Label-Free MS Imaging from Drug Discovery to Preclinical Development

Hochart, G; Hamm, Grégory; Stauber, Jonathan

doi:10.4155/bio.14.202

Cited by 11 publications

(10 citation statements)

References 39 publications

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“…To reduce the variability of IMS data, different strategies have been used to compensate for matrix crystallization effects and ion suppression during data acquisition. Approaches used include normalizing the spectra against the total ion count (TIC), other calculated normalization factors, or the signal intensity of an internal standard applied to the tissue section (Hamm et al 2012; Hochart et al 2014; Kallback et al 2012; Stoeckli et al 2007). The majority of published research concerns the quantification of small-molecule drugs (Chumbley et al 2016; Groseclose and Castellino 2013; Koeniger et al 2011; Nilsson et al 2010).…”

Section: Maldi Imaging Mass Spectrometry For Localization and Quantifmentioning

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: Maldi Imaging Mass Spectrometry For Localization and Quantifmentioning

confidence: 99%

Imaging mass spectrometry in drug development and toxicology

2016

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“…26,27 A number of recent review articles have summarized the state-of-the-art of the topic. [28][29][30][31][32] One of the most promising applications for MSI is the measurement of the spatial distribution of xenobiotics in CNS tissue. 33 A number of studies have described CNS spatial distribution of different drugs, 34,35,[44][45][46][36][37][38][39][40][41][42][43] narcotics, 47-49 neurotoxin 50 and positron emission 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 tomography (PET) ligands.…”

Section: Introductionmentioning

confidence: 99%

Toward Higher Sensitivity in Quantitative MALDI Imaging Mass Spectrometry of CNS Drugs Using a Nonpolar Matrix

et al. 2018

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Tissue-specific ion suppression is an unavoidable matrix effect in MALDI mass spectrometry imaging (MSI), the negative impact of which on precision and accuracy in quantitative MALDI-MSI can be reduced to some extent by applying isotope internal standards for normalization and matrix-matched calibration routines. The detection sensitivity still suffers, however, often resulting in significant loss of signal for the investigated analytes.An MSI application considerably affected by this phenomenon is the quantitative spatial analysis of central nervous system (CNS) drugs. Most of these drugs are low molecular weight, lipophilic compounds, which exhibit inefficient desorption and ionization during MALDI using conventional polar acidic matrices (CHCA, DHB). Here, we present the application of the (2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2-enylidene]malononitrile) matrix for high sensitivity imaging of CNS drugs in mouse brain sections. Since DCTB is usually described as electron-transfer matrix, we provide a rationale (i.e. computational calculations of gas-phase proton affinity and ionization energy) for an additional protontransfer ionization mechanism with this matrix. Furthermore, we compare the extent of signal suppression for five different CNS drugs when employing DCTB versus CHCA matrices. The results showed that the signal suppression was not only several times lower with DCTB than with CHCA, but also depended on the specific tissue investigated. Finally, we present the application of DCTB and ultra-high resolution Fourier-transform ion cyclotron resonance mass spectrometry to quantitative MALDI imaging of the anesthetic drug xylazine in mouse brain sections based on a linear matrix-matched calibration curve. DCTB afforded up to 100fold signal intensity improvement over CHCA when comparing representative single MSI pixels, and > 440-fold for the averaged mass spectrum of the adjacent tissue sections.

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“…• Drug distribution and concentration per se has some important technologies now available such as MS imaging [13]. The most important concentration is the unbound free concentration.…”

Section: The Pd Phase Of Drug Discoverymentioning

confidence: 99%

A New Phase of Drug Discovery? The Rise of Pk/Pd Means Extremely Challenging Work at The Coalface

Smith¹

2015

Bioanalysis

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Label-Free MS Imaging from Drug Discovery to Preclinical Development

Cited by 11 publications

References 39 publications

Imaging mass spectrometry in drug development and toxicology

Imaging mass spectrometry in drug development and toxicology

Toward Higher Sensitivity in Quantitative MALDI Imaging Mass Spectrometry of CNS Drugs Using a Nonpolar Matrix

A New Phase of Drug Discovery? The Rise of Pk/Pd Means Extremely Challenging Work at The Coalface

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