分载两类药的耦合式环境响应型靶向给药系统的研究

Multiple drugs combining to use usually increase their efficacy, however targeting delivery system about combination drug has not been reported. This project fabricates targeting multi-drug delivery system by means of two polymer materials with functional groups such as amide, hydroxyl, carboxylic acid groups to load two drugs respectively. Two materials are coupled because of their functional groups forming cooperative "zipping" interactions through hydrogen bonds under the stimulation of environmental signals, otherwise their groups are separated each other resulting from the breakage of hydrogen bonds in other regions. When being away from the sick issues, two vectors can move respectively and each device contains a large quantity of drug, releases little or no drug. While reaching the diseased area, two vectors can be coupled together through hydrogen bonds to release the drugs under the environmental signals, thus completing targeting release of the combination drug. The basic content of the proposed project is the release mechanism of multi-drug controlling delivery system response to environmental stimuli. Contents include mainly the choice of materials responding to the environmental stimuli, the design of targeting multi-drug delivery systems, the dynamic characteristics of microscopic structure of the carriers and their coordination under environmental stimuli, kinetics and kinematics characteristics of drug molecules. The final results will help to provide theoretical foundation for design and preparation of new intelligent stimuli-responsive targeting controlling delivery system for multi-drug.

多重药物联合使用通常会起到增加药效的作用，但是目前关于释放联合药的靶向给药系统研究尚未见报道。本项目选用两种聚合物材料分别装载两类药物，组成靶向给药系统。这两类材料分别带有酰胺基、羟基、羧酸基等功能基团，在环境信号的刺激下，两类聚合物的功能基团通过氢键等作用耦合在一起，在其他区域氢键等作用断裂。当远离病变区域时，两载体能单独运动且不释放或少释放药物，起到安全携带的作用；而到达病变区域时，受到微环境处刺激信号的作用，两载体能通过氢键等作用耦合在一起释放药物，从而完成联合药的靶向释放。本课题研究的基本问题是分载联合用药式环境响应型靶向给药系统的控释机制，主要包括环境响应材料的选择、靶向给药系统的设计、对环境刺激信号响应时载体微观结构动态特征和两者间的协调性、以及药物分子释放动力学及运动学特性等。研究结果将为新一代智能化多重药物靶向式药物控制释放系统的设计与制备及其运用提供理论基础。

移动给药系统是一种新型给药形式，关于研究尚未见报道。本项目围绕移动开关开展工作，以聚丙烯酰胺-聚丙烯酸和壳聚糖-丝心蛋白为例，采用不同方法组建了移动开关。因为这些对应材料分别带有酰胺基、羟基、羧酸基等功能基团，在环境信号的刺激下，两类聚合物的功能基团通过氢键等作用耦合在一起，在其他区域氢键等作用断裂。本文系统地探讨移动开关的制备方法及结构优化的条件，测定移动开关的微观状态特性及其环境感应动态行为、和药物释放的动力学，探索其影响及作用的机理与动力学行为；还研究移动开关摩尔配比的优化匹配、以及其对药物控制释放的影响，建立了控释传质动力学模型。以聚丙烯酰胺-聚丙烯酸为主来说，系统研究了聚丙烯酰胺接枝膜（微球）-聚丙烯酸微球（膜）的制备过程和相互作用过程，获得较为直观的聚丙烯酰胺微球-聚丙烯酸接枝膜系统的作用关系：当温度低于较高相变温度时，两载体相互靠近，当温度高于较高相变温度，两载体分离，过程具有重复性；定量获得了当酰胺基团与羧酸基团的摩尔比为26到38之间时开关效果明显；当系统进行温度交替变化时，具有开关重复性。同时还研究了壳聚糖-丝心蛋白系统的微球，不同释放系统的定性、定量研究。研究结果将为新一代智能式多重药物靶向式药物控制释放系统的设计与制备及其运用提供理论基础。