级联靶向型的多功能人工分子伴侣用于阿尔兹海默症协同治疗的研究

阿尔兹海默症（AD）是21世纪威胁人类生命健康的最严重疾病之一。由于AD的发病机制极为复杂，涉及β-淀粉样蛋白（Aβ）聚集、金属离子稳态失衡和过量氧化脑损伤等多种因素，所以单一靶点的药物难以满足AD的治疗需求；同时目前的AD药物还存在血脑屏障穿透率低、AD病灶部位靶向性差等缺点。为此，本项目拟通过嵌段共聚物自组装模拟天然分子伴侣，形成表面具有独特疏水微区的胶束，同时与小分子药物结合，并在胶束外层修饰血脑屏障靶向肽和AD病灶区域靶向肽，构建级联靶向型的多功能人工分子伴侣用于AD的协同治疗。该策略通过双靶向肽的联合介导，可高效穿过血脑屏障，然后选择性富集在AD病灶部位，达到“级联靶向”的效果；利用表面疏水微区模拟天然分子伴侣的疏水结构域，可有效抑制Aβ聚集，并利用结合的小分子药物赋予其调控金属离子稳态和降低氧化损伤的功能，从而实现“多靶点治疗”的目的。本项目将为AD的靶向协同治疗开辟新的途径。

Alzheimer's disease (AD) is one of the most serious diseases that threaten human health in the 21st century. Because the pathogenesis of AD is extremely complex which was involved multiple factors including β-amyloid (Aβ) aggregation, imbalance of metal ion homeostasis and excessive oxidative brain injury, it is difficult for single-target drugs to meet the treatment needs of AD. Moreover, the current AD drugs still have shortcomings such as low blood-brain barrier penetration efficiency and poor targeting of AD lesions. Therefore, the project intends to develop a novel cascade targeted multifunctional artificial molecular chaperone based on the self-assembly of block copolymers for the synergistic treatment of AD. This artificial molecular chaperone is composed of four parts, micelles with unique hydrophobic micro-domains on the surface which simulating natural molecular chaperones, small molecule drug in the core of micelles, blood brain barrier targeting peptide and AD lesion tissue targeting peptide modified on the outer layer of micelles. Through the mediation of dual-targeting peptides, this strategy can efficiently cross the blood-brain barrier and then selectively concentrate in the site of AD lesions, achieving the effect of "cascade targeting". At the same time, by simulating the hydrophobic domain of natural molecular chaperones, the surface hydrophobic micro-domains of micelles can effectively inhibit the aggregation of Aβ, and the combined small-molecule drugs can regulate metal ion homeostasis and reduce oxidative damage, thereby achieving the purpose of “multi-target therapy”. This project will open up new avenues for targeted and synergistic treatment of AD.