光控“开-关”释药温敏糖基智能水凝胶设计合成及其构效研究

To obtain a two-dimensional spatiotemporal drug release function, our research is focused on design and preparation of a novel kind of temperature-sensitive saccharide-based hydrogels for photo-controllable "on-off" drug delivery. Meanwhile, the aim hydrogel can overcome the drawback of rapid drug release of small molecular smart hydrogel due to weak interaction, and solve the problem of unintelligent drug delivery of polymeric smart hydrogel because of no linkage of polymer with drug. The structure of the aim hydrogel is S-T-P as a whole. P unit designed to perform a photo-controllabe "on-off" function is a photo-controllable chain with caged drugs, and it is prepared by the reaction of ortho-nitro benzyl derivative used as photolysis group with a certain small molecular drug such as 5-fluororouracil, 6-mercaptopurine. T unit is a temperature-sensitive one which is derived from N-isopropylacrylamide. S unit is to get a good biocompatibility, and its monomer is 2-glucosamine acrylamide. In order to get the block structure and control its molecular weight and the ratio of three chains, Reversible Addition-Fragmentation Chain Transfer polymerization is employed to prepare the aim S-T-P hydrogels. The structure-activity relationship of the hydrogel will be revealed by the photolysis efficiency, Sol-Gel phase transition, theoretical calculation, and so on. The hydrogel structure will be optimized, and the model structure will be established to guide the synthesis of this kind of hydrogel. Furthermore, these research results and laws will put up with a new method in photo-controllable drug delivery system.

本课题为了克服超分子智能水凝胶作用力弱而导致药物瞬间释放的缺陷，解决现有聚合物智能水凝胶因未建立药物与凝胶之间的联系而不能实现药物智能释放的问题，设计合成一类具有光控"开-关"释药功能的温敏糖基智能水凝胶，以实现光控条件下药物的二维时空智能释放。目标水凝胶整体为S-T-P三元嵌段结构。P是光控锁合药物单元，用于实现光控"开-关"释药，由光解基团邻硝基苄基衍生物与小分子抗癌拮抗剂（5-氟尿嘧啶或6-巯嘌呤）制得；T是温敏单元，选取N-异丙基丙烯酰胺为温敏单体；S是糖基单元，拥有良好的生物相容性，以2-氨基葡萄糖丙烯酰胺为单体。为了实现S-T-P嵌段结构、分子量以及各单元比例可控，采用可逆加成断裂自由基聚合制备目标水凝胶。通过研究光解效率、Sol-Gel相转变和理论计算，明确目标分子构效关系，优化分子结构，建立分子模型，为分子设计提供理论依据，为凝胶在光控药物释放体系提供一种新思路。

本课题为了克服超分子智能水凝胶作用力弱而导致药物瞬间释放的缺陷，解决现有聚合物智能水凝胶因未建立药物与凝胶之间的联系而不能实现药物智能释放的问题，设计合成了一类具有光控“开-关”释药功能的温敏糖基智能水凝胶。具体完成了以下三个方面的工作：（1）以D-氨基葡萄糖和丙烯酰氯为原料制备了2-氨基葡萄糖丙烯酰胺S单体。以对溴甲基苯甲酸为原料，经硝化、酰氯化、还原等5步，5-FU的光敏锁合药物P单体。（2）将2-氨基葡萄糖丙烯酰胺S单体与NIPAAM温敏T单体和光敏锁合药物P单体采用RAFT聚合，制备一系列S-T-P光控糖基智能水凝胶。（3）研究S-T-P光控糖基智能水凝胶的光控开关性能；研究S-T-P光控糖基智能水凝胶的温敏性能；优化水凝胶的分子量范围；研究了水凝胶的胶束与药物释放的规律；研究了光解波长对光解效率之间的影响。这些工作共发表SCI论文12篇，授权专利8件；培养硕士生5人；完成了项目既定的研究工作和任务。