Identification and High-Resolution Imaging of α-Tocopherol from Human Cells to Whole Animals by TOF-SIMS Tandem Mass Spectrometry

Bruinen, Anne L.; Fisher, Gregory L.; Balez, Rachelle; Sar, Astrid M. van der; Ooi, Lezanne; Heeren, Ron M. A.

doi:10.1007/s13361-018-1979-x

Cited by 19 publications

(16 citation statements)

References 33 publications

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“…1 Various desorption/ionization methods, including desorption electrospray ionization (DESI) 2,3 and secondary ionization mass spectrometry (SIMS), 4−6 have been deployed for drug and metabolite imaging in tissues and even individual cells. 7−9 Of these, matrix-assisted laser/desorption ionization (MALDI) has been most widely utilized. Nowadays, imaging for pharmaceutical compounds is one of the emerging applications of MSI, 10,11 which enables monitoring both drug metabolism and pharmacokinetics (DMPK), even with absolute quantification.…”

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confidence: 99%

Enhanced Sensitivity Using MALDI Imaging Coupled with Laser Postionization (MALDI-2) for Pharmaceutical Research

et al. 2019

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Visualizing the distributions of drugs and their metabolites is one of the key emerging application areas of matrix-assisted laser desorption/ionization–mass spectrometry imaging (MALDI-MSI) within pharmaceutical research. The success of a given MALDI-MSI experiment is ultimately determined by the ionization efficiency of the compounds of interest, which in many cases are too low to enable detection at relevant concentrations. In this work we have taken steps to address this challenge via the first application of laser-postionisation coupled with MALDI (so-called MALDI-2) to the analysis and imaging of pharmaceutical compounds. We demonstrate that MALDI-2 increased the signal intensities for 7 out of the 10 drug compounds analyzed by up to 2 orders of magnitude compared to conventional MALDI analysis. This gain in sensitivity enabled the distributions of drug compounds in both human cartilage and dog liver tissue to be visualized using MALDI-2, whereas little-to-no signal from tissue was obtained using conventional MALDI. This work demonstrates the vast potential of MALDI-2-MSI in pharmaceutical research and drug development and provides a valuable tool to broaden the application areas of MSI. Finally, in an effort to understand the ionization mechanism, we provide the first evidence that the preferential formation of [M + H] + ions with MALDI-2 has no obvious correlation with the gas-phase proton affinity values of the analyte molecules, suggesting, as with MALDI, the occurrence of complex and yet to be elucidated ionization phenomena.

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Enhanced Sensitivity Using MALDI Imaging Coupled with Laser Postionization (MALDI-2) for Pharmaceutical Research

et al. 2019

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“…With a spatial resolution of 200 -300 nm, ToF-SIMS image is able to visualize the subcellular distribution of chemicals. 26,[35][36][37][38][39][40] However, the low content of trace elements and complex components in cells made it difficult to obtain high quality of images which can discriminate the trace element located in cytoplasm and nuclei of the single cells as shown in Fig. 4 and Fig.…”

Section: Resultsmentioning

confidence: 99%

The Disturbance of Anticancer Drug Cisplatin to Cellular Homeostasis of Trace Elements Revealed by ICP-MS and ToF-SIMS

Jia¹,

Li²,

Zhang³

et al. 2021

At.Spectrosc.

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Trace elements play important roles in many physiological processes. The disorder in the metabolism and/or homeostasis of the trace elements will cause pathogenic changes, and finally lead to the development of diseases. This present work aimed to investigate the effect of anticancer metallodrug cisplatin on the homeostasis of trace metal elements, iron (Fe), zinc (Zn) and copper (Cu), in both human HEK293 normal cells and A549 lung cancer cells by using inductively coupled plasma mass spectrometry (ICP-MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The levels of trace metal elements in both whole cells and nuclei subjected to cisplatin treatment were measured by ICP-MS, and results showed that accompanying with the increasing concentration of cisplatin, the content of Fe inside whole cells and nuclei of both normal and cancer cells increased, implying that cisplatin may induce ferroptosis, contributing to its anticancer activity. While the level of Cu and Zn in the whole cells increased with increase in cisplatin concentration, the level of Cu and Zn, in particular the latter, in nuclei decreased with increase of cisplatin concentration. These implicate that cisplatin may compete with Zn for binding to metalloproteins in nuclei, leading to efflux of Zn from nucleus. The normalized signal intensity of Fe, Zn, and Cu in single cells detected by ToF-SIMS increased accompanying with increased cisplatin concentration, being in line with that obtained by quantitative ICP-MS on large quantity of cells. These findings provide novel insights into better understanding in the mechanism of action of cisplatin.Trace metal elements, such as iron, zinc, copper, are essential in the human body as they consist of many metalloproteins or enzymes which are involved in vital physiological regulation processes and play crucial roles in maintaining the normal function

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“…77 There are several recent review articles and studies that have described the implementation of multiple complementary MS technologies. 78,79 Some such examples have highlighted the use of TOF-SIMS. TOF-SIMS has been implemented extensively in academia and has the benefit of improved spatial resolution over DESI and MALDI-MSI, achieving a lateral resolution of <500 nm in some cases.…”

Section: Established and Emerging Methods: Mass Spectrometry Imagingmentioning

confidence: 99%

“…Bruinen et al describe the combined use of TOF-SIMS MS and tandem MSI (imaging of the instrumentally induced fragments of the molecules sampled) for the intracellular localization of α-tocopherol. 79 This provided simultaneous identification and localization of the molecule of interest in a 3D manner, utilizing the depth profiling capability of SIMS and potential for high-resolution imaging.…”

Section: Established and Emerging Methods: Mass Spectrometry Imagingmentioning

confidence: 99%

The Opportunities and Use of Imaging to Measure Target Engagement

Maynard

Hart

2020

SLAS Discovery

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Lack of efficacy and poor safety outcomes are deemed to be the greatest causes of clinical failure of novel therapeutics. The use of biomarkers that give accurate information on target engagement, providing confidence that pharmacological activity in the target organ is being achieved, is key in optimizing clinical success. Without a measurement of target engagement, it can be very difficult to discern the basis for any lack of efficacy of a drug molecule within the pharmaceutical industry. Target engagement can be measured in both an in vitro and in vivo setting, and in recent years imaging measurements have been used frequently in drug discovery and development to assess target engagement and receptor occupancy in both human and animal models. From this perspective, we assess and look at the advancements in both in vivo and ex vivo imaging to demonstrate the enormous potential that imaging has as an application to provide a greater understanding of target engagement with a correlative therapeutic impact.

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Identification and High-Resolution Imaging of α-Tocopherol from Human Cells to Whole Animals by TOF-SIMS Tandem Mass Spectrometry

Cited by 19 publications

References 33 publications

Enhanced Sensitivity Using MALDI Imaging Coupled with Laser Postionization (MALDI-2) for Pharmaceutical Research

Enhanced Sensitivity Using MALDI Imaging Coupled with Laser Postionization (MALDI-2) for Pharmaceutical Research

The Disturbance of Anticancer Drug Cisplatin to Cellular Homeostasis of Trace Elements Revealed by ICP-MS and ToF-SIMS

The Opportunities and Use of Imaging to Measure Target Engagement

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