A New Method and Mass Spectrometer Design for TOF-SIMS Parallel Imaging MS/MS

Fisher, Gregory L.; Bruinen, Anne L.; Ogrinc, Nina; Hammond, John S.; Bryan, Scott R.; Larson, Paul E.; Heeren, Ron M. A.

doi:10.1021/acs.analchem.6b01022

Cited by 100 publications

(100 citation statements)

References 26 publications

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“…At present, IMS could be considered as a complementary method that may give valuable information during preclinical studies of drug candidates as well as in toxicological research. As the work with technical improvements is continuously ongoing, IMS could be expected to become a standard method in drug development and toxicology (Fisher et al 2016; Ogrinc Potocnik et al 2015; Prentice et al 2016). …”

Section: Discussionmentioning

confidence: 99%

Imaging mass spectrometry in drug development and toxicology

2016

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During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general.

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Section: Discussionmentioning

confidence: 99%

Imaging mass spectrometry in drug development and toxicology

2016

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“…That is, the correlation between the secondary ion yield of the drug fragment and drug parent molecular ions as a function of the therapeutic treatment can be used as a confirmation of the presence of potential interferences in the mass channels utilized to generate the drug specific chemical maps. While this uncertainty may be overcome with ultrahigh resolution mass analyzers [39, 63] and MS/MS [46, 64] approaches, TOF-SIMS provides high sensitivity and shorter analysis times when 3D-MSI analyses are required. These results provide proof-of-concept validation that the chemotherapeutic drug delivery can be evaluated at the single cell level using label-free, 3D-MSI-TOF-SIMS with high spatial resolution.…”

Section: Resultsmentioning

confidence: 99%

Analysis of Chemotherapeutic Drug Delivery at the Single Cell Level Using 3D-MSI-TOF-SIMS

Vanbellingen

Castellanos

Rodriguez-Silva

et al. 2016

J. Am. Soc. Mass Spectrom.

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In the present work, we show the advantages of label-free, tridimensional mass spectrometry imaging using dual beam analysis (25 keV Bi3+) and depth profiling (20 keV with a distribution centered at Ar1500+) coupled to time of flight secondary ion mass spectrometry (3D-MSI-TOF-SIMS) for the study of A-172 human glioblastoma cell line treated with B-cell lymphoma 2 (Bcl-2) inhibitor ABT-737. The high spatial (~250 nm) and high mass resolution (m/Δm ~ 10,000) of TOF-SIMS permitted the localization and identification of the intact, unlabeled drug molecular ion (m/z 811.26 C42H44ClN6O5S2−[M-H]−) as well as characteristic fragment ions. We propose a novel approach based on the inspection of the drug secondary ion yield which showed a good correlation with the drug concentration during cell treatment at therapeutic dosages (0 – 200 μM with 4 h incubation). Chemical maps using endogenous molecular markers showed that the ABT-737 is mainly localized in subsurface regions and absent in the nucleus. A semi-quantitative workflow is proposed to account for the biological cell diversity based on the spatial distribution of endogenous molecular markers (e.g., nuclei and cytoplasm) and secondary ion confirmation based on the ratio of drug-specific fragments to molecular ion as a function of the therapeutic dosage.

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“…[54] Aunique strength of SIMS imaging is its ability to capture molecular distributions in three dimensions with very high spatial and depth resolutions to enable subcellular studies.For example,t he spatial and temporal distributions of lipid fragments on the surface of Xenopus laevis embryos during embryo cleavage were analyzed by TOF-SIMS 3D imaging. ments are limited in their identification capabilities.T o overcome this issue,anew type of SIMS instrument has been designed to allow the fragmentation of selected precursor ions through collision-induced dissociation in parallel with conventional TOF-SIMS imaging.…”

Section: Transcriptsmentioning

confidence: 99%

Single‐Cell Mass Spectrometry Approaches to Explore Cellular Heterogeneity

2018

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Compositional diversity is a fundamental property in cell populations. Single-cell analysis promises new insight into this cellular heterogeneity on the genomic, transcriptomic, proteomic, and metabolomic levels. Mass spectrometry (MS) is a label-free technique that enables the multiplexed analysis of proteins, peptides, lipids, and metabolites in individual cells. The abundances of these molecular classes are correlated with the physiological states and environmental responses of the cells. In this Minireview, we discuss recent advances in single-cell MS techniques with an emphasis on sampling and ionization methods developed for volume-limited samples. Strategies for sample treatment, separation methods, and data analysis require special considerations for single cells. Ongoing analytical challenges include subcellular heterogeneity, non-normal statistical distributions of cellular properties, and the need for high-throughput, high molecular coverage and minimal perturbation.

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A New Method and Mass Spectrometer Design for TOF-SIMS Parallel Imaging MS/MS

Cited by 100 publications

References 26 publications

Imaging mass spectrometry in drug development and toxicology

Imaging mass spectrometry in drug development and toxicology

Analysis of Chemotherapeutic Drug Delivery at the Single Cell Level Using 3D-MSI-TOF-SIMS

Single‐Cell Mass Spectrometry Approaches to Explore Cellular Heterogeneity

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