还原响应性阿霉素糖脂聚合物胶束抗肿瘤研究

发布时间：2018-03-03 06:04

本文选题：壳寡糖硬脂酸　切入点：胶束　出处：《浙江大学》2014年硕士论文　论文类型：学位论文

【摘要】：聚合物前药是指药物通过共价键嫁接至高分子聚合物上,得到的在体外无活性或活性较小,在体内经生物转化释放出活性药物而发挥药效的化合物。还原响应性聚合物前药在传递过程中保持相对稳定,而达到肿瘤细胞后快速释放药物,发挥药效。本课题通过酶解得到壳寡糖,并在其上嫁接硬脂酸,合成得到两亲性壳寡糖硬脂酸聚合物(CSO-SA)。CSO-SA能在水性介质中自组装形成胶束。以3,3-二硫代二丙酸二(N-琥珀酰亚胺)酯(DSP)为交联剂,将抗肿瘤药物阿霉素通过二硫键嫁接至CSO-SA胶束上,合成得到还原响应性阿霉素糖脂聚合物(DOX-SS-CSO-SA)。用紫外分光光度法测得该聚合物前药的药物含量为5.5%,核磁共振氢谱确认其化学结构；芘荧光法测得临界胶束浓度(CMC)为49.1μg/mL;微粒粒度分析仪测得胶束的粒径为62.8nm,且分布均匀。荧光光谱变化和体外释放研究表明DOX-SS-CSO-SA胶束在模拟细胞外环境的低还原性介质中相对稳定,而在模拟细胞内环境的高还原性介质中二硫键断裂并快速释放出药物。体外细胞研究显示,DOX-SS-CSO-SA胶束能迅速被肿瘤细胞摄取,在胞内快速释放药物,且药物聚集于细胞核,拥有优于DOX的细胞药效。DOX-SS-CSO-SA胶束可以有效克服MCF-7/Adr细胞的耐药性,克服耐药倍数高达34.8。荷瘤裸鼠体内分布研究表明,DOX-SS-CSO-SA胶束在肿瘤组织大量聚集,且在心脏分布较少。动物药效结果显示,DOX-SS-CSO-SA胶束的抑瘤率为70.2%,同时降低药物的毒性,对模型动物的体重影响较少。心肌组织切片显示DOX-SS-CSO-SA胶束能显著减少DOX引起的心脏损伤。
[Abstract]:A polymer prodrug is a drug grafted onto a polymer by covalent bonding, which is inactive or less active in vitro. A compound that releases active drugs through biotransformation in vivo. The reductive responsive polymer prodrugs remain relatively stable in the course of transmission, and release the drugs quickly after reaching tumor cells, giving full play to their effects. In this paper, chitosan oligosaccharides were prepared by enzymatic hydrolysis, on which stearic acid was grafted. Amphiphilic oligosaccharide stearic acid polymer, CSO-SAA, CSO-SA, was synthesized and self-assembled to form micelles in aqueous medium. The antitumor drug doxorubicin was grafted onto CSO-SA micelle by disulfide bond, using DSP3 dithiodipropionate (DSP) as crosslinker, the antitumor drug doxorubicin was grafted onto the CSO-SA micelle by disulfide bond, the antitumor drug doxorubicin was grafted onto the CSO-SA micelle. A reductive doxorubicin glycolipid polymer (DOX-SS-CSO-SA-SAG) was synthesized. The content of prodrug was 5.5 by UV spectrophotometry, and the chemical structure was confirmed by nuclear magnetic resonance (NMR). The critical micelle concentration measured by pyrene fluorescence method was 49.1 渭 g / mL, the particle size was 62.8 nm by particle size analyzer, and the fluorescence spectrum changes and in vitro release studies showed that DOX-SS-CSO-SA micelles were relatively stable in the low reductive medium simulating the extracellular environment. In vitro cell studies showed that DOX-SS-CSO-SA micelles could be rapidly ingested by tumor cells, rapidly released in cells and accumulated in the nucleus. DOX-SS-CSO-SA micelles, which have a better effect than DOX, can effectively overcome the drug resistance of MCF-7/Adr cells, and the drug resistance multiple is up to 34.8. The distribution of Dox-SS-CSO-SA micelles in nude mice bearing tumor showed that the micelles of DOX-SS-CSO-SA accumulated in tumor tissues. The inhibitory rate of DOX-SS-CSO-SA micelle was 70.2, and the toxicity of the drug was decreased, and the weight of model animal was less affected. Myocardial tissue section showed that DOX-SS-CSO-SA micelle could significantly reduce the cardiac injury induced by DOX.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

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