Utility of imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) on an ion trap mass spectrometer in the analysis of drugs and metabolites in biological tissues
Utility of imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) on an ion trap mass spectrometer in the analysis of drugs and metabolites in biological tissues
复制标题
DOI：
10.1016/j.vascn.2006.11.004
复制
发表时间：
2007-05-01
影响因子：
1.9
通讯作者：
Sanders, Mark
中科院分区：
文献类型：
--
作者：
Drexler, Dieter M.;Garrett, Timothy J.;Sanders, Mark
简介：在详细的ADME试验和毒性研究中研究了候选药物的性质和潜在责任，其中将结果置于暴露于给药药物和代谢产物的背景下。生物样品的复杂性质可能需要在内源性或外源性化合物的高效液相色谱-质谱（HPLC-MS）分析之前进行后处理程序。该概念可以容易地应用于生物流体，例如血液或尿液，但是在局部样品中，例如器官和组织，由于均质化和提取过程，在样品制备期间潜在重要的空间信息，因此解剖信息丢失。然而，供试品的定位或代谢产物的空间鉴别对于理解靶器官毒性机制及其与临床安全性的相关性可能至关重要。研究方法：采用基质辅助激光解吸电离（MALDI）和离子阱质谱（MS）的组织成像质谱（IMS）和高阶质谱扫描功能，用于组织中给药药物或代谢物的定位。激光捕获显微镜（LCM）被用来获得相关的组织样品进行分析，通过标准的MALDI-MS和HPLC-MS。结果：在毒理学研究中，大鼠给予高剂量的前药2周。在组织病理学福尔马林固定的组织样本中观察到生物相容性微晶物质（10-25 μ m）。通过INIS的直接分析提供了作为循环活性药物的微晶中的材料的身份，同时保持空间取向。来自视觉交叉偏振光显微镜以及LCM样品的标准NIALDI-MS和HPLC-MS实验的补充数据验证了IMS获得的定性结果。此外，LCM样品的HPLC-MS分析提供了组织样品中结晶物质的半定量评估。讨论内容：通过MALDI离子阱MS的IMS被证明是灵敏的、特异性的，并且非常适合于直接在组织中对传统小分子候选药物进行图像分析。(c)2006年爱思唯尔公司All rights reserved.
Introduction: The properties and potential liabilities of drug candidate are investigated in detailed ADME assays and in toxicity studies, where findings are placed in context of exposure to dosed drug and metabolites. The complex nature of biological samples may necessitate work-up procedures prior to high performance liquid chromatography-mass spectrometric (HPLC-MS) analysis of endogenous or xenobiotic compounds. This concept can readily be applied to biological fluids such as blood or urine, but in localized samples such as organs and tissues potentially important spatial, thus anatomical, information is lost during sample preparation as the result of homogenization and extraction procedures. However, the localization of test article or spatial identification of metabolites may be critical to the understanding of the mechanism of target-organ toxicity and its relevance to clinical safety. Methods: Tissue imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) and ion trap mass spectrometry (MS) with higher order mass spectrometric scanning functions was utilized for localization of dosed drug or metabolite in tissue. Laser capture microscopy (LCM) was used to obtain related samples from tissue for analyses by standard MALDI-MS and HPLC-MS. Results: In a toxicology study, rats were administered with a high dosage of a prodrug for 2 weeks. Birefringent microcrystalline material (10-25 mu m ) was observed in histopathologic formalin-fixed tissue samples. Direct analysis by INIS provided the identity of material in the microcrystals as circulating active drug while maintaining spatial orientation. Complementary data from visual cross-polarized light microscopy as well as standard NIALDI-MS and HPLC-MS experiments on LCM samples validated the qualitative results obtained by IMS. Furthermore, the HPLC-MS analysis on the LCM samples afforded a semi-quantitative assessment of the crystalline material in the tissue samples. Discussion: IMS by MALDI ion trap MS proved sensitive, specific, and highly amenable to the image analysis of traditional small molecule drug candidates directly in tissue. (c) 2006 Elsevier Inc. All rights reserved.