光激活探针用于药物致肝损伤过程相关活性小分子的荧光成像研究

The incidence of drug-induced liver injury (DILI) is increasing year by year in the worldwide, which has been paid serious attention by the clinical medical and drug research and development fields. However, the clinical indicators of DILI suffer from low specificity and sensitivity, leading misdiagnosis and error diagnosis. Intracellular active small molecules (ASM) show high sensibility and correlation to the occurrence and development of DILI, and exhibit definite biological effects. In view of this, a series of novel fluorescent probes with high sensitivity and good specificity towards ASM, as well as organelle targeting ability are planned to synthesize. Phototriggers will be introduced to the probes to increase the detection accuracy in organelles. The probes will be applied to in situ monitor the subcellular generation and level fluctuation of ASM in DILI biological models. The data obtained will be used to study the occurrence and development mechanism of DILI. The possibility of ASM as DILI biomarkers will be studied and discussed. Moreover, the antidote effect of sulfydryl-containing compounds will be investigated. This project will provide a new analytical method for the information acquisition of ASM-regulated cell functions, and bring breakthrough in DILI mechanism study and the diagnosis and treatment of DILI.

药致肝损伤的发生率逐年提高，是临床医疗及药物研发领域密切关注的问题。目前诊断药致肝损伤的临床指标存在特异性差和灵敏度低等不足，常导致误诊和漏诊。细胞内源性活性小分子在药致肝损伤发生发展过程中显示了良好的灵敏性和相关性，并具有明确的生物学效应。因此，本项目拟设计合成灵敏度高、特异性好、细胞器定位的分子荧光探针，利用光板机修饰探针增加探针细胞器定位响应的精准性，实时、原位检测药物代谢过程中细胞器内产生的活性小分子。通过建立生物模型，研究活性小分子产生、分布与药致肝损伤发生发展的相关性，探讨活性小分子作为药致肝损伤标志物的可行性，并研究巯基类还原性物质对药致肝损伤的解毒效应。通过研究，获得创新性研究成果，为活性小分子调控细胞功能分子信息的获取提供新的分析方法，为药致肝损伤相关机理研究及其诊治带来新突破。

药致器官损伤始终是临床医疗及药物研发领域密切关注的问题。但是目前诊断药致器官损伤的临床指标存在特异性差和灵敏度低等不足，亟需发现更为敏感的药致器官损伤的生物标志物，并针对这些标志物建立灵敏度高、特异性好的分析方法。本项目基于新颖的化学识别反应，设计、合成荧光探针，研究了荧光信号的调控与触发机制，发展了光解反应和光控释放策略，取得了如下研究进展：（1）以探针实现了药物致器官（肝脏、心脏、肾脏等）损伤过程中重要活性小分子的可视化成像检测，证明活性小分子有作为早期生物标志物预测药致器官损伤的潜质，有望用于药致器官损伤的预警、评估和治疗，从而为药致器官损伤研究提供了新的思路和分析方法；（2）发展了光激活释放策略，以探针实现了CO、NO等气体信号分子的光控释放及原位示踪；（3）以探针实现了细胞及活体内重要活性小分子的高特异性、高灵敏度原位荧光成像，为生物活性小分子的病理生理学功能研究提供了信息和分析工具。项目共发表文章15篇，包括Angew. Chem. Int. Ed. 1篇、Anal. Chem. 6篇、Chem. Commun.7篇、化学学报1篇；获4项国家发明专利授权；培养硕士研究生8人；参加国际学术会议3次（做口头报告1次）、国内学术会议2次；研究成果获中国分析测试协会科学技术奖（CAIA 奖）二等奖。