Interleukin-13 overexpressing mice represent an advanced pre-clinical model for detecting the distribution of anti-mycobacterial drugs within centrally necrotizing granulomas

The Mycobacterium tuberculosis (Mtb)-harboring granuloma with a necrotic center surrounded by a fibrous capsule is the hallmark of tuberculosis (TB). For a successful treatment, antibiotics need to penetrate these complex structures to reach their bacterial targets. Hence, animal models reflecting the pulmonary pathology of TB patients are of particular importance to improve the pre-clinical validation of novel drug candidates. Mtb-infected interleukin-13 overexpressing (IL-13 tg ) mice develop a TB pathology very similar to patients and, in contrast to other mouse models, also share pathogenetic mechanisms. Accordingly, IL-13 tg animals represent an ideal model for analyzing the penetration of novel anti-TB drugs into various compartments of necrotic granulomas by matrix-assisted-laser-desorption/ionization-mass spectrometry imaging (MALDI MS imaging). In the present study, we evaluated the suitability of BALB/c IL-13 tg mice for determining the antibiotic distribution within necrotizing lesions. To this end, we established a workflow based on the inactivation of Mtb by gamma irradiation while preserving lung tissue integrity and drug distribution, which is essential for correlating drug penetration with lesion pathology. MALDI MS imaging analysis of clofazimine, pyrazinamide and rifampicin revealed a drug-specific distribution within different lesion types including cellular granulomas, developing in BALB/c wild-type mice, and necrotic granulomas of BALB/c IL-13 tg animals, emphasizing the necessity of pre-clinical models reflecting human pathology. Most importantly, our study demonstrates that BALB/c IL-13 tg mice recapitulate the penetration of antibiotics into human lesions. Therefore, our workflow in combination with the IL-13 tg mouse model provides an improved and accelerated evaluation of novel anti-TB drugs and new regimens in the pre-clinical stage.

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Unraveling the drug distribution in brain enabled by MALDI MS imaging with laser-assisted chemical transfer

Acta Pharmaceutica Sinica B ◽

10.1016/j.apsb.2021.11.007 ◽

2021 ◽

Author(s):

Shuai Guo ◽

Kening Li ◽

Yanwen Chen ◽

Bin Li

Keyword(s):

Drug Distribution ◽

Maldi Ms ◽

Ms Imaging ◽

Chemical Transfer

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Quantitative Assessment of Anti-Cancer Drug Efficacy From Coregistered Mass Spectrometry and Fluorescence Microscopy Images of Multicellular Tumor Spheroids

Microscopy and Microanalysis ◽

10.1017/s1431927619014983 ◽

2019 ◽

Vol 25 (6) ◽

pp. 1311-1322 ◽

Cited By ~ 4

Author(s):

Jan Michálek ◽

Karel Štěpka ◽

Michal Kozubek ◽

Jarmila Navrátilová ◽

Barbora Pavlatovská ◽

...

Keyword(s):

Mass Spectrometry ◽

Fluorescence Microscopy ◽

Laser Scanning ◽

Drug Distribution ◽

Cancer Cell Line ◽

Drug Efficacy ◽

Maldi Ms ◽

Cancer Drug ◽

Ionization Mass ◽

Cell Nuclei

AbstractSpheroids—three-dimensional aggregates of cells grown from a cancer cell line—represent a model of living tissue for chemotherapy investigation. Distribution of chemotherapeutics in spheroid sections was determined using the matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). Proliferating or apoptotic cells were immunohistochemically labeled and visualized by laser scanning confocal fluorescence microscopy (LSCM). Drug efficacy was evaluated by comparing coregistered MALDI MSI and LSCM data of drug-treated spheroids with LSCM only data of untreated control spheroids. We developed a fiducial-based workflow for coregistration of low-resolution MALDI MS with high-resolution LSCM images. To allow comparison of drug and cell distribution between the drug-treated and untreated spheroids of different shapes or diameters, we introduced a common diffusion-related coordinate, the distance from the spheroid boundary. In a procedure referred to as “peeling”, we correlated average drug distribution at a certain distance with the average reduction in the affected cells between the untreated and the treated spheroids. This novel approach makes it possible to differentiate between peripheral cells that died due to therapy and the innermost cells which died naturally. Two novel algorithms—for MALDI MS image denoising and for weighting of MALDI MSI and LSCM data by the presence of cell nuclei—are also presented.

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Development of an Integrated Tissue Pretreatment Protocol for Enhanced MALDI MS Imaging of Drug Distribution in the Brain

Journal of the American Society for Mass Spectrometry ◽

10.1021/jasms.0c00003 ◽

2020 ◽

Vol 31 (5) ◽

pp. 1066-1073

Author(s):

Yanwen Chen ◽

Weiwei Tang ◽

Andrew Gordon ◽

Bin Li

Keyword(s):

Drug Distribution ◽

Maldi Ms ◽

Ms Imaging ◽

The Brain

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Application of Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging for Food Analysis

Foods ◽

10.3390/foods8120633 ◽

2019 ◽

Vol 8 (12) ◽

pp. 633 ◽

Cited By ~ 9

Author(s):

Mizuki Morisasa ◽

Tomohiko Sato ◽

Keisuke Kimura ◽

Tsukasa Mori ◽

Naoko Goto-Inoue

Keyword(s):

Mass Spectrometry ◽

Food Analysis ◽

Laser Desorption ◽

Maldi Ms ◽

Ionization Mass ◽

Laser Desorption Ionization ◽

Desorption Ionization ◽

Ms Imaging ◽

Matrix Assisted Laser ◽

Matrix Assisted Laser Desorption

Food contains various compounds, and there are many methods available to analyze each of these components. However, the large amounts of low-molecular-weight metabolites in food, such as amino acids, organic acids, vitamins, lipids, and toxins, make it difficult to analyze the spatial distribution of these molecules. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging is a two-dimensional ionization technology that allows the detection of small metabolites in tissue sections without requiring purification, extraction, separation, or labeling. The application of MALDI-MS imaging in food analysis improves the visualization of these compounds to identify not only the nutritional content but also the geographical origin of the food. In this review, we provide an overview of some recent applications of MALDI-MS imaging, demonstrating the advantages and prospects of this technology compared to conventional approaches. Further development and enhancement of MALDI-MS imaging is expected to offer great benefits to consumers, researchers, and food producers with respect to breeding improvement, traceability, the development of value-added foods, and improved safety assessments.

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Toward Revealing Microcystin Distribution in Mouse Liver Tissue Using MALDI-MS Imaging

Toxins ◽

10.3390/toxins13100709 ◽

2021 ◽

Vol 13 (10) ◽

pp. 709

Author(s):

Daria Kucheriavaia ◽

Dušan Veličković ◽

Nicholas Peraino ◽

Apurva Lad ◽

David J. Kennedy ◽

...

Keyword(s):

Mass Spectrometer ◽

Algal Blooms ◽

Maldi Ms ◽

High Mass ◽

Ionization Mass ◽

Ion Cyclotron Resonance ◽

Tissue Preparation ◽

Matrix Deposition ◽

Ms Imaging ◽

Ft Icr

Cyanotoxins can be found in water and air during cyanobacterial harmful algal blooms (cHABs) in lakes and rivers. Therefore, it is very important to monitor their potential uptake by animals and humans as well as their health effects and distribution in affected organs. Herein, the distribution of hepatotoxic peptide microcystin-LR (MC-LR) is investigated in liver tissues of mice gavaged with this most common MC congener. Preliminary matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging experiments performed using a non-automated MALDI matrix deposition device and a MALDI-time-of-flight (TOF) mass spectrometer yielded ambiguous results in terms of MC-LR distribution in liver samples obtained from MC-LR-gavaged mice. The tissue preparation for MALDI-MS imaging was improved by using an automated sprayer for matrix deposition, and liver sections were imaged using an Nd:YAG MALDI laser coupled to a 15 Tesla Fourier-transform ion cyclotron resonance (FT-ICR)-mass spectrometer. MALDI-FT-ICR-MS imaging provided unambiguous detection of protonated MC-LR (calculated m/z 995.5560, z = +1) and the sodium adduct of MC-LR (m/z 1017.5380, z = +1) in liver sections from gavaged mice with great mass accuracy and ultra-high mass resolution. Since both covalently bound and free MC-LR can be found in liver of mice exposed to this toxin, the present results indicate that the distribution of free microcystins in tissue sections from affected organs, such as liver, can be monitored with high-resolution MALDI-MS imaging.

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