常压激光解析/同步辐射二次光电离对GCs及其代谢物组织原位质谱成像方法学研究

质谱成像是一种灵敏度高、特异性强、无需标记的多通道分子影像技术，已经发展成为药物调控机制研究的重要工具。由于生物组织表面高盐的基质环境和强极性磷脂酰胆碱类脂质的基质干扰，传统电离技术对组织表面中性的糖皮质激素（GCs）药物及其代谢物和内源性小分子等物质的分析面临严重的离子抑制，离子化效率低的问题。二次光电离是提高中性成分电离效率的一种有效方法。本项目拟将同步辐射可调谐真空紫外光作为激光解析的二次电离源，构建一套高分辨高灵敏的常压激光解析/同步辐射二次光电离质谱成像分析平台；整合化学衍生与二次光电离技术提高痕量GCs药物检测效率，建立GCs药物及其代谢物的表面定量分析方法；针对模型动物炎症微区GCs药物、代谢物和内源性小分子等物质的原位可视化分析，结合多变量统计分析和分子生物学技术，旨在研究GCs药物炎症调控机制，为GCs类新药研发与精准用药提供线索和新思路。

Owing to its high sensitivity, high specificity and label-free advantages, mass spectrometry imaging (MSI) has become one of the most important techniques in the study of regulation mechanism of drug. Due to the ion suppression effect from highly concentrated salt and highly polar quaternary ammonium-carrying phosphatidylcholines in biological tissues, poor ionization efficiencies of neutral glucocorticoids (GCs), its metabolites and endogenous small molecules were found in traditional ionization methods. Post-photoionization is an applicable way to improve the ionization efficiency of neutral compounds. In this proposal, we plan to develop a new MSI method named ambient laser desorption/post-photoionization mass spectrometry by using tunable vacuum ultraviolet synchrotron radiation as the post-photoionization source, combine in situ chemical derivatization with post-photoionization for the analysis of trace GCs and develop a quantitative approach in tissue. The simultaneous imaging of GCs drugs, metabolites and endogenous small molecules etc. in the inflammation microregions of model animals, with the assistance of multivariate statistical analysis and molecular biology techniques, aims to study the mechanism of GCs drug in the regulation of inflammation and provides new ideas for GCs drugs development.