药物性肝损伤的光声传感成像体系的设计及在中草药安全性评价中的应用

Drug-induced liver injury (DILI) has become a major and challenging public health issue in terms of medicine development and clinical therapy. Thus, the preclinical screening methods for hepatotoxicity should be operated as early as possible, and should result in improved patient safety and therapeutic outcomes. Researches also reveal that some herbal medicines can induce herb-induced liver injury (HILI). Herein we propose to employ photoacoustic tomography to diagnose DILI through imaging DILI-related biomarkers in mouse models. Photoacoustic probes for sensitive and selective detecting and imaging DILI-related biomarkers will be designed, synthesized, and incorporated into reactive oxygen species (ROS)-responsive polymeric systems which has liver-targeted element in their structures. The structure and optical properties of the imaging systems will be optimized so that they can preferably locate at the focus of DILI and produce prominent photoacoustic and fluorescent signals for DILI diagnosis. The imaging systems will also be used to investigate the herb-induced liver injury. Upon implementation, this project may not only serves as the proof of concept for designing photoacoustic detection and imaging systems for disease diagnosis, but also demonstrate the great potential of polymer systems for targeting, delivering and releasing optical sensors.

药物（包括中草药）性肝损伤可导致肝脏病变甚至死亡，对药物性肝损伤的诊断是保障病人生命安全和健康的重要手段；而对中草药安全性进行科学评价是促进中草药现代化的必要途径。本项目拟采用光声断层成像技术，通过检测肝损伤生物标志物来诊断药物性肝损伤。设计和制备几种肝损伤标志物的光声探针，分别将它们引入对活性氧物种敏感的、且具有肝靶向能力的聚合物体系中，形成聚合物基肝损伤光声检测及成像体系。该体系能够富集于肝区并能在活性氧物种大量存在条件下释放探针并实现成像。优化成像体系的结构，使探针能够在肝区释放后对特定生物标志物产生特异性的光声和荧光响应，并对药物性肝损伤进行诊断和准确定位。将光声成像体系用于中草药诱导的小鼠肝损伤的诊断，考察中药剂量、炮制及配伍对损伤程度的影响。本研究有望借助于有机分子和聚合物体系的结构设计的多样性和灵活性，为药物性肝损伤的诊断和中草药安全性评价提供一种较为便捷的新方法。

有些中草药的不当使用能导致肝损伤，对中草药安全性进行科学评价是促进中草药现代化的重要手段。本项目以光声断层扫描成像技术和荧光成像技术，通过检测特定生物标志物来诊断药物性肝损伤。制备了一系列D-A型近红外生色团，其吸收谱带和发射谱带可随其分子结构中的推-拉电子状态的改变而发生变化，其吸光度和荧光强度的变化可达20倍，最终实现了对特定被检测物的光声和荧光双重检测；利用活性物种响应型聚合物负载分子光声探针，形成了聚合物基光声检测成像体系，并在680 nm至980nm范围内产生光声信号；以明确可致肝损伤的药物刺激小鼠，建立了药物性肝损伤的小鼠模型，观察了一系列光声成像体系在小鼠肝区对几种肝损伤标志物进行成像，验证了成像体系对药物性肝损伤的光声检测和成像能力，成像深度达到1cm以上；以光声成像和荧光成像为检测方法，考察了几种中草药诱导的小鼠肝损伤状况，探讨了不同中草药制剂对小鼠肝损伤的程度，同时也证明了光声成像这种新型检测方法在中草药安全性检测中的成功应用。还设计了多种其他疾病的检测成像探针，用光声成像法和荧光成像法考察了它们在疾病诊断中的应用。通过上述研究的开展，可为包括药物性肝损伤在内疾病的诊断和治疗提供更优的分析手段和可靠的依据。本项目还实现了对几种疾病的诊断和治疗一体化，拓展了光学探针的应用范围。本研究的相关结果和形成的策略可为设计其他基于荧光和光声信号的疾病诊断和/或治疗体系提供思路。本研究形成的一些技术有望将来应用于一些疾病的诊断和治疗领域。