基于双模式响应的高性能近红外II区荧光染料分子设计及应用研究

This project focuses on the development of dual-modal imaging dyes to integrate the benefits from both second near-infrared (NIR-II) fluorescence and photoacoustic imaging (PA) with an ultimate goal of improving overall cancer diagnosis efficacy. It is of great significance to provide the detailed information with high quality spatial resolution and deep tissue penetration. The key point is how to build the design strategy of improving the photoacoustic conversion efficiency, which is usually based on the reduction of the fluorescence quantum yield of organic dyes. Herein, we will explore novel NIR-II cyanine compounds via tunable energy gaps, large Stokes shifts, and quantum yields, so that combining these two modalities together to acquire complementary information and synergistically enhance the efficacy in diagnosis. In particular, NIR-II dyes with sequential responses (such as active enzyme, GSH, pH, etc.) based on the “smart” recognition have ability to efficiently integrate multiple imaging information such as the targets preoperatively and intraoperatively in a synergistic manner, resulting in significant implications in preclinical and clinical research. This study will provide an important tool for understanding the pathogenesis and related diseases diagnosis and treatment at the molecular level.

本项目针对如何有效解决近红外荧光染料在成像应用中探测深度与分辨率之间的性能平衡问题，从设计新型近红外II区染料母体入手，探索建立染料荧光和光声双模式与特异性分子识别之间规律，发展兼具靶向性和可激活的近红外识别染料，应用于多尺度、高分辨率结构和功能成像。研究难点在于如何突破通常采用降低有机染料的荧光量子产率来提高光声转换效率的设计策略，以近红外染料母体设计、分子能级精准调控为手段探索解决染料光与声机制的协同作用，发展兼顾荧光和光声模式的双模式响应识别染料。特别是如何基于“智能”识别过程，创制具有次序响应（如活性酶、GSH和pH等）的近红外II区双模式识别染料，充分发挥荧光和光声成像各自的优势，实现在体的“实时、可视、定量”活体影像研究，应用于临床疾病的早期、特异性诊断，以及靶向性的药物传输与控释，最终构建检测、诊断与治疗并举的近红外II区识别染料体系。

发展面向生命健康、环境生态应用的近红外功能染料，聚焦近红外染料理性设计及功能强化，本项目围绕发展集成多模式响应的生物识别分子探针，特别是结合荧光和光声模式的各自优势，实现多尺度、跨层次、高分辨率结构和功能成像。发展了能够对肿瘤组织特征微环境特异性识别的多模式近红外II区染料，成功设计基于黄酮的近红外I区和II区新型母体，解决近红外染料在活体成像应用中探测深度与成像分辨率之间的矛盾，发展特异性、高灵敏、比率型、激活型近红外荧光识别染料。在项目执行期间，共发表SCI论文21篇，括该项目已先后在Coord Chem Rev (2篇)、Nature Protocols (1 篇)、J. Am. Chem. Soc. (1篇)、Angew. Chem. Int. Ed. (4篇)、Adv Mater. (1篇)、 Nat. Commun. (2篇) 、Chem. Sci. (5篇)、Sci. China Chem. (2 篇)等主流学术刊物上发表了28篇学术论文，申请中国发明专利6项，授权3项中国发明专利。项目资助期间项目负责人获得国家杰出青年基金、上海市曙光学者等资助，荣获2020年上海市青年科技杰出贡献奖。