温度敏感水凝胶的制备及共载VPA与抗肿瘤药物的体外抗肿瘤效果研究

发布时间：2018-07-10 04:30

本文选题：温度敏感水凝胶 + PEG-PELG　；参考：《吉林大学》2017年硕士论文

【摘要】：目的:癌症作为一种世界范围内的公共卫生问题,是造成人类死亡的第二大死因,其具有广泛的发病范围、逐年升高的死亡率,严重威胁人类的健康。化疗是目前非手术治疗癌症的重要方法,但存在注射频率高、药物利用率低、体内代谢迅速、毒副作用大等缺点,使其治疗效果无法达到预期。温度敏感水凝胶作为药物载体具有良好的生物可降解性和组织相容性,应用于肿瘤局部治疗具有提高局部药物浓度、药物缓释(长效性)、给药频率低,机体毒性小等优点,作为药物载体已广泛用于肿瘤的局部治疗研究中。药物联合治疗是增强治疗效果的有效途径,目前常用的联合治疗方案包括手术/化疗,化疗/放疗、化疗/免疫治疗以及多种化疗药物联用等均可明显提高治疗效果。聚乙二醇-聚(γ-乙基-L-谷氨酸酯)(PEG-PELG)水凝胶作为新型的温度敏感型水凝胶,在体内可以快速成胶,并作为可注射材料为药物缓释提供载体。本研究的目的是探索这种水凝胶材料共担载组蛋白去乙酰化酶抑制剂丙戊酸钠(sodium valproate,VPA)与抗肿瘤化疗药顺铂(cis-platinum,CDDP)后对耐药细胞株的杀伤效果,为进一步研究及临床应用提供依据。具体方案如下:利用开环聚合方法制备二嵌段聚合物PEG-PELG并进行性状表征以确定其聚合度和分子量得到具体结构PEG2K-PELG15,其成胶温度随浓度的增高而降低,丙戊酸钠和顺铂联用细胞毒性实验表明两药联用后可提高对A549/CDDP细胞抗肿瘤效果,诱导细胞凋亡和细胞周期阻滞,利用物理混匀的方法担载VPA和CDDP后,细胞毒性实验表明联合载药后可提高对耐药细胞A549/CDDP抗肿瘤效果,表明PEG2K-PELG15作为药物缓释载体联合担载VPA和CDDP后可提高A549/CDDP的治疗效果,并降低A549/CDDP肿瘤耐药性,在肺癌治理中具有良好的应用前景。综上所述,温度敏感水凝胶PEG-PELG具有良好的生物相容性、生物可降解性和药物缓释性能,担载药物后在肿瘤局部治疗中具有良好的应用前景。丙戊酸钠作为组蛋白去乙酰化酶抑制剂与化疗药顺铂联合使用具有协同抑制肿瘤细胞的能力,在肿瘤体外探索实验中具有潜在的研究价值。
[Abstract]:Objective: cancer, as a worldwide public health problem, is the second leading cause of human mortality. Cancer has a wide range of morbidity and increases year by year, which is a serious threat to human health. Chemotherapy is an important method for non-surgical treatment of cancer at present, but there are some disadvantages such as high injection frequency, low utilization rate of drugs, rapid metabolism in vivo and large toxic side effects, which make the therapeutic effect unattainable. Thermosensitive hydrogel as a drug carrier has good biodegradability and histocompatibility. The application of thermo-sensitive hydrogel in tumor local treatment has the advantages of increasing local drug concentration, drug release (long-term effect), low administration frequency, low toxicity, and so on. As a drug carrier, it has been widely used in the study of local treatment of tumor. Drug combination therapy is an effective way to enhance the therapeutic effect. At present, the commonly used combination treatment schemes include surgery / chemotherapy, chemotherapy / radiotherapy, chemotherapy / immunotherapy and the combination of various chemotherapeutic drugs. As a new type of temperature sensitive hydrogel, PEG-PELG hydrogel can be used as injectable material for drug delivery. The aim of this study was to explore the killing effect of sodium valproate and cis-platinum cisplatin (cis-platinum CDDP), a hydrogel material, on drug-resistant cell lines, and to provide evidence for further study and clinical application. The specific scheme is as follows: the diblock polymer PEG-PELG was prepared by ring-opening polymerization and its properties were characterized to determine its polymerization degree and molecular weight to obtain a specific structure PEG2K-PELG15, and the gelation temperature decreased with the increase of the concentration of PEG-PELG. The cytotoxicity test of sodium valproate and cisplatin showed that the combination of the two drugs could improve the anti-tumor effect, induce apoptosis and cell cycle arrest of A549% CDDP cells. VPA and CDDP were loaded by physical mixing method. Cytotoxicity test showed that combined drug loading could improve the anti-tumor effect of A549% CDDP on resistant cells, which indicated that PEG2K-PELG15 combined with VPA and CDDP as drug sustained-release carrier could increase the therapeutic effect of A549% CDDP and reduce the drug resistance of A549% CDDP tumor. It has a good application prospect in the treatment of lung cancer. In conclusion, PEG-PELG has good biocompatibility, biodegradability and drug release properties. Sodium valproate as a histone deacetylase inhibitor combined with cisplatin has a synergistic ability to inhibit tumor cells and has potential research value in tumor exploration in vitro.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;R96

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