Fine mapping the spatial distribution and concentration of unlabeled drugs within tissue micro-compartments using imaging mass spectrometry.
Fine mapping the spatial distribution and concentration of unlabeled drugs within tissue micro-compartments using imaging mass spectrometry.
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DOI：
10.1371/journal.pone.0011411
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发表时间：
2010-07-14
期刊：
影响因子：
3.7
通讯作者：
Andrén PE
中科院分区：
文献类型：
--
作者：
Nilsson A;Fehniger TE;Gustavsson L;Andersson M;Kenne K;Marko-Varga G;Andrén PE
定义药物在组织中的生理分布的读数是一个未满足的挑战，充其量也是不精确的，但为了了解与疗效相关的药代动力学和药效学特性，需要读数。在这里，我们证明，它是可行的，遵循在特定的器官和组织隔室的平台上，适用于MALDI成像质谱的组织切片，其特征在于高清晰度组织学的体内运输的未标记的药物。我们采用系统性逐点MS和MS/MS采样（间隔200 µm），跟踪并定量吸入参比化合物噻托溴铵在给药大鼠肺内的分布。通过比较相邻组织切片中的药物离子分布模式，我们观察到在暴露后15分钟内，噻托溴铵母体MS离子（质荷比; m/z 392.1）和碎片化的子体MS/MS离子（m/z 170.1和152.1）以浓度梯度（80 fmol-5 pmol）分散在远离中心气道的肺实质和胸膜中。这些药物水平与通过化学提取在肺隔室中检测到的量一致。此外，定位在2-D组织空间内的分子离子特征的同时全局定义提供了组织学标志内的离子身份的准确分配，提供了在药物存在部位发生的动态生物过程的背景。我们的研究结果突出了一个重要的新兴技术，允许特定的高分辨率识别未标记的药物在体内摄取和保留的网站。
Readouts that define the physiological distributions of drugs in tissues are an unmet challenge and at best imprecise, but are needed in order to understand both the pharmacokinetic and pharmacodynamic properties associated with efficacy. Here we demonstrate that it is feasible to follow the in vivo transport of unlabeled drugs within specific organ and tissue compartments on a platform that applies MALDI imaging mass spectrometry to tissue sections characterized with high definition histology. We have tracked and quantified the distribution of an inhaled reference compound, tiotropium, within the lungs of dosed rats, using systematic point by point MS and MS/MS sampling at 200 µm intervals. By comparing drug ion distribution patterns in adjacent tissue sections, we observed that within 15 min following exposure, tiotropium parent MS ions (mass-to-charge; m/z 392.1) and fragmented daughter MS/MS ions (m/z 170.1 and 152.1) were dispersed in a concentration gradient (80 fmol-5 pmol) away from the central airways into the lung parenchyma and pleura. These drug levels agreed well with amounts detected in lung compartments by chemical extraction. Moreover, the simultaneous global definition of molecular ion signatures localized within 2-D tissue space provides accurate assignment of ion identities within histological landmarks, providing context to dynamic biological processes occurring at sites of drug presence. Our results highlight an important emerging technology allowing specific high resolution identification of unlabeled drugs at sites of in vivo uptake and retention.
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影响因子：
5.3
作者：
Rohner, TC;Staab, D;Stoeckli, M
通讯作者：
Stoeckli, M
DOI：
10.1016/j.vascn.2006.11.004
发表时间：
2007-05-01
影响因子：
1.9
作者：
Drexler, Dieter M.;Garrett, Timothy J.;Sanders, Mark
通讯作者：
Sanders, Mark
影响因子：
48
作者：
Andersson, Malin;Groseclose, M. Reid;Caprioli, Richard M.
通讯作者：
Caprioli, Richard M.
影响因子：
2
作者：
Atkinson, Sally J.;Loadman, Paul M.;Clench, Malcolm R.
通讯作者：
Clench, Malcolm R.
影响因子：
7.4
作者：
Khatib-Shahidi, Sheerin;Andersson, Malin;Caprioli, Richard M.
通讯作者：
Caprioli, Richard M.