State Key Laboratory of Natural Medicines and School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Am Soc Mass Spectrom. 2020 May 6;31(5):1066-1073. doi: 10.1021/jasms.0c00003. Epub 2020 Apr 6.
The matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique has attracted intense interest in the visualization of drug distribution in tissues. Its capability to spatially resolve individual molecules makes it a unique tool in drug development and research. However, low drug content and severe ion suppression in tissues hinder its broader application to resolve drug tissue distribution, especially small molecule drugs with a molecular weight below 500 Da. In this work, an integrated tissue pretreatment protocol was developed to enhance the detection of central nervous system drugs in the mouse brain using MALDI MSI. To evaluate the protocol, brain sections from mice dosed intraperitoneally with donepezil, tacrine, clozapine, haloperidol, and aripiprazole were used. The tissue sections were pretreated serially by washing with ammonium acetate solution, incubation with trifluoroacetic acid vapor, and -hexane washing before MALDI MSI. Compared with the untreated sample, the signal intensities for the test drugs increased by 4.7- to 31.5-fold after pretreatment. Besides the enhancement of signal intensity, fine optimization of pretreatment time and washing solvents preserved the spatial distribution of target drug molecules. The utility of the developed protocol also provided tissue-specific distribution for five drugs which were well resolved when imaged by MALDI MS.
基质辅助激光解吸/电离质谱成像（MALDI MSI）技术在组织中药物分布的可视化方面引起了极大的兴趣。它能够空间分辨单个分子，使其成为药物开发和研究的独特工具。然而，组织中药物含量低和严重的离子抑制阻碍了其更广泛地应用于解决药物组织分布问题，特别是分子量低于 500Da 的小分子药物。在这项工作中，开发了一种集成的组织预处理方案，以增强使用 MALDI MSI 检测小鼠脑中的中枢神经系统药物。为了评估该方案，使用了经腹膜内给予多奈哌齐、他克林、氯氮平、氟哌啶醇和阿立哌唑的小鼠脑切片。组织切片先用乙酸铵溶液洗涤，然后用三氟乙酸蒸气孵育，再用正己烷洗涤，然后进行 MALDI MSI。与未处理的样品相比，预处理后测试药物的信号强度增加了 4.7 到 31.5 倍。除了信号强度的增强外，精细优化预处理时间和洗涤溶剂还保留了目标药物分子的空间分布。所开发方案的实用性还为 5 种药物提供了组织特异性分布，当通过 MALDI MS 成像时，这些药物得到了很好的分辨。
