纤维素基”门控式“双网络结构水凝胶双药物载体的构筑及其联合释放行为调控

At present, intelligent hydrogel drug delivery technology is a great potential drug delivery technology. In the previous studies, there are some problems in the application of conventional hydrogels to multi-drug sustained release, that the simultaneous controlled release of isolated loads of impermeable drugs can not be realized at the same time. In other words, the combined controlled release pathway of multiple drugs can not match the structure design of hydrogel. Based on this phenomenon, the applicant intends to combine the function of intelligent response sites triggering "gated" open or close transmission channels with the dual network structure of internal-external layered mode. Expectation for the combined release of the two drugs will be achieved simultaneously with the isolated loading of the two drugs. Through systematically research on the multistage release characteristics of drugs in hydrogel system, study the Gated switching channel forming mechanism under Local Volume Phase Transition, clarify the drug isolation loading mechanism and the synergistic release mechanism of diffusion-heat shrinkage-erosion in dual-network structure system, explore the regulation pathway of combined drug use stage under multi-stage drug release. Expectation for the providing experimental basis and theoretical guidance for multi-drug multi-stage release and combined drug use of intelligent hydrogel delivery system.

智能水凝胶药物缓释技术是当今极具潜力的药物传递技术。但是，常规水凝胶应用于多药物缓释存在无法实现隔离装载互不渗透的多种药物在同一时间内的联合控释这一问题。即多药物联合控释途径与水凝胶体系结构的不匹配。针对此问题，本项目拟将智能响应位点引发“门控式”开或关传输通道作用与自内向外分层模式的双网络结构体系相结合，期望在两种药物隔离装载的同时达到联合释放的研究目标。课题通过系统研究各药物在水凝胶体系内的多级释放规律特性，探讨局部体积相转变状态对“门控式”开关通道的形成规律，明确双网络结构体系的药物隔离装载机制及扩散-热缩-侵蚀多重作用协同释放机理，掌握各药物多级释放下的联合用药阶段调控途径。本项目为智能水凝胶递药体系多药物的多级释放和联合用药提供实验依据和理论指导。

本项目将水凝胶的双网络结构体系与外层中的温敏响应“门控式”通道相结合，将两种药物物理隔离的同时，初步实现双药物的多级联合释放的目标，为解决水凝胶多药物传输的隔离装载和联合释放问题提供提供一种可行的途径。研究了温敏单体在纤维素纳米粒子表面的接枝而引发的温敏响应状态，得出了温敏改性纤维素纳米粒子的相转变幅度及速度特征。结合改性纳米粒子在凝胶中的分布状态对其局部温敏响应状态的影响规律，证明了改性粒子的物理分散特征，得出了改性粒子的存在促进凝胶中负载分子的透过速度和透过量的结论。研究了单/双网络结构水凝胶体系在一定条件下的单/双药物的释放特性，分析了各层药物在扩散-热缩-侵蚀多重作用下的释放变化规律，证明了凝胶内层的固定化作用和凝胶外层的厚度决定了内外层负载的药物的物理隔离效果，且各层药物的释放特征与凝胶基体材料的选择以及与实际应用场景相关。考察了不同反应条件下双药物的释放顺序组成特性，初步确定了联合用药阶段的调控途径。同时进一步调控联合用药阶段，探索了多重刺激合作响应对联合用药中双药物释放特征的影响研究，证明了NIR-温度的联级作用可以有效调控复合水凝胶的双药物释放效果。