新型近红外诊疗一体荧光探针的设计、合成和生物学应用研究

With the development of fluorescent detection technology, the research of design, synthesis of fluorescent probes and the imaging applications for the diagnosis and treatment of cancer cells and tumors, has become an active field in recent years. At present, the development of the integrated fluorescent probes for diagnosis and therapy mainly focuses on the sensing mechanism of S-S bond cleavage, triggered by GSH. The study of new near-infrared fluorophore is rare. In view of this, we intend to carry out the research of a series of new type near infrared fluorophores, especially about the new type of cyanine dye and the dicyanomethylene-4H-pyran (DCM) chromophore. Therefore, we proposed to introduce subcellular-targeting groups to near-infrared fluorophores, which are with excellent performance of photo-physics and biocompatibility, and study the cytotoxicity and the subcellular imaging capability of these new fluorophores. Finally, based on the characteristics of these new near-infrared fluorophores, we will introduce an anti-cancer prodrug at a suitable site, and develop 5-8 reasonable near-infrared integrated fluorescent probes, which triggered by the other species beyond GSH, for diagnosis and therapy. Based on the single-cell fluorescence imaging, the explorations of the biology applications of these fluorescence probes, to dynamically record in vivo and detect the other species beyond GSH in living cells and tumor tissue, are our goals. Through all these efforts, we wish we could promote the developments of the research of fluorescence sensing and fluorescence imaging.

随着荧光检测技术的不断发展，对诊疗一体的荧光探针的设计、合成及生物荧光成像研究逐渐成为近年来的研究热点。目前开发的诊疗一体荧光探针主要集中在GSH触发的S-S键断裂机理上，且基于新型近红外荧光团的开发并不普遍。鉴于此，我们打算深入开展新型近红外荧光团的研究工作，特别是重点开展新型半菁染料和新型苯并吡喃腈荧光团的研究。在此基础上，我们拟在光物理性能优良、生物相容性好的近红外荧光团上引入亚细胞器靶向定位基团，研究这些新型荧光团的细胞毒性和亚细胞器荧光成像能力。最后，我们将根据这些新型近红外荧光团的特点，在合适位点引入抗癌前药，合理设计相应的由GSH以外的其它生物物种触发的诊疗一体的近红外荧光探针5-8种。在单细胞荧光成像的基础上，深入开展该系列荧光探针分子的生物学应用研究，实现生物活体体内实时荧光成像及对GSH以外的其它生物物种在活体细胞和肿瘤中的动态成像监测，推动生物分子荧光分析法的发展。

随着荧光检测技术的不断发展，对诊疗一体的荧光探针的设计、合成及生物荧光成像研究逐渐成为近年来的研究热点。以往开发的诊疗一体荧光探针主要集中在GSH触发的S-S键断裂机理上，且基于新型近红外荧光团的开发并不普遍。本项目开发了几种基于半菁染料和新型苯并吡喃腈荧光团的由癌症标志物（活性氧、活性硫、活性氮物种）触发的近红外可激活荧光探针。系统研究了这些荧光探针的光物理性质和生物荧光成像性质。在单细胞荧光成像的基础上，将成像模型拓展到线虫、斑马鱼、实验小鼠等活体生物。我们在荧光探针中引入具有癌细胞靶向功能的吲哚美辛和氟尼酸基团，以使其具有肿瘤靶向能力，开发了一系列检测活性氧、活性硫、活性氮、和重要生命物质的近红外荧光探针，为后续近红外II区荧光探针的开发和癌症的治疗奠定了基础，积累了合成和测试经验，推动了近红外诊疗一体荧光探针研究的发展。