近红外荧光/光声双模态成像探针用于药物性肝损伤检测与治疗药物疗效评估的研究

Drug-induced liver injury (DILI) is one of the most serious adverse drug reactions and also the most frequent reason for restriction of indication and withdrawal of drugs. But the lack of simple, accurate and specific methods hampers the real-time determination of DILI and the evaluation of DILI treatment. Near infrared optical (fluorescent and photoacoustic) technologies has manifested remarkable biocompatibility and chemical diversity. This project thus aims to develop dual modal near-infrared fluorescent/photoacoustic in vivo imaging methods for in vivo real-time detection of DILI. Our first step is to develop potent near-infrared dyes through the combination of rational design and dye-screening. The construction of dual-modal fluorescent and photoacoustic dual-modal probes will then be achieved by covalently incorporating liver targeting group and recognition group that responsive to DILI-related analytes (include ALP, LAP and ONOO-). Thus we will design dual modal probes targeting these analytes. With such elegant probes, we aim at real-time monitoring of drug-induced liver oxidative damage and the screening of drugs for the treatment of DILI through in vivo fluorescence and photoacoustic dual-modality imaging.

药物性肝损伤（DILI）是最严重的药物不良反应之一，但迄今仍缺乏简便、准确和特异的方法来实时检测及评估肝损伤程度。近红外光学（荧光与光声等）成像为DILI的活体实时检测提供了有力工具。针对目前光学探针在DILI检测与DILI治疗药物疗效评估中所面临的组织穿透深度有限和假阴性干扰等关键科学问题，本项目拟通过合理设计和染料筛选相结合的策略，发展近红外荧光/光声双模态DILI活体原位成像检测新方法。首先，筛选出对ONOO-等生物活性分子高稳定性的近红外染料。在此基础上，引入肝靶向基团和肝氧化损伤过程中异常表达的ALP、LAP或ONOO-识别响应位点，构建一系列具有高化学稳定性的近红外荧光/光声双模态探针。利用探针与分析物间快速特异的反应引发近红外荧光和光声信号的响应，同时采用近红外荧光和光声双模成像显著提高检测的可靠性，进而实现药物诱导肝氧化损伤的原位分析以及DILI药物治疗效果的初步评估。

药物性肝损伤（DILI）是最严重的药物不良反应之一，但迄今仍缺乏简便、准确和特异的方法来实时检测及评估肝损伤程度。近红外光学（荧光与光声等）成像为DILI的活体实时检测提供了有力工具。针对目前光学探针在DILI检测与DILI治疗药物疗效评估中所面临的组织穿透深度有限和假阴性干扰等关键科学问题，本项目通过合理设计和染料筛选相结合的策略，发展了系列近红外一区和二区染料作为新型荧光/光声探针平台，在此基础上设计、合成了一系列近红外荧光/光声双模成像探针，详细研究了其体外性能，并将其用于药物性肝损伤成像研究。目前，该项目已经顺利完成，发展一系列新型的高灵敏、高选择性检测细胞和活体内亮氨酸氨基肽酶（LAP）、γ-谷氨酰转肽酶（γ-GGT）和活性氧（超氧阴离子、过氧化亚硝酰阴离子）的荧光/光声双模态分子探针，并获得药物诱导肝损伤过程和药物保肝护肝过程中，细胞内ALP、LAP GGT和活性氧水平变化的可靠信息及相关的分子调控机制，为急性肝损伤检测与治疗药物的疗效评估提供新的方法，相关研究成果发表在J. Am. Chem. Soc (2篇)、Angew. Chem (3篇)、Nat. Commn. (1篇)、CCS Chem. (1篇)、Chem. Sci. (1篇) 和Anal. Chem. (5篇)等化学领域高水平学术期刊，获授权专利2项，受邀在Acc. Chem. Res（2021, 54, 403−415）撰写了药物诱导急性肝损伤成像荧光探针的专题综述。

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