“全链式-多靶点”同源仿生AD治疗系统的研究

Combination anti-Alzheimer (AD) therapy is greatly significant for improving its clinical efficacy, of which the early drug intervention effect is remarkable. In this project, we firstly propose a novel technology of ‘bioinspired-assembly strategy’ to prepare drug (physical embedded donepezil and lipophilic anchored curcumin)-loaded reconstituted high density lipoprotein (E sub-type) delivery system by utilizing isolated, dehydrated human all-components. The system possesses characteristics of high BBB permeability from apolipoprotein and Aβ targetablility from curcumin to achevie the efficient brain transfer sequentially, and AD positive target. By intergration of ease cholinergic nerve block by donepezil, synapses repair by curcumin, and capacity of Aβ-targeted clearance induced by “reverse cholesterol transport” in brain, the system provides a design idea for combination therapy of remission, repair and reverse lesions of the nervous system based on "whole chain-multiple targets" manner. Furthermore, the system is of high homology and biocompatibility, BBB permeability, AD targetablility, high efficient co-therapeutic efficacy, and provided with simple preparation process, high drug loading, green and renewable resources. The mechanisms of AD combination therapy will be investigated by in vitro and in vivo studies, which will provide a new strategy, solution and technology on targeted treatment of central nervous system.

药物联合治疗对提高阿尔茨海默病（AD）临床疗效意义重大，其早期的药物干预治疗效果显著。本项目首次提出先拆分-后重组技术，以人源高密度脂蛋白全组分为原材构建载药（物理包埋多奈哌齐，脂质锚定姜黄素）E型重组高密度脂蛋白纳米传递系统，凭借载脂蛋白的BBB高渗透性和姜黄素的Aβ沉积靶向性，实现序贯式脑内高效运转、AD病区高度靶向；将多奈哌齐缓解胆碱能神经传导阻滞，姜黄素神经元突触修复，与脑内“胆固醇逆转运”再生的盘状高密度脂蛋白靶向清除Aβ功能相结合，实现针对AD病变神经系统的缓解、修复与逆转的“全链式-多靶点”联合治疗设计思路。该系统具有高度同源性和生物相容性、BBB高渗透性、AD主动靶向性、联合治疗高效性，且制备工艺简单、载药量高、绿色环保和资源再生利用等特征。通过细胞水平及体内外药效实验，探讨该系统的AD联合作用机制，为中枢神经系统靶向治疗提供新思路、新方案和新技术。

针对阿尔茨海默病（AD）复杂的病变特征和血脑屏障（BBB）临床药物治疗屏障，构建BBB高渗透性载体以实现AD多药联合治疗，临床意义重大。本项目首创提出“先拆分-后重组”技术获得同源高密度脂蛋白（HDL），联合脂质锚定表面荷载姜黄素（CUR）和物理包埋核心荷载多奈哌齐（Don），构建了CUR-rHDL/Don纳米给药系统。该给药系统凭借载脂蛋白的BBB高渗透性和姜黄素的Aβ沉积靶向性，实现了脑内序贯高效运转、AD病区高度靶向的功能，在病灶磷脂转运蛋白PLTP触发下完成HDL变构释放药物Don改善胆碱能功能障碍，并再生为盘状HDL高效靶向清除Aβ。本项目通过细胞水平及体内外药效实验，深入探讨了CUR-rHDL/Don纳米给药系统的变构过程、BBB渗透性及AD联合治疗机制，实现了针对AD病变胆碱能功能障碍修复、病因清除和神经保护的“全链式-多靶点”联合治疗设计思路。本项目攻克了AD临床治疗的治疗模式单一和BBB受限等难点，且具有高度生物安全性和制备工艺简单易放大等优势，临床转化前景良好。本项目超额完成了预期研究任务，在国内外核心期刊发表论文20篇，其中SCI 收录的论文18篇（3篇IF>10），授权专利1项，申请国际专利一项；获得包括江苏省科学技术二等奖等省级及以上奖励10余项；培养博士研究生2名、硕士研究生6名。