基于柱芳烃自组装制备糖靶向-多刺激响应性超分子囊泡的研究

发布时间：2018-06-15 20:51

本文选题：糖靶向 + 柱芳烃　；参考：《西北农林科技大学》2016年硕士论文

【摘要】：药物对正常细胞的毒副作用是癌症化疗面临的重大难题之一,而纳米药物载体以其可生物降解、低毒副作用等特点为解决此难题提供了一个新途径。特别是,纳米囊泡表面易于修饰不同的功能基团,从而使其具有可智能化的特点,进一步实现药物在癌细胞内的可控高效释放,减少药物对正常细胞的毒副作用。基于此,本研究拟制备含二茂铁甲酸的柱芳烃衍生物主体分子和含吡啶基的糖衍生物客体分子,通过超分子自组装作用形成具有GSH-pH双响应的糖靶向双亲性分子,进一步在水溶液中利用亲疏水作用制得具有GSH-pH双响应的糖靶向阳离子囊泡,从而构建靶向-多刺激响应性的纳米药物载体。具体如下：(a) GSH-pH双响应的糖靶向双亲性分子的合成：以大环分子柱芳烃为基础,通过点击反应将具有pH响应性的二茂铁甲酸基团修饰在柱芳烃两端,利用FeCl3将柱芳烃上二茂铁氧化为氧化态二茂铁使其具有GSH响应性,得到GSH-pH双响应的柱芳烃主体分子,进一步将其与制得的含吡啶基半乳糖衍生物客体分子通过超分子自组装作用构建具有GSH-pH双响应的糖靶向双亲性分子。(b) GSH-pH双响应的糖靶向阳离子囊泡的制备与研究：运用制备的GSH-pH双响应的糖靶向双亲性分子,在水溶液中结合亲疏水作用制得GSH-pH双响应的糖靶向超分子囊泡,利用癌细胞表面半乳糖类凝集素含量高,通过糖与蛋白相互作用,实现靶向选择性的目的,并通过GSH-pH双调控达到高效释放药物的目的。本研究首次合成了具有GSH-pH双响应的糖靶向双亲性分子,并成功用于构建靶向-多刺激响应性的超分子囊泡；初步利用体外模拟释放试验验证了该囊泡可在GSH-pH双调控下高效释放抗癌药物,进一步利用流式细胞仪测量荧光强度验证了该囊泡的糖靶向选择性,为构建靶向-多刺激响应性的纳米药物载体提供了一个新途径,对癌症化疗中降低药物对正常细胞的毒副作用具有重要的意义。
[Abstract]:The side effects of drugs on normal cells are one of the major problems in cancer chemotherapy, and nano-drug carriers provide a new way to solve this problem because of their biodegradability and low toxic side effects. In particular, the surface of nano-vesicles is easy to modify different functional groups, so that it has the characteristics of intelligence, further achieve the controllable release of drugs in cancer cells, and reduce the toxic side effects of drugs on normal cells. Based on this, we intend to prepare the host molecule of column aromatic derivatives containing ferrocene formic acid and the guest molecule of sugar derivative containing pyridyl group, and form sucrose-targeted amphiphilic molecules with double response of GSH-pH by supramolecular self-assembly. Furthermore, carbohydrate targeted cationic vesicles with double GSH-pH response were prepared by hydrophilic interaction in aqueous solution. Synthesis of carbohydrate targeting amphiphilic molecules with double GSH-responsive pH: based on macrocyclic aromatic hydrocarbons, the pH responsive ferrocenyl formate groups are modified at both ends of the column aromatics by a click-through reaction. Ferrocene on the column aromatics was oxidized to ferrocene in the oxidation state by FeCl _ 3 to make it GSH-responsive, and the host molecule of the column aromatics with double GSH-pH response was obtained. Preparation and study of Sugar targeted Cationic vesicles with double response of GSH-pH to Glycer-targeted Amphiphilic molecules by supramolecular Self-assembly with the guest molecules containing Pyridyl galactose Derivatives Glucose targeting amphiphilic molecules with double response to GSH-pH were used. Glucose targeting supramolecular vesicles with double response to GSH-pH in aqueous solution were prepared by combining with hydrophobicity. Galactose lectins on the surface of cancer cells were high in content. The aim of targeting selectivity was achieved by the interaction of sugar and protein. The aim of release of drugs was achieved by double regulation of GSH-pH. In this study, carbohydrate targeting amphiphilic molecules with double GSH-pH response were synthesized for the first time, and successfully used to construct supramolecular vesicles with targeting to multiple stimuli. The in vitro simulated release test proved that the vesicle could release anticancer drugs efficiently under the double regulation of GSH-pH, and the glucose targeting selectivity of the vesicle was verified by fluorescence intensity measurement by flow cytometry. It provides a new way for the construction of targeting-multi-stimuli-responsive nano-drug carriers and plays an important role in reducing the toxicity and side effects of drugs on normal cells in cancer chemotherapy.
【学位授予单位】：西北农林科技大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O641.3;TQ460.1

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