The Maastricht MultiModal Molecular Imaging Institute (M4I), Division of Imaging Mass Spectrometry , Maastricht University , Universiteitssingel 50 , 6229 ER Maastricht , The Netherlands.
School of Chemistry , University of Wollongong , Wollongong , Australia.
Anal Chem. 2019 Aug 20;91(16):10840-10848. doi: 10.1021/acs.analchem.9b02495. Epub 2019 Aug 9.
Visualizing the distributions of drugs and their metabolites is one of the key emerging application areas of matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) within pharmaceutical research. The success of a given MALDI-MSI experiment is ultimately determined by the ionization efficiency of the compounds of interest, which in many cases are too low to enable detection at relevant concentrations. In this work we have taken steps to address this challenge via the first application of laser-postionisation coupled with MALDI (so-called MALDI-2) to the analysis and imaging of pharmaceutical compounds. We demonstrate that MALDI-2 increased the signal intensities for 7 out of the 10 drug compounds analyzed by up to 2 orders of magnitude compared to conventional MALDI analysis. This gain in sensitivity enabled the distributions of drug compounds in both human cartilage and dog liver tissue to be visualized using MALDI-2, whereas little-to-no signal from tissue was obtained using conventional MALDI. This work demonstrates the vast potential of MALDI-2-MSI in pharmaceutical research and drug development and provides a valuable tool to broaden the application areas of MSI. Finally, in an effort to understand the ionization mechanism, we provide the first evidence that the preferential formation of [M + H] ions with MALDI-2 has no obvious correlation with the gas-phase proton affinity values of the analyte molecules, suggesting, as with MALDI, the occurrence of complex and yet to be elucidated ionization phenomena.
可视化药物及其代谢物的分布是基质辅助激光解吸/电离-质谱成像（MALDI-MSI）在药物研究中新兴的应用领域之一。给定的 MALDI-MSI 实验的成功最终取决于感兴趣化合物的离化效率，而在许多情况下，这些化合物的离化效率太低，无法在相关浓度下进行检测。在这项工作中，我们通过首次将激光后电离与 MALDI（所谓的 MALDI-2）应用于药物化合物的分析和成像，来解决这一挑战。我们证明，与传统的 MALDI 分析相比，MALDI-2 将 10 种药物化合物中的 7 种的信号强度提高了 2 个数量级。这种灵敏度的提高使得可以使用 MALDI-2 可视化人软骨和狗肝组织中的药物化合物分布，而使用传统的 MALDI 几乎无法获得组织信号。这项工作证明了 MALDI-2-MSI 在药物研究和药物开发中的巨大潜力，并提供了一个有价值的工具来拓宽 MSI 的应用领域。最后，为了了解离化机制，我们首次提供了证据表明，MALDI-2 中优先形成 [M + H]+离子与分析物分子的气相质子亲和值没有明显的相关性，这表明与 MALDI 一样，存在复杂且尚未阐明的离化现象。
