Quantitative Determination of Irinotecan and the Metabolite SN-38 by Nanoflow Liquid Chromatography-Tandem Mass Spectrometry in Different Regions of Multicellular Tumor Spheroids
Quantitative Determination of Irinotecan and the Metabolite SN-38 by Nanoflow Liquid Chromatography-Tandem Mass Spectrometry in Different Regions of Multicellular Tumor Spheroids
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DOI：
10.1007/s13361-014-1071-0
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发表时间：
2015-04-01
影响因子：
3.2
通讯作者：
Hummon, Amanda B.
中科院分区：
文献类型：
--
作者：
Liu, Xin;Hummon, Amanda B.
建立了一种新的、简单的方法，通过将连续胰蛋白酶消化和纳米流液相色谱-串联质谱（nLC-MS/MS）相结合来评估治疗药物在三维多细胞肿瘤球体（MCTS）中的分布。通过定量测定HCT 116 MCTS不同空间区域中的伊立替康及其生物活性代谢产物SN-38，验证了该方法。伊立替康对MCTS的渗透性呈时间依赖性，给药24小时后，大部分药物蓄积在核心中。检测到的SN-38的量比母体药物低30倍，并且在存在增殖细胞的MCTS的外缘和中间区域中更丰富。该方法可用于研究新的和已建立的药物。它能够研究药物的渗透特性，并在MCTS中识别具有空间特异性的代谢物。新方法在促进药物评价过程中具有很大的价值。
A new and simple method was developed to evaluate the distribution of therapeutics in three-dimensional multicellular tumor spheroids (MCTS) by combining serial trypsinization and nanoflow liquid chromatography-tandem mass spectrometry (nLC-MS/MS). This methodology was validated with quantitative measurements of irinotecan and its bioactive metabolite, SN-38, in distinct spatial regions of HCT 116 MCTS. Irinotecan showed a time-dependent permeability into MCTS with most of the drug accumulating in the core after 24 h of treatment. The amount of SN-38 detected was 30 times lower than that of the parent drug, and was more abundant in the outer rim and intermediate regions of MCTS where proliferating cells were present. This method can be used to investigate novel and established drugs. It enables investigation of drug penetration properties and identification of metabolites with spatial specificity in MCTS. The new approach has great value in facilitating the drug evaluation process.