏感性。体外药物释放实验模拟了人体的生理环境,演示出胶束在血液循环中的稳定性,而在类似肿瘤细胞的强还原和微酸性环境下,包载的药物阿霉素迅速地释放出来。共聚焦和流式细胞仪的检测分别定性和定量地说明了细胞的内在化情况,该多功能胶束在细胞内明显的DOX荧光有力证明了叶酸赋予粒子的靶向作用,促进癌细胞的吞噬。动物活体成像实验以及分离出的器官的荧光成像,进一步验证了该载药胶束的靶向性。对荷4T1肿瘤的BALB/c小鼠静脉注射载药胶束,收集了治疗过程中21天的体重和肿瘤体积变化等数据,兼具靶向和还原敏感性的星形共聚物载药胶束未对小鼠体重有明显影响,相比其他治疗组,该组肿瘤的体积最小,动物存活时间最长。组织学讨论分析载药胶束的治疗效果,同样证明star-PECLss-FA载药胶束组的肿瘤细胞凋亡最显著。综合的分析,这种多功能的载药胶束有潜力作为抗癌药的靶向传递载体。
[Abstract]:Drug carriers based on polymeric polymers can be designed in combination with cellular characteristics and intracellular microenvironments, such as targeted modification of responsive stimulus carriers or carriers. The development of intelligent drug delivery system is also a hot topic in recent years. In the drug carriers for cancer treatment, the star-shaped copolymers show some unique advantages over linear copolymers, such as better stability, smaller particle size distribution and higher drug loading. In this paper, we have constructed a multifunctional micelle with target function and reduction sensitivity based on star copolymer. The material is characterized by the selection of polyethylene glycol and polycaprolactone, which have good biocompatibility, are connected by disulfide bonds, and pentaerythritol is used as nucleus to form starlike amphiphilic block copolymers, and then grafted with acid as target group. Star copolymer (star-PECLss-FA) was prepared and characterized by HNMR-FT-IR and GPC. The micelles were prepared by solvent volatilization method. The critical micelle concentration (CMC) was determined. The micelles had good stability and dilution resistance. The particle size and morphology of the micelles were investigated. The effect of 10mm GSH on the micelles was simulated. The micelles showed a reduced response to glutathione, and showed changes in particle size, morphology and molecular weight. It is proved that it is sensitive to reduction. The drug release experiments in vitro simulated the physiological environment of human body and demonstrated the stability of micelles in blood circulation. However, in the strong reduction and micro-acid environment of tumor-like cells, the encapsulated drug doxorubicin was released rapidly. The results of confocal and flow cytometry showed the internalization of the cells qualitatively and quantitatively. The obvious DOX fluorescence of the multifunctional micelles in the cells demonstrated the targeting effect of folic acid on the particles and promoted the phagocytosis of cancer cells. In vivo imaging experiments and fluorescence imaging of isolated organs further verify the targeting of the drug-loaded micelles. BALB / c mice bearing 4T1 tumor were injected intravenously with drug carrier micelles. The data of body weight and tumor volume during 21 days of treatment were collected. The star-shaped copolymers carrying micelles with both targeting and reducing sensitivity had no significant effect on the weight of mice. Compared with other treatment groups, this group had the smallest tumor size and the longest survival time. Histological analysis showed that the apoptosis of tumor cells in star-PECLss-FA micelle group was the most significant. Comprehensive analysis shows that this multifunctional drug-carrying micelle has the potential as a target delivery carrier for anti-cancer drugs.
【学位授予单位】：西南交通大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

【共引文献】