溶酶体内原位生成大复合载药胶束多靶点阿尔茨海默症协同治疗研究

Alzheimer's disease clinical treatment dilemma lies in that the conventional single-target drug can not restrain deteriorate of the disease for multiple factors may be involved in the pathogenesis of cognitive impairment. The vector-mediated synergistic drug delivery systems were expected to solve this problem. However, the drug delivery systems that containing multiple drugs in a nanoparticle faces the problems of interference of various drugs as well as the drug competition defect. Moreover, the efflux mechanisms of the nerve cells leading to brain retain inefficient of drug. To address this problem, this project will aim to develop PCL-PMPC-PAA-AK-Tf micelle to load Huperzine, Paclitaxel, Insulin and γ-secretase inhibitor. Four types of drug loaded micelles access into brain parenchyma by nasal administration. Lysosomes asparaginyl endopeptidase of nerve cells trigger fracture of polypeptide Ala-Ala-Asn-Cys-Lys (AK) outer of PCL-PMPC-PAA-AK-Tf micelle, click cyclization reaction occurs, and large compound drug loaded micelle formed in lysosomes. On the one hand, large compound drug-loaded micelle simultaneously release four mechanisms drugs into the cytoplasm, synergistic targeting of neuronal synapses, mitochondria, microtubules, and amyloid precursor protein. On the other hand, through the formation of large-size compound drug-loaded micelle inside the cell, the drug efflux blocked. Through the above study, it is expected to achieve Alzheimer's disease multi-target simultaneous drug release system. This study provide new ideas for Alzheimer's disease synergistic therapeutic basic research and clinical application.

阿尔茨海默症临床治疗的困境在于发病机制多因素性与现有药物单一靶点治疗矛盾的现状。载体介导的协同给药体系被赋予希望。然而，多种药物共同包载体系存在载体内部各类药物相互干扰以及竞争的缺陷。同时，细胞外排机制导致药物保留效率低下。鉴于此，申请人提出用PCL-PMPC-PAA-AK-Tf胶束分别包载石杉碱甲、紫杉醇、胰岛素、γ-分泌酶抑制剂四类不同AD药物，经鼻给药进入神经元细胞以后，利用溶酶体内天冬酰胺内肽酶触发载药胶束外层多肽AK断裂，促使载药胶束与同步递送至溶酶体内的PCL-PMPC-PAA-CABT-Tf胶束发生点击环化反应，生成大复合载药胶束。一方面，大复合载药胶束在细胞质内同步释放四种药物，协同靶向突触、线粒体、微管以及淀粉蛋白前体治疗。另一方面，通过形成大尺寸复合载药胶束，阻断细胞外排。通过上述研究，有望实现阿尔茨海默症多靶点同步释药，为多药物协同治疗基础研究以及临床应用提供新思路。

近年来包括在我国在内的多个国家和地区，阿尔茨海默症、帕金森症等多种老年病人数逐年增长，老年病的治疗和护理的医疗负担剧增。早期的淀粉蛋白斑致病假说遭到质疑，包括炎症、胰岛素抵抗等多种机制的治疗研究开始进行。针对多个靶点的多药联合治疗纳米药物被基于厚望。纯的药物跨越血脑屏障递送效率低下。血脑屏障以其非常致密的结构在保护脑稳态的同时，对药物的脑部递送构成了巨大的屏障。经鼻给药提供了嗅神经、三叉神经通路，部分药物可以绕过血脑屏障，一定程度提高药物了入脑效率。但是药物入脑后，仍面临外排的风险。本项为降低药物脑部外排，研制了阿尔茨海默症患者脑内高度表达酶响应的原位纳米药物聚集体，阻断脑外排。能够包载亲水药物、疏水药物的胶束囊泡，获得了取得了高于90%的脑保留效果。进一步的，我们又进行了基于炎症机制、胰岛素抵抗机制的阿尔茨海默症多药联合治疗纳米药物，取得良好的动物实验效果。本项目通过载体材料设计保护并递送药物入脑、脑部高保留、脑部响应释放、减少非靶向组织留存等多种目标，为包括阿尔茨海默症在内的多种老年病治疗提供了极具优势的候选药物体系。