脑神经元靶向纳米递药系统的构建及对阿尔茨海默病双靶点联合用药的研究

项目名称： 脑神经元靶向纳米递药系统的构建及对阿尔茨海默病双靶点联合用药的研究

项目编号： No.81473150

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张奇志

作者单位： 复旦大学

项目金额： 70万元

中文摘要： 阿尔茨海默病(AD)治疗难度大，目前药物治疗面临三大关键问题：①AD病理机制复杂，只针对单一靶点的药物疗效有限；②血脑屏障(BBB)对药物入脑的阻碍作用；③药物入脑后难以浓集于病变部位，不仅降低了对AD的治疗效果，也给正常脑组织带来了重大安全隐患。为此，本项目拟将联合用药与脑神经元靶向策略相结合，同时以AD重要的神经病理标志物-β-淀粉样蛋白和tau蛋白为治疗靶点，选择两个针对性多肽药物-β-片层阻断肽H102和微管蛋白稳定剂NAP，将其分别载于表面修饰有短肽d-TGN(靶向BBB)和Tet1(靶向神经元)的纳米粒中，构建载多肽的脑神经元靶向递释系统。通过双靶向功能基的介导，增加多肽药物的入脑递释和在病变神经元的浓集；通过联合用药发挥协同作用，增强对AD的治疗效果。本项目既是针对β-淀粉样蛋白和tau蛋白联合用药治疗AD的有益探索，又是脑靶向递药系统研究的拓展。

中文关键词： 阿尔茨海默病；β-淀粉样蛋白；tau蛋白；脑神经元靶向；联合用药

英文摘要： Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with few effective treatments. Currently, there are mainly three key problems exit in its therapy. Firstly, most drugs available now just aim at one target and provide symptomatic therapy, which could not cover the complex pathologic mechanisms of AD. Secondly, the blood-brain barrier (BBB) acts as a protective barrier for the central nerves system (CNS) and prevents the brain delivery of most drugs. Thirdly,most drugs are difficult to concentrate on the diseased region after passage through the BBB. drug distribution in normal brain tissues would not only decrease the amount of drugs at the lesion, but might cause serious CNS side effects. Considering these problems, combination therapy and precise brain neuron delivery are applied together in this project for AD therapy. For combination therapy, a novel β-sheet breaker peptide, H102 peptide, and a microtubule- stabilizing agent, NAP peptide, are chosen as therapeutic drugs for the two key hallmarks of AD, β-amyloid and tau protein, respectively. Moreover, precise drug delivery to the brain lesion is critical for AD therapy due to the complexity of brain and the susceptibility to damage of neurons. For this purpose, d-TGN (consensus peptide sequence TGNYKALHPHNG), a specific ligand of BBB, is chosen to enhance the brain penetration of the delivery system, while Tet1(consensus peptide sequence HLNILSTLWKYP), with high binding affinity to GTb1 trisialganglioside expressed on neuronal cells, is used as a brain neuron targeting moiety. Thus, H102 and NAP are respectively encapsulated into nanoparticles modified with both d-TGN and Tet1, constructing a brain neuron-targeted delivery system. This drug delivery system is supposed to increase the specific delivery of AD therapeutic drugs to the brain neuron lesion, exerting the combined effects of two drugs to enhance the curative effects. This project would be not only a beneficial exploration in the combination therapy of drugs targeting β-amyloid and tau protein for AD, but also an extensive research of brain targeted drug delivery.

英文关键词： Alzheimer's disease;β-amyloid;tau protein;brain neuron targeting;drug combination