生物酶靶向功能有机小分子双光子荧光染料的构建及其在疾病诊断成像中的应用研究

Because of the extraordinary fluorescence quantum yield, excellent photostability and other advantages, traditional fluorescent dyes have played the important roles in fluorescence microscopic imaging of living cell, and promoted the development of the environmental sciences, bioscience and medical diagnosis. But traditional fluorescent dyes have many defects in the detection specificity for the enzyme and depth imaging in vivo, which limits its application in the diagnostic imaging of disease in vivo. Based on the earlier studies works, that is, the establishment of functional organic small molecular two-photon fluorescent dyes using isoquinoline and fluorine as fluorophore, the enzyme-targeted organic small molecular two-photon fluorescence dyes were developed. The dyes were obtained by selecting the efficient enzyme substrates as receptor and connecting different fluorescence energy donors and acceptors. The designing mentality of this project was reasonability and universal, which was verified by the theoretical calculation, preliminary synthesis and spectral properties studies. These dyes are expected to be used for the specificity recognition and depth imaging of enzyme, and they will improve the specificity of disease early diagnosis and imaging depth in vivo.

传统荧光染料因具有高的荧光量子产率和光稳定性等特点，已在活细胞荧光显微成像中起到重要作用，并推动着环境科学、生命科学及医学诊断的发展。但由于传统荧光染料存在对生物酶检测特异性低以及在活体成像深度方面的缺陷，限制了其在活体疾病诊断成像中的应用。申请人基于前期开发以异喹啉、芴为母体的有机小分子双光子荧光染料的工作，在本项目中拟构建生物酶靶向功能有机小分子双光子荧光染料。通过选择高效的生物酶底物作为识别基团，尝试分别与不同的荧光能量供体、受体相结合获得相应目标染料。通过理论计算、初步合成及光谱性能研究，验证本项目设计思路的合理性和普适性。本项目有望获得对活体内生物酶有专一识别性、适于活体深度成像的荧光染料，为提高疾病早期诊断特异性、疾病活体成像深度做出贡献。

传统荧光有机小分子因具有高的荧光量子产率和良好的光稳定性等特点，已在活细胞荧光显微成像中发挥着重要作用，并推动着环境科学、生命科学及医学诊断的发展。但由于传统荧光有机小分子存在对生物酶检测特异性低以及在活体成像深度方面的缺陷，限制了其在生化分析与生物成像中的应用。按照计划书的内容，本项目以构建生物酶靶向有机功能小分子双光子荧光染料为主要研究目标。选取吲哚类半菁染料、萘酰亚胺类、苯乙烯基苯并咪（噁/噻）唑类、含腈萘杂环类、螺吡喃类等有机小分子作为合成基元母核，合成获得30余种性能良好的有机小分子双光子荧光染料，其中20余种有机小分子双光子功能染料可专一靶向到目标生物酶。项目揭示了功能有机小分子双光子荧光染料体系构建规律，为靶向生物酶功能有机小分子的设计合成提供新的思路和方法。揭示双光子荧光功能有机小分子对生物酶分析检测的分子机制，为可用于生化分析与生物成像的功能有机小分子的设计合成提供理论依据。目前相关研究成果已发表学术论文9篇；授权国家发明专利4项；培养、协助培养硕士、博士研究生7名；参加国际和全国学术会议6次，邀请报告2次，口头报告3次。