微泡及超声介导BBB开放递送纳米硒/硫及其载药 抑制阿尔兹海默病的研究

Until now, there are no effective treatments to cure or prevent Alzheimer's disease (AD). Although the molecular mechanisms of AD pathogenesis are not clearly understood, the Aβ and Tau protein is believed as the pathological hallmark of AD, moreover, these two proteins have synergistic effect in the development of AD. Many clinical experience revealed that multitarget drug is a promising therapeutic for the treatment of AD. However, another challenge of the application of this drug in AD is the blood brain barrier (BBB). In this research, metal chelators and neuron restoration agents are loaded on the surface of selenium/sulphur nanoparticles. Then, the nanoparticles are inlay on microbubble and cross BBB via microbubble and ultrasound-induced BBB opening. Effects of targeted drug delivery via non-invasive microbubble and ultrasound-induced BBB opening will be evaluated in vitro and in vivo and the new method and technology for crossing BBB will also be established. The effects of this nanoparticles system on prevent Aβ aggregation, Tau phosphorylation and protein aggregates-induced neurotoxic will be assessed. The mechanism of nanoparticles in alleviating neuron damage and promoting nerve regeneration will be elucidated. The ability of nanoparticles to interdict the Aβ mediated PI3K/AKT signaling pathway and the activating of GSK3β will be measured. The effects of nanoparticles in improving cognitive function of AD transgenic model mice will be analyzed. This project is expected to obtain multifunctional nanoparticles with ability of targeting to Aβ, Tau protein, promoting nerve regeneration, traversing BBB and provide a new strategy for the exploitation of multifunctional AD drugs.

阿尔茨海默病（AD）迄今尚无有效治疗措施。AD发病机制尚未清楚，其中Aβ和tau蛋白是AD病理学的重要标志，且两者存在交互和协同效应。众多临床经验提示复方多靶点AD药物是有效途径，另一挑战是如何有效地使药物透过血脑屏障（BBB）。本项目利用纳米硒或纳米硫等双载金属螯合剂和神经修复剂，将纳米颗粒镶嵌在微泡外壳表面，通过微泡超声波介导BBB开放实现纳米药物传递。体外、体内研究微泡超声波介导纳米体系透过BBB的效果，建立透过BBB的新方法和技术。评价纳米体系在体外和体内减少Aβ沉积、防止Tau磷酸化的功能，降低因蛋白质聚集产生的毒性；揭示其减轻神经元损伤，促进神经再生的机制；阐明纳米减少Aβ激活GSK3β信号通路抑制tau蛋白磷酸化的功能；评价纳米体系对AD转基因模型小鼠认知功能的改善。旨在获得靶向Aβ蛋白、tau蛋白、促进神经再生、跨越血脑屏障的多功能纳米体系。为开发多靶点AD药物提供新策略。

阿尔茨海默病（AD）迄今尚无有效治疗措施。AD 治疗药物非常有限，国际上一致推荐的一线治疗药物仅有多奈哌齐、卡巴拉汀、加兰他敏及美金刚等，患者常常面临着无药可治或无药可选的境地。AD发病机制十分复杂，存在着多种致病假说，例如：氧化应激假说，炎症假说，病毒感染假说，代谢功能障碍假说、基因突变假说等等。另一挑战是如何有效地使药物透过血脑屏障（BBB）。众多临床经验提示复方多靶点AD药物是有效途径。.针对AD的多靶点假说，本项目设计合成了7个系列近20种纳米体系，纳米核心包括纳米硒、纳米硫、纳米钌、纳米钯、抗氧化活性纳米酶等，双载金属螯合剂和神经修复剂，赋予纳米材料透过血脑屏障和多靶点功能。.针对透过血脑屏障的难题，我们采用了多种方案，包括：（1）将纳米颗粒镶嵌在微泡外壳表面，通过微泡超声波介导BBB开放实现纳米药物传递，（2）纳米表面修饰透过血脑屏障的多肽，（3）设计成逐级释放的纳米体系，实现一级释放冰片，Bor瞬间打开BBB，使介孔硒载药体系迅速持续的积累在脑内，（4）采用温度刺激响应性相变材料十四醇作为热响应开关，纳米系统可以有效透过BBB递送NGF和智能响应热效应控制NGF释放。体外、体内研究纳米体系透过BBB的效果，建立了透过BBB 的新方法和技术。在AD作用靶点方面，设计了多靶点纳米体系，纳米体系具有减少Aβ沉积、防止Tau磷酸化的功能，降低因蛋白质聚集产生的毒性；减少Aβ激活G SK3β信号通路抑制tau蛋白磷酸化的功能；减轻神经元损伤，促进神经再生；促进小胶质细胞从促炎M1型向抗炎M2型极化，恢复小胶质细胞对Aβ的吞噬能力和神经修复功能；在低功率NIR照射下促使Aβ纤维降解，同时作为ROS清除剂，彻底降低Aβ纤维介导的神经毒性。通过多种手段，研究了纳米体系在体外体内促进神经再生的机制；抑制Aβ聚集、防止神经炎症重新触发、避免恶性循环重新形成的潜力。调节小胶质细胞和星形胶质细胞的神经保护功能，改善神经炎症，减轻Aβ负担，并最终挽救APP/PS1转基因小鼠的记忆力下降和认知障碍。.本项目为获得靶向Aβ蛋白、tau蛋白、促进神经再生、抗氧化/PTT协同对抗AD、调节小胶质细胞极化等跨越血脑屏障的多功能纳米体系。为开发多靶点AD药物提供新策略。