基于荧光共振能量转移机理构建药物性肝氧化损伤荧光探针的研究

Drug-induced hepatotoxicity is a long-standing general concern of modern medicine. It is an important part to test drug-induced hepatotoxicity during the clinical trials. Conventionally, blood tests are taken as a standard means for evaluating liver damage. However, such tests fail to offer real-time unambiguous visualization and quantification of the level of drug-induced hepatotoxicity in vivo. Fluorescence imaging offers the potential approach to assess hepatotoxicity in living animals. lanthanide-doped upconversion nanoparticles (UCNPs) possess many intriguing characteristics, such as high photostability and high signal-to-noise ratio. The developed optical method for drug-induced hepatotoxicity suffered from the limited penetration depth and auto-fluorescence from biosample. To address this issue, we aim to develop multilayered UCNPs coated with chromophore as the nanoprobes based on the process of fluorescence energy transfer efficiency. UCNPs was used as the energy donor and chromophore was taken as the energy acceptor. The validity of this probe in the animal model was studied systematic with paracetamol (acetaminophen or APAP), a commonly used anti-pain/fever drug as the model drug. Combined with the high tissue-penetration capability of near-infrared excitation and emission, these turn-on luminescent nanoprobes allow for real-time monitoring of hepatotoxicity to be performed in living animals, thereby providing a convenient screening strategy for assessing hepatotoxicity of a wide range of synthetic drugs.

药物性肝毒性是导致上市药物撤市和药物临床试验失败最主要的原因之一。因此，检测药物性肝损伤是药物临床试验非常重要的环节。传统的离体血液检测难以准确实时地反映肝损伤程度。荧光检测法为活体实时检测药物性肝毒性提供了新的思路。上转换荧光纳米材料（UCNPs）采用高穿透力的近红外光作为激发光源，具有高稳定性、高信噪比等特点。针对目前开发的肝氧化损伤荧光探针穿透深度有限和生物背景荧光干扰的问题，本项目旨在将UCNPs与小分子探针相结合，基于荧光共振能量转移原理设计检测肝氧化损伤的新型荧光探针。以近红外发射光作为检测信号，构建一系列具有良好活体穿透深度和低生物背景荧光干扰的上转换荧光探针。拟用常见的感冒药-退热息痛为模型药物引发小鼠的肝氧化损伤，系统考察该探针的检测效果。结合探针的近红外激发和发射的高组织穿透深度和低背景荧光干扰的优点，发展的探针有望为新药开发过程中肝毒性筛查提供直观有效的新方法。

药物性肝损伤是导致上市药物撤市和药物临床试验失败最主要的原因之一。检测药物性肝损伤是药物临床试验非常重要的环节。传统的离体血液检测难以准确实时地反映肝损伤程度。荧光检测法为活体实时检测药物性肝毒性提供了新的思路。本研究小组在已有的高穿透力、高稳定性和高信噪比等特点的上转换荧光材料基础上。针对目前开发的肝氧化损伤小分子荧光探针穿透深度有限和生物背景荧光干扰的问题，本项发展的基于荧光共振能量转移原理设计检测肝氧化损伤的新型荧光探针。选取近红外发射光作为检测信号，将上转换荧光材料与小分子探针相结合构建了具有良好活体穿透深度和低生物背景荧光干扰的上转换比率荧光探针。拟用CCl4为模型药物引发小鼠肝氧化损伤，系统考察构建探针的检测效果。结合探针的近红外激发和发射的高组织穿透深度和低背景荧光干扰的优点，发展的探针解决了传统的小分子荧光探针穿透深度低和背景荧光干扰的问题。