基于食管癌体外培养多细胞肿瘤球的紫杉醇药物质谱成像代谢组学研究  

Study of mass spectrometry imaging metabolomics of paclitaxel based on esophageal cancer multicellular tumor spheroids cultured in vitro

作　　者：储小平 臧清策 刘家兴 李丽美 马立颖 贺玖明 张瑞萍 再帕尔·阿不力孜 CHU Xiao-ping;ZANG Qing-ce;LIU Jia-xing;LI Li-mei;MA Li-ying;HE Jiu-ming;ZHANG Rui-ping;ABLIZ Zeper(State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;State Key Laboratory of Molecular Oncology,Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China;Center for Imaging and Systems Biology,Minzu University of China,Beijing 100081,China)

机构地区：[1]中国医学科学院,北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050 [2]中国医学科学院,北京协和医学院肿瘤医院,分子肿瘤学国家重点实验室,北京100021 [3]中央民族大学,生物成像与系统生物学研究中心,北京100081

出　　处：《药学学报》2022年第3期793-801,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(21874156);新药创制国家科技重大专项(2018ZX09711001-002-004)。

摘　　要：体外培养多细胞肿瘤球(multicellular tumor spheroids, MCTS)可以模拟体内肿瘤组织结构与代谢特征,对于研究肿瘤细胞代谢表型及其药物干预机制具有重要意义。本研究构建食管癌MCTS,经紫杉醇(paclitaxel,PTX)普通注射液、紫杉醇脂质体和白蛋白结合型紫杉醇三种剂型分别处理后制备MCTS冰冻切片,采用空气动力辅助解吸电喷雾离子化质谱成像技术(AFADESI-MSI)建立了MCTS质谱成像分析方法,实现了对紫杉醇不同剂型处理后PTX在MCTS中渗透和富集过程的可视化,并对紫杉醇注射液组开展了空间分辨代谢组学研究。结果表明,紫杉醇在MCTS模型中的渗透和富集行为与剂型有关,紫杉醇注射剂给药后MCTS中内源性代谢物变化具有时间和空间特征,最初的0~4 h MCTS代谢变化以中高极性代谢物和一些脂类代谢物的下调为主,主要发生在MCTS中心区域;给药8~72 h, MCTS代谢变化以脂类代谢物上调为主,主要发生在MCTS外周区域。本研究将体内相关性强的MCTS模型与免标记、高灵敏、高覆盖的质谱成像技术相结合,为药物代谢组学研究提供了新的方法策略。Multicellular tumor spheroids(MCTS) can simulate the structure and metabolic characteristics of tumors in vivo, which is of great significance to study the metabolic phenotype of tumor cells and the mechanism of drug intervention. In this study, esophageal cancer MCTS were constructed, and MCTS frozen sections were prepared after treated with different formulations of paclitaxel(PTX) including common PTX injection, PTX liposome and albumin bound PTX. MCTS mass spectrometry imaging analysis method was established by using air flow assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI). The visualization of the permeation and enrichment process of PTX in MCTs after PTX treatment was realized, and the spatially resolved metabolomics of PTX injection group was studied. The results showed that the permeation and enrichment behavior of PTX in MCTs model were related to the formulations. The changes of endogenous metabolites in MCTs of esophageal cancer after treated with PTX injection had temporal and spatial characteristics. The metabolic changes of MCTS during the initial 0-4 hours were dominated by the down-regulation of middle-high polarity metabolites and some lipids in the central region of MCTS, while the metabolic changes of MCTS during 8-72 hours were mainly up-regulated by lipid metabolites in the peripheral region of MCTS. The combination of in vivo tumor-associated MCTs model with label free, highly sensitive and high coverage mass spectrometry imaging technology provided a new method and strategy for the study of pharmacometabolomics.

关 键 词：多细胞肿瘤球 质谱成像 代谢组学 紫杉醇 食管癌细胞 

分 类 号：R917[医药卫生—药物分析学]