Abstract
Although drug distribution in tumor tissues has a significant impact on efficacy, conventional pharmacokinetic analysis has some limitations with regard to its ability to provide a comprehensive assessment of drug tissue distribution. Erlotinib is a tyrosine kinase inhibitor that acts on the epidermal growth factor receptor; however, it is unclear how this drug is histologically distributed in lung cancer. We used matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze erlotinib distribution in the tumor and normal lung tissues of a mouse xenograft model and patient with non-small cell lung cancer. LC-MS/MS showed that the erlotinib tissue concentration in the xenograft tumor tissue was clearly lower than that in the normal tissue at the time of maximum blood concentration. MALDI-MSI showed the heterogeneous distribution of erlotinib at various levels in the murine tissues; interestingly, erlotinib was predominantly localized in the area of viable tumor compared to the necrotic area. In the patient-derived tissue, MALDI-MSI showed that there were different concentrations of erlotinib distributed within the same tissue. For drug development and translational research, the imaging pharmacokinetic study used the combination of MALDI-MSI and LC-MS/MS analyses may be useful in tissues with heterogeneous drug distribution.
Highlights
The measurement of drug concentrations in target tissues plays a critical role in determining the appropriate drug dosage and evaluating the therapeutic window in the development of anticancer drugs[1]
Erlotinib is a tyrosine kinase inhibitor that works by inhibiting epidermal growth factor receptor (EGFR); a mutation in EGFR confers an increased response to this drug[9,10]
The aim of this study was to use a combination of matrix-assisted laser desorption ionization (MALDI)-mass spectrometry imaging (MSI) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to evaluate the distribution of erlotinib in the tumor and normal lung tissues of a mouse xenograft model and patient with non-small cell lung cancer
Summary
The measurement of drug concentrations in target tissues plays a critical role in determining the appropriate drug dosage and evaluating the therapeutic window in the development of anticancer drugs[1]. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), which is generally used to measure drug concentrations in blood or tissues, provides accurate quantitative information; it has not been of substantial benefit in evaluating drug distribution in tissues. LC-MS/MS requires liquid samples, so the homogenization of tissue samples is needed to measure drug concentrations in tissues[5]. It was recently suggested that mass spectrometry imaging (MSI) may be used to study tissues with heterogeneous morphology[6,7,8]. The aim of this study was to use a combination of matrix-assisted laser desorption ionization (MALDI)-MSI and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to evaluate the distribution of erlotinib in the tumor and normal lung tissues of a mouse xenograft model and patient with non-small cell lung cancer
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