Journal
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
Volume 28, Issue 1, Pages 136-144Publisher
SPRINGER
DOI: 10.1007/s13361-016-1501-2
Keywords
Imaging mass spectrometry; TOF/TOF; Tandem mass spectrometry; MS/MS; Rifampicin; Multiplexed
Funding
- National Institutes of Health/National Institute of General Medical Sciences [5P41 GM103391-05]
- Bill and Melinda Gates Foundation [N01 HD23342]
- National Institutes of Health [T32 ES007028]
- Aegis Sciences Corporation
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [T32ES007028] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103391] Funding Source: NIH RePORTER
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Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) allows for the visualization of molecular distributions within tissue sections. While providing excellent molecular specificity and spatial information, absolute quantification by MALDI IMS remains challenging. Especially in the low molecular weight region of the spectrum, analysis is complicated by matrix interferences and ionization suppression. Though tandem mass spectrometry (MS/MS) can be used to ensure chemical specificity and improve sensitivity by eliminating chemical noise, typical MALDI MS/MS modalities only scan for a single MS/MS event per laser shot. Herein, we describe TOF/TOF instrumentation that enables multiple fragmentation events to be performed in a single laser shot, allowing the intensity of the analyte to be referenced to the intensity of the internal standard in each laser shot while maintaining the benefits of MS/MS. This approach is illustrated by the quantitative analyses of rifampicin (RIF), an antibiotic used to treat tuberculosis, in pooled human plasma using rifapentine (RPT) as an internal standard. The results show greater than 4-fold improvements in relative standard deviation as well as improved coefficients of determination (R-2) and accuracy (> 93% quality controls, < 9% relative errors). This technology is used as an imaging modality to measure absolute RIF concentrations in liver tissue from an animal dosed in vivo. Each microspot in the quantitative image measures the local RIF concentration in the tissue section, providing absolute pixel-to-pixel quantification from different tissue microenvironments. The average concentration determined by IMS is in agreement with the concentration determined by HPLC-MS/MS, showing a percent difference of 10.6%.
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