通过二硫键共价载药可聚合单体的合成及纳米药物控释系统的构建研究

The concentration of glutathione in the tumor tissue was 1000 times higher than that in the normal tissue, a disulfide bond possesses the outstanding advantage that would be broken with the existence of glutathione. Thus, a disulfide bond shows attractive application prospect in the field of controlled drug delivery.Up to date, most of the controlled drug delivery systems, based on covalently loading drug via a disulfide bond, were constructed by chemically modifying the drug carrier and drug molecules, respectively, and then the two portions are covalently connected. The aim of this project is to develop a new method to construct a controlled drug delivery system covalently loading drug via disulfide bonds. We aim to synthesize a polymerizable disulfide linker, that covalently connected with drug. The structure of the released drug could remain unchanged by designing the structure of the linker. Then, a controlled drug delivery system, based on copolymer that covalently loading drug via disulfide bonds, could be prepared by the copolymerization between the polymerizable disulfide linker and other hydrophilic acrylic monomers (such as polyethyleneglycol methacrylate). This copolymer would form a micelle with hydrophobic drug as the core and hydrophilic polymer as the shell in water. This controlled drug delivery system would not release drug in the blood circulation and normal tissues, however, the loaded drug would be released in tumor tissues. This is favorable to improve the drug efficacy, reduce the side effects, and provide a new strategy and experimental evidences for cancer chemotherapy.

肿瘤组织中的谷胱甘肽浓度是正常组织中的1000倍以上，二硫键具有在谷胱甘肽作用下会发生断键反应的突出优点，因此，二硫键在药物控释领域具有诱人的应用前景。目前基于二硫键共价载药的药物控释系统大多是采用分别对载体和药物分子进行化学改性，再将二者通过共价键相连接的方式。本项目拟发展一种构建基于二硫键共价载药的药物控释系统的新方法，即合成可聚合的载药二硫键linker，通过分子结构设计使释放出的药物结构保持不变，再利用该linker与其他亲水性丙烯酸单体（如聚乙二醇甲基丙烯酸酯）的共聚反应，制备侧链通过二硫键共价载药的共聚物，构建基于二硫键共价载药的药物控释系统。该药物控释系统在水中可形成疏水药物为核,亲水性聚合物为壳的胶束结构,可实现在血液循环和正常组织中不释放药物，进入肿瘤组织后才释放药物。有利于提高药效，降低药物的毒副作用，为癌症化疗提供新的途径和实验依据。

基于二硫键的氧化还原响应性药物控释系统在没有外加辅助手段的情况下既对肿瘤组织和正常组织具有较高的区分灵敏度，是理想的药物控释开关，在药物控释领域具有诱人的应用前景。目前基于二硫键共价载药的药物控释系统大多是采用分别对载体和药物分子进行化学改性，再将二者通过共价键相连接的方式。本项目中，我们发展了一种构建基于二硫键共价载药的药物控释系统的新方法，并已获授权国家发明专利（一种含二硫键可聚合紫杉醇单体及其合成方法，胡建华，杨东，丁艺，陈武炼，公告号：CN 104163414 A）。合成了两种可聚合的载紫杉醇二硫键linker，通过分子结构设计使释放出的药物结构保持不变，再利用该linker与聚乙二醇甲基丙烯酸酯共聚，制备侧链通过二硫键共价载药的共聚物。该药物控释系统在水中可形成疏水药物为核,亲水性聚合物为壳的胶束结构。体外释药实验证明该聚合物在无还原剂存在条件下基本不释放药物，而在当GSH浓度为5 mmol/L的条件下，该前药聚合物对紫杉醇具有一定的缓释作用，经过70 h，释药率可达到55.2%。体外细胞实验证明该未负载药物的聚合物大分子骨架具有良好的生物相容性，十分适合用作药物载体，而负载药物的前药聚合物对人体正常细胞与癌细胞具有一定的特异识别杀伤性。.通过本项目的研究，我们已发表标注本项目资助的SCI论文25篇，其中影响因子>3.0的20篇；申请国家发明专利3项，其中2项已授权。通过本项目的研究，我们培养了博士研究生4名，其中2名毕业，硕士研究生8名，其中5名已毕业。