基于生物共轭体的荧光探针的构建及构效关系研究

Cancer and neurodegenerative diseases are major diseases that threaten human health. It is of extremely important practical significance to develop biological probes that can detect these diseases at low concentration with high efficiency and accuracy. The design and synthesis of novel fluorescent probes and their applications in biosensing and bioimaging are currently the hot topics of interdisciplinary frontier research. Luminogens with aggregation-induced emission attribute (AIEgens) enjoy the advantages of low cost, high brightness and superb photostability and hence are the attractive choice for constructing fluorescent probes. However, the improvement of the sensitivity, specificity and clinical utility of AIE-based probes has become a critical scientific issue in this area. In view of this and on the basis of the applicant’s preliminary foundation in the field of AIE-based molecular probes, this project is proposed to construct a kind of novel fluorescent probes based on the AIE bioconjugates, with multifarious biomolecules and various AIEgens possessing different optical properties, and to conduct in-depth studies on their sensing performance/activity. The main objectives of this project are for one thing to improve the water-solubility, biocompatibility, signal-to-noise ratio, sensitivity and specificity of the AIE-based probes, and for another to unveil and systematically study the structure-activity relationship of these AIE-bioconjugate-based fluorescent probes. Ultimately, the project is also intended to optimize the structures and detection conditions of such probe system to obtain bioprobes that can be used for clinical real sample analysis, providing a new chemical tool for the diagnosis of cancer and Alzheimer's disease.

癌症和神经退行性疾病是威胁人类健康的重大疾病，发展高效、微量、精确检测这些疾病的生物探针具有极其重要的现实意义。新型荧光探针的设计合成及其传感与生物成像应用是目前跨学科的前沿交叉研究热点。聚集诱导发光（AIE）荧光团具有低成本、高亮度及光稳定性好等诸多优点，是构筑荧光探针的诱人之选，但AIE探针的灵敏度、特异性和临床实用性的提高已成该领域面临的关键科学问题。鉴于此，基于申请人在AIE分子探针领域的前期基础，本项目提出基于AIE生物共轭体构筑新型荧光探针的新思路，拟构建一系列含有不同生物分子及不同光学性质的AIE荧光团的生物探针，深入研究各类基于AIE生物共轭体的探针体系的传感性能，旨在提高AIE探针的水溶性、生物相容性、信噪比、灵敏度以及特异性，阐明这类新型荧光探针的构效关系，进而优化其结构及检测条件，得到可用于临床实际样品分析的生物探针体系，为癌症及阿尔茨海默病的诊断提供新的化学工具。

在项目的资助下，项目团队围绕“基于生物共轭体的荧光探针的构建及构效关系研究”开展研究，取得了如下进展：（1）构筑了基于聚集诱导发光基元与多肽、药物等的系列生物共轭体，分别开发了对癌症标志物谷氨酰转肽酶和乏氧微环境等特异性响应的近红外荧光探针，并探索了其构效关系；（2）基于聚集诱导发光和振动诱导发光机制，构建了系列荧光探针，包括Aβ沉积活体内早期示踪剂、高性能荧光光敏剂、巯基氨基酸探针、亚硫酸盐实际样品检测探针、粘度与温度等物性参数探针、嵌段共聚物微相分离过程原位实时监测比率型荧光探针以及非掺杂温敏荧光墨水等，并系统研究了其构效关系；（3）通过实验与理论的有机结合，阐明了基于聚集诱导发光基元构筑生物荧光共轭体的分子设计原理，建立了基于聚集诱导发光和振动诱导发光机制开发高性能荧光探针的基本方法，为拓展新型发光材料在荧光探针领域的应用提供了新思路，丰富了高性能荧光探针的种类及分子设计方法。在基金的支持下，以第一作者身份/通讯作者身份在国际知名或权威学术期刊上发表标注受本项目资助的论文10篇，撰写英文学术专著章节1章、中文学术专著章节1章，获得授权发明专利1项。指导博士研究生3人，硕士研究生7人，已独立培养毕业硕士2名，协助培养毕业博士3名、硕士2名。