含磺酸甜菜碱两性离子的多功能高分子药物载体

In this project, in order to obtain polymeric drug carriers with integrated multifunctions of detection, drug entrapment and real-time observation, we put forward to design polymeric micelles constituted by a new kind of triblock copolymers as main ingredients and by modified copolymers of the triblock copolymers in end groups. The triblock copolymers are composed by disulfide bond connecting nontoxic biodegradable polyesters with pH sensitive block and polysulfobetaine resistant to nonspecific protein adsorption. The modified triblock copolymers are the polymers which connect fluorophores as observation groups on hydrophobic ends or target functional groups on hydrophilic ends of the triblock copolymers. The effect of the interaction between the targeted groups/observation groups and zwitterionic groups and of the interaction between the pH sensitive block and polysulfobetaine on surface properties of multifunctional polymer micelles will be investigated. The uptake difference of the polymeric micelles by tumor cells, macrophages and normal cells will be studied. The in vivo pharmacokinetics of the micelles will be evaluated by the retention time of the micelles in blood. The in vivo tissue biodistributions/ accumulation in liver, spleen, kidney and tumor of different polymeric micelles will be investigated using tumor-bearing mice. Based on these studies, the mechanism of multifunctional polymer micelles evading multiple biological defenses will be explored. Finally, the obtained multifunctional polymeric drug carriers will have the properties targeted to tumor tissue and/or tumor cells, internalized by tumor cells and triggered to release drugs quickly in tumor cells. Therefore, the completion of this project will provide an ideal multifunctional drug delivery system and a new approach to the design of drug carriers with polysulfobetaine zwitterionic groups.

为获得集检测、载药及实时观测多功能为一体的高分子药物载体，本课题设计和合成由生物降解聚酯通过二硫键连接pH敏感的嵌段及抗非特异性蛋白吸附的聚磺酸甜菜碱组成的三嵌段聚合物，在其疏水末端连接荧光基团作为观测基团、亲水末端连接靶向功能基团，便捷地构建多功能高分子药物载体。研究多功能药物载体中靶向基团和观测基团、pH敏感性基团与磺酸甜菜碱两性离子基团的相互作用对药物载体表面性质的影响，及其与肿瘤细胞、巨噬细胞相互作用的差异，并通过动物体内实验研究其在血液中的循环时间，在肝、脾、肾以及肿瘤等组织中的分布，揭示多功能胶束逃避多重生物防御进入肿瘤细胞的机理，实现药物载体在组织、细胞层次上的靶向传递以及在进入肿瘤细胞、在细胞内的智能控制释放。本课题为磺酸甜菜碱两性离子作为新的具有长循环性质的高分子药物载体的设计提供思路和方法，所获得的多功能高分子药物载体对治疗肿瘤病人具有重要意义。

为达到高分子药物载体在血液中能够滞留较长时间、在血液和正常组织中释放率低、选择性地进入癌细胞及进入癌细胞后快速释放药物的目的，选择生物降解聚酯、抗非特异蛋白质吸附和强亲水性的聚磺酸甜菜碱通过二硫键连接具有pH敏感的嵌段作为高分子的主链作为多功能载体材料，同时将具有实时观测功能的荧光基团连接到上述特性的药物载体上，使之能有效地克服体内各种生理屏障，获得良好的治疗效果。.项目系统地构建了多功能聚磺酸甜菜碱药物载体，形成了敏感于肿瘤部位及肿瘤细胞的低pH和高还原微环境药物载体。项目按期完成，并获得了一系列研究成果。合成了不同构型的pH敏感的含磺酸甜菜碱两亲性聚酯、具有pH敏感功能/还原敏感功能的含磺酸甜菜碱两亲性聚酯并将其用作为药物载体，研究了这些药物载体的性质；在磺酸甜菜碱两亲性聚酯药物载体的末端连接观测基团，得到了具有荧光的聚合物胶束。研究了聚磺酸甜菜碱药物载体与肿瘤细胞、巨噬细胞的相互作用，并通过动物体内实验研究其在血液中的循环时间，在肝、脾、肾以及肿瘤等组织中的分布，揭示多功能胶束逃避多重生物防御进入肿瘤细胞的机理；二硫键在高谷胱甘肽浓度下会断裂，破坏胶束结构，使载体中的药物快速释放，表现出还原敏感性；进行了连接观测基团cy5.5的磺酸甜菜碱两亲性聚酯药物载体进入肿瘤细胞的研究。合成和研究了磺酸甜菜碱的温敏聚合物及胶束温敏性；.本研究已经发表了20篇期刊论文（其中SCI收录18篇，EI收录2篇），还有3篇SCI论文在审稿中。获准专利一项。.因此，本课题为磺酸甜菜碱两性离子作为新的具有长循环性质的高分子药物载体的设计提供了思路和方法，所获得的多功能高分子药物载体对治疗肿瘤病人具有重要意义。