高活性双重靶向近红外荧光探针的设计合成及对酶类标志物检测性能研究

Early diagnosis is one of the most effective measures to reduce cancer mortality and the monitoring of tumor markers has gained increasing interest in early diagnosis of cancer. In this project, research on tumor associated enzyme markers. We plan to develop a series of hemicyanine-based near-infrared fluorescent dyes with multiple active sites. For the preparation of near-infrared fluorescent probes with dual-targeted function of tumor tissue and cell mitochondria. A high selectivity and sensitivity method for analyzing the enzyme markers in specific tumor cells base on its high catalytic activity and specificity was constructed. The probes were used for the detection of corresponding enzyme markers in tumor patient’s serum. The aim of this project is to study the binding pattern of enzymes and probe at the molecular level, reveal the relationship between the expression of enzyme markers and the mitochondria in tumor cells，investigate the relationship between enzyme markers and tumor pathogenesis at the organelle level. Contribute to improve the accuracy of the cancer early diagnosis and provide a new strategy for the multi-functional targeted theranostic drug development.

早期诊断是降低肿瘤死亡率最有效的措施之一，而对肿瘤标志物的检测是肿瘤早期诊断的研究热点。围绕与肿瘤密切相关的酶类标志物，本项目拟设计合成一系列具有多个活性位点的半花菁近红外荧光染料，制备具有肿瘤组织和细胞线粒体双靶向功能的近红外荧光探针。基于酶的高催化活性和专一性，构建高选择性、高灵敏度的检测分析方法用于特定肿瘤细胞线粒体中酶类标志物的检测。并将探针用于肿瘤患者血清中相应酶类标志物的检测。该项目旨在从分子水平上研究酶与探针分子的结合模式，揭示酶类标志物表达与肿瘤细胞线粒体之间的关系，从细胞器层面研究酶类标志物与肿瘤发病的联系。为提高肿瘤早期诊断的准确性做出贡献，也为新型多功能靶向诊断治疗型药物的开发提供新的思路。

近红外荧光探针以及性能优异的新型荧光探针在生化分析和生物成像中的应用是目前荧光检测的研究热点。本项目致力于设计合成具有发光性能优异、选择性好、灵敏度高的荧光探针用于细胞中疾病标志物和有害物质的检测。以构-效关系研究为核心，借助量化计算软件辅助分子结构设计，开发具有斯托克斯位移较大的近红外荧光团以及其他一系列性能优异的荧光团，期间对荧光团的结构进行优化，对光学性质进行调控，再将荧光团修饰上特异性识别基团，构建具有特异性检测功能的荧光探针。实现了对氟离子、钍离子、锌离子、铀酰离子和光气等有害物质的可视化定量检测和成像。考察探针对特定检测物的检测性能，包括灵敏度、选择性、检测下限和潜在应用前景（实际样品检测和活细胞成像和检测）探究。这些研究探索对于荧光团性能的精准调控、高性能荧光探针构建以及新型固态便携式荧光探针的开发具有重要意义。目前该项目已经取得了一系列研究成果，以第一作者或通讯作者在Sensors and Actuators B: Chemical，Dyes and Pigments，Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy和Tetrahedron等国际著名期刊发表论文7篇，授权发明专利1项。通过本项目资助培养了研究生6名，达到了既定预期目标。