阿尔茨海默病光控诊疗一体化药物的设计和性能研究

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that affects millions of people around the world. Currently, there is no cure to efficiently prevent or slow down the disease. The aggregation of amyloid-β peptide (Aβ), one of the primary pathological hallmarks of AD, plays a key role in the AD pathogenesis. Considering that the Aβ aggregation occurs in the early “preclinical AD” stages, the Aβ-targeted disease-modifying therapy would be a promising strategy for the treatment of AD. However, traditional therapies use diagnostic and therapeutic drugs separately, which are unfavorable to exploring the early therapeutic time window, pathology of AD, and exerting the optimal efficacy of drugs. Theranostic agents that combine diagnosis and therapy together could overcome the weakness of current approaches through the complementary action between two functions. In this project, we will design and synthesize a series of photoactivatable near-infrared (NIR) fluorescent Pt(IV) complexes, which could target and modulate the Aβ aggregates, and simultaneously self-monitor the changes of Aβ aggregation by real-time NIR imaging. Due to their unique properties such as photoactivity and strong blood brain barrier permeability, they can also be utilized as oral-administered small-molecular theranostic agents for AD to realize site-specific photoresponsive drug delivery and NIR/PA dual-modality imaging. This study is of great significance for understanding the AD pathogenesis and development of anti-AD drugs.

阿尔茨海默病（AD）是一种慢性神经退行性疾病，威胁着全球上千万人的健康与生命，目前还没有有效的治疗方法阻止或延缓其病程。β-淀粉样蛋白（Aβ）聚集是AD的主要病理特征和致病因子。由于Aβ聚集始于临床前AD阶段，以Aβ为靶点的早期修饰性干预成为抗AD的重要策略。但是传统方法将诊断和治疗药物分开使用，不利于探寻AD早期治疗窗口和病理机制以及发挥最佳药效。诊疗剂集诊断与治疗功能于一体能够有效发挥二者的互补作用，从而弥补上述不足。本项目拟设计合成一类具有光激活活性的近红外荧光铂（IV）配合物，它们不仅能靶向Aβ并调控其聚集，还能通过近红外荧光成像实时跟踪Aβ聚集变化。这类化合物具有光响应和穿透血脑屏障等特性，可作为潜在的小分子诊疗剂，通过口服给药和定点光激活，实现同时调控Aβ聚集和近红外荧光/光声（NIR/PA）双模态成像的“诊疗一体化”目的。本研究对了解AD发病机制和抗AD药物开发具有重要意义。

阿尔茨海默病（AD）是一种慢性神经退行性疾病，威胁着全球上千万人的健康与生命，目前还没有有效的治疗方法阻止或延缓其病程。β-淀粉样蛋白（Aβ）聚集是AD的主要病理特征和致病因子。由于Aβ聚集始于临床前AD阶段，以Aβ为靶点的早期修饰性干预成为抗AD的重要策略。但是传统方法将诊断和治疗药物分开使用，不利于探寻AD早期治疗窗口和病理机制以及发挥最佳药效。诊疗剂集诊断与治疗功能于一体能够有效发挥二者的互补作用，从而弥补上述不足。为此本项目基于Aβ聚集特性，设计、合成并筛选出三种Aβ靶向性荧光铂配合物，详细研究了它们对Aβ聚集的荧光响应和调控性能。具体包括：（1）构筑了具有潜在诊疗性能的荧光铂（Ⅱ）金属配合物BTA-Pt(Ⅱ)和BTA-Cur-Pt(Ⅱ)。BTA-Pt(II)对Aβ聚集体具有浓度依赖性荧光增强响应且时间保持荧光稳定，而且对Aβ自聚集和金属诱导的Aβ聚集均具有出色的抑制活性。BTA-Cur-Pt(II)具有可见光光活化性能。光活化的BTA-Cur-Pt(II)对Aβ聚集体表现出了更显著的荧光增强响应，并且能够明显抑制金属诱导的Aβ聚集体的PC12神经细胞毒性。（2）构筑了荧光铂（IV）金属配合物BTA-Pt(IV)。它可通过可见光光照还原成铂（II）活性物种，抑制Aβ自聚集和金属诱导的Aβ聚集，而且光活化后其荧光显著增强可用于Aβ的荧光标记。BTA-Pt(IV)几乎不具有细胞毒性，能明显延缓AD线虫因Aβ毒性造成的瘫痪。以上研究为开发铂类AD诊疗剂提供了有效策略。（3）利用铂配合物的荧光配体构建了比例计量型荧光探针BPNS，通过Zn（II）介导策略实现了可溶性Aβ的准确定量检测，为AD早期诊疗提供了新方法。