智能有机荧光点纳米复合材料助力β-淀粉样蛋白检测

Early diagnosis of Alzhemier's disease (AD) based on the target of Amyloid-β protein (Aβ) not only requries low-cost, operational security solutions, but the key challenges are how to successfully design and synthesize of biocompatible reagnets with characteristic performances such as controllable location and high efficiency recognition, which will limit the development level of the early diagnosis and treatment on AD. This proposal plans to use some common organic acid and amino acid reagents as the basic raw reagents, and to prepare biocompatible fluorescent organic dots with high fluorescence quantum yield. Meanwhile, under the guidance of intramolecular charge transfer mechanism and theoretical calculation simulation, some probe molecules (reporter) with functions of the specific recognition, the photoluminescence imaging and the photo-oxidation kinetic therapy will be designed and synthesized. Furthermore, a "smart" organic dots@reporter nanocomposite with features of recognition ligand, functional group and auxiliary enhancement will be prepared through chemical functionalization, and its fluorescence labeling capability as well as the singlet oxygen generation efficiency will be enhanced by förster resonance energy transfer between the organic dots and the reporter, which will be helpful for the Aβ protein target detection and the early diagnosis on AD.

对于以β-淀粉样蛋白(Amyloid-β protein, Aβ)为靶点的阿尔兹海默氏症(Alzhemier's disease, AD)的早期诊断，在探索低成本、操作安全性强的方案的同时，如何设计合成生物性质良好的检测试剂并实现其对Aβ蛋白的可控定位和高效识别是影响AD早期预防水平的关键问题。本项目拟选用普通有机酸和氨基酸为基础原料制备具有良好生物相容性的荧光有机点。同时，依据分子内电荷转移理论并结合理论模拟计算方法，设计合成具有特异性识别、荧光标记和光动力学诊疗功能的探针分子。在此基础上，采用化学功能化方式制备“配体+效团+增效”型有机点@探针分子复合材料，并通过荧光共振能量转移增强探针分子的荧光标记性能以及提高单线态氧产生效率，助力Aβ蛋白检测和AD早期诊疗。

β-淀粉样肽（Aβ42）经历错误聚集形成淀粉样纤维被认为是导致阿尔茨海默病(简称AD)发生的原因，抑制Aβ42蛋白错误聚集是AD临床诊疗的重要措施。新型Aβ42蛋白聚集抑制剂的探索和开发引起了科学家们的广泛关注。本项目综合利用化学反应方法、后化学功能化手段和主客体相互作用机制，精准设计并高效制备了智能纳米粒子，将其作为 Aβ42 蛋白聚集抑制剂。该类材料具有较大的比表面积、均一的纳米尺寸、特定孔径大小以及优异的表面电荷特性，能够通过主-客体识别和静电作用实现对Aβ42的特异性捕获，高效抑制Aβ42蛋白聚集进程，并显著改善Aβ42聚集诱导的细胞毒性。本项目通过分子动力学模拟、硫黄素T荧光监测，圆二色谱和等温吸附曲线等系列表征测试探究了纳米粒子与Aβ42的作用机理。通过蛋白聚集过程中关键的错误折叠蛋白的信息提取、特征确定和可视化功能研究，实现了对蛋白聚集抑制的发展进程和抑制效果的客观反馈，对于临床诊断、治疗过程和预后评价具有重要意义。