Direct Demonstration of Tissue Uptake of an Inhaled Drug: Proof-of-Principle Study Using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging
Direct Demonstration of Tissue Uptake of an Inhaled Drug: Proof-of-Principle Study Using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging
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DOI：
10.1021/ac2014349
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发表时间：
2011-11-01
影响因子：
7.4
通讯作者：
Marko-Varga, Gyorgy
中科院分区：
文献类型：
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作者：
Fehniger, Thomas E.;Vegvari, Akos;Marko-Varga, Gyorgy
药物治疗通常针对特定的器官和组织区室，其中化合物的作用模式影响特异性靶向的生物过程。然而，直接测量药物摄取的时间动力学和浓度达到在当地网站还没有现成的临床指标，为大多数药物。进行了一项原理验证研究，以测试应用基质辅助激光解吸电离质谱成像（MALDI-MSI）证明局部给药药物在靶向作用组织部位内的定性分布模式的实用性。在这里，我们测量了吸入性支气管扩张剂，毒蕈碱受体拮抗剂异丙托溴铵，在人体支气管活检中获得的纤维支气管镜给药后不久暴露的发生。将来自五名受试者的冷冻保存的活检样本制备为薄冷冻切片，以评估气道阻塞或潜在肿瘤发展。用MALDI基质包被的样品通过MALDI LTQ Orbitrap XL质谱仪在大（100 μ m）和小（30 μ m）光栅尺寸下进行分析。我们的研究结果表明，异丙托溴铵被迅速吸收到气道壁。异丙托铵母离子（m/z 332.332）和子离子（m/z 166.2和290.2）在5例受试者中的4例中同时分配在含有靶向气道平滑肌的粘膜下空间内。异丙托铵碎片离子的信号强度估计在气道壁内达到3至80 nM的局部药物浓度。据我们所知，这是第一个报告的研究应用MALDI-MSI来证明本地化的药物管理在治疗水平。该研究强调了MALDI-MSI在临床环境中提供药物疗效重要测量的潜在益处。
Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound affects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained by fiber optic bronchoscopy shortly after dosing exposure. Cryo-preserved biopsy samples from five subjects being evaluated for airway obstruction or potential tumor development were prepared as thin frozen sections. Samples coated with a MALDI matrix were analyzed by a MALDI LTQ Orbitrap XL mass spectrometer at large (100 mu m) and small (30 mu m) raster sizes. Our results demonstrate that ipratropium is rapidly absorbed into the airway wall. Ipratropium parent ion (m/z 332.332) and daughter ions (m/z 166.2 and 290.2) were coincidently partitioned within submucosal spaces containing targeted airway smooth muscle in four out of five subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3 and 80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in applying MALDI-MSI to demonstrate the localization of a drug administered at therapeutic levels. The study highlights the potential benefit of MALDI-MSI to provide important measurements of drug efficacy in clinical settings.