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MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids.
X. Liu, et al., Journal of American Society for Mass Spectrometry, (2018).
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Pharmacokinetics and dynamics: Irinotecan in human derived colorectal tumor organoids.
Bruker product: UltrafleXtreme MALDI/TOF-TOF with SCiLS Lab analytical software suite.
Sample: Cell cultures.
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Colorectal tumor organoids (CTOs) can simulate tumor microenvironment, allowing for various pharmacokinetics and dynamics studies on chemotherapeutic drug.
MALDI-imaging was able to map irinotecan and its metabolites, showing the effects of treatment time and dosage within the CTOs. Analysis using SCiLS Lab correlated the compounds' spatial distributions and their relative concentration, allowing for insights in the drug's efficacy within the CTO complex microenvironment.
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DOI: 10.1007/s13361-017-1851-4
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MALDI imaging facilitates new topical drug development process by determining quantitative skin distribution profiles.
D. Bonnel, et al., Analytical and Bioanalytical Chemistry, (2018).
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Pharmacokinetics: Skin penetration of Roflumilast, Tofacitinib, Ruxolitinib, LEO 29102 to treat Psoriasis and dematitis.
Bruker product: Solarix MRMS.
Sample: Human skin explants .
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Topical drug development depends on designing compounds that can penetrate human skin where the therapeutic action can take place. Techniques that can track and quantify drug penetration through the skin is therefore essentially in topical drug development.
Here qMALDI-imaging was tested for sensitivity, reproducibility, and robustness for drug PK studies in skin, quantifying the penetration of LEO 29102, tofacitinib and ruxolitinib into skin layers. High spatial resolution reliably gave fine details of the detected drug distribution and concentration showing that the detectable drugs were mostly localized within the epidermis layer, information that would be very difficult to obtain in LC/MS even with manually separated layers.
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DOI: 10.1007/s00216-018-0964-3
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The downfall of TBA-354 – a possible explanation for its neurotoxicity via mass spectrometric imaging.
S. Ntshangase, et al., Xenobiotica, (2018).
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Pharmacokinetics: Neurotoxicity of tuberculosis targeted drug, TBA-354.
Bruker product: UltrafleXtreme MALDI/TOF-TOF.
Sample: Rat brains.
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Important insights into TBA-354 actions in the brain could provide possible clues into the neurotoxicity of this once promising tuberculosis drug.
MALDI-imaging revealed that TBA-354 penetrated blood brain barrier (BBB), and was found to localize in the cerebral cortex within 2 hours after dosing and only excreted after 6 hours. TBA-354 high penetration and longevity within the brain likely contributed to its neurotoxicity effects. MALDI-imaging thus provides a mean to study drug's spatial distribution after dosing in various organs, allowing another dimension in pre-clinical screening.
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DOI: 10.1080/00498254.2017.1375168
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Quantitative MALDI Imaging of Spatial Distributions and Dynamic Changes of Tetrandrine in Multiple Organs of Rats.
W. Tang, et al., Theranostics, (2019).
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Pharmacokinetics: Quantifying the penetration of tetrandrine in various organs in mice.
Bruker product: UltrafleXtreme MALDI/TOF-TOF and solariX MRMS with SCiLS Lab analytical software suite.
Sample: Multiple organs from rat models.
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Tetrandrine was dosed in rat models to simulate therapeutic conditions and demonstrating qMALDI-imaging across multiple organ.
To achieve qMALDI-imaging, internal standards dissolved in matrix solution prior to spraying on tissue sample, reducing effects from ion suppression, heterogeneity of tissue and cell types, and various other matrix effects. The authors were able to demonstrate a single practical method for quantification of tetrandrine for different organs. As a multiplexing detection technique, tetrandrine metabolites were also detected and identified in the liver by MS/MS, providing additional utility in pre-clinical drug screening.
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DOI: 10.7150/thno.30408
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Application of Imaging Techniques to Cases of Drug-Induced Crystal Nephropathy in Preclinical Studies.
B. Lenz et al., Toxicological Sciences, (2018).
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In-vivo crystallization: Precipitation of several neurological drugs in kidney.
Bruker product: solariX MRMS and Hyperion 3000 FTIR microscope.
Sample: Kidneys from rat, mouse and cynomolgus monekey.
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Crystal nephropathy was simulated in animal models and examined under various imaging techniques.
The multiplexing capability of MALDI-imaging gave more comprehensive molecular information while IR/Raman microscopy are far more selective. The generality of MALDI-imaging suggest that it can be a first line detection technique for pre-clinical screening of possible crystal nephropathy, against the high specificity of IR/Raman microscopy.
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DOI: 10.1093/toxsci/kfx044
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Quantification of 11β-hydroxysteroid dehydrogenase 1 kinetics and pharmacodynamic effects of inhibitors in brain using mass spectrometry imaging and stable-isotope tracers in mice.
D.F. Cobice et al., Biochemical Pharmacology, (2018).
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Pharmacokinetics and dynamics: 11β-hydroxysteroid dehydrogenase inhibitor UE2316 penetration and metabolism.
Bruker product: Solarix MRMS.
Sample: Mouse brain and liver.
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11β-hydroxysteroid dehydrogenase (11β-HSD) is able to generate glucocorticoid, d3-cortisol (d3F) within tissue, which is implicated in various diseases such as dementia and diabetes. As such, 11β-HSD inhibitors like UE2316, are prescribed to treat dementia and must penetrate into regions of brain such as the hippocampus for therapeutic effect.
Using MALDI imaging, penetration of UE2316 within the brain was detected, along with its metabolites. Suppression of 11β-HSD activity by UE2316 was also detected by MALDI-imaging, shown by the reduced expression of d3F in mice infused with the drug. The reduction in d3F expression however was not evenly distributed with most suppression in the hippocampus and cortex region and least in the amygdala, reflecting the lower enzymatic activity within that region.
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DOI: 10.1016/j.bcp.2017.12.013
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Spatial distribution of elvitegravir and tenofovir in rat brain tissue: Application of matrix‐assisted laser desorption/ionization mass spectrometry imaging and liquid chromatography/tandem mass spectrometry.
S. Ntshangase, et al., Rapid Communications in Mass Spectrometry, (2019).
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Pharmacokinetics: BBB penetration of anti-retroviral drugs elvitegravir and tenofovir.
Bruker product: autofleX III.
Sample: Rat brains.
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HIV is known to penetrate the central nervous system (CNS) and continue to replicate despite high level of anti-retroviral drugs in the plasma. Understanding the PK properties of anti-retroviral drugs through the BBB is crucial in preventing or treating HIV related CNS injury and managing overall viral load.
MALDI-imaging is used to study the penetration of the BBB by elvitegravir and tenofovir within rat brains. Imaging results show that elvitegravir has far better penetration into the brain than tenofovir. Elvitegravir remained in high abundance in the thalamus, hypothalamus and corpus callosum and reached the cortex within an hour after dosing. The spatial distribution of these drugs becomes crucial as they can be co-related to HIV primary reservoir sites within the brain and provide insights into the drug's on-site efficacy.
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DOI: doi.org/10.1002/rcm.8510
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Quantitative Mass Spectrometry Imaging Reveals Mutation Status-independent Lack of Imatinib in Liver Metastases of Gastrointestinal Stromal Tumors.
D.A. Sammour, et al., Scientific Reports, (2019).
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Pharmacokinetics: Penetration and quantification of imatinib in gastrointestinal stromal tumors (GIST).
Bruker product: UltrafleXtreme MALDI/TOF-TOF and solariX MRMS.
Sample: Gastrointestinal stromal tumor biopsy.
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An extensive study into qMALDI with comparison of TOF-TOF and -FTICR imaging capability, along with UPLC-ESI. This study tracked the penetration of imatinib into GIST tissue, demonstrating the viability of qMSI on a variety of highly heterogenous tissue, including liver, peritoneum, stomach and intestinal.
Fundamental insights were gained by tackling the unique challenges of qMSI, such as the highly differing LOQ in various tissue, both normal and tumorous. Results showed a striking lack of imatinib uptake by metastatic liver tumors despite high concentration detected in surrounding normal tissue.
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DOI: 10.1038/s41598-019-47089-5
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Target Exposure and Pharmacodynamics Study of the Indoleamine 2,3-Dioxygenase-1 (IDO-1) Inhibitor Epacadostat in the CT26 Mouse Tumor Model.
L. Poncelet, et al., Journal of Pharmaceutical and Biomedical Analysis, (2019).
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Pharmacokinetics and dynamics: PK/PD of Epacadostat into colon carcinoma and its inhibition of indoleamine-2,3-dioxygenase.
Bruker product: solariX MRMS.
Sample: Colon carcinoma grafted from mice.
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Indoleamine-2,3-dioxygenase (IDO1) was identified as a potential target for cancer immunotherapy. IDO1 conversion of Trp to Kyn is a key pathway that regulates immune suppression. Epacadostat (EPA), an IDO1 inhibitor was shown to enhance the body's natural immunity for antitumor activity.
MALDI-imaging was able to track and quantify EPA penetration into colon carcinoma grafted on mice. The presence of EPA spatially is correlated to suppressing Kyn expression, suggesting effective IDO1 inhibition. MALDI-imaging was able to successfully elucidate EPA's PK/PD activity within tumor environment.
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DOI: 10.1016/j.jpba.2019.02.038
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Mass Spectrometry Imaging of atherosclerosis-affine Gadofluorine following Magnetic Resonance Imaging.
F. Lohöfer, et al., Scientific Reports, (2020).
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Pharmacokinetics and enhanced imaging: Gadofluorine P accumulation in atherosclerotic plaques.
Bruker product: UltrafleX III MALDI/TOF-TOF.
Sample: Mouse atherosclerotic aorta.
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MRI contrast agents such as Gadoflourine P is used to image atherosclerosis due to its preferred accumulation in atherosclerotic plaques. However, MR signal from T1 relaxation can originate from both gadolinium and intraplaque hemorrhage.
MALDI imaging was validated as a potential tool to detect Gadofluorine P. Concentration of Gadofluorine P within the atherosclerotic wall peaked at 30 mins after injection but remained very low in the adjacent myocardium over the entire hour of the experiments. Since MALDI-imaging was also able to detect the Gadofluroine P intact molecule while LA-ICP-MS can only detect elemental Gd and cannot distinguish Gd from the intact molecule or released by decomposition.
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DOI: 10.1038/s41598-019-57075-6
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Combining MALDI mass spectrometry imaging and droplet-base surface sampling analysis for tissue distribution, metabolite profiling, and relative quantification of cyclic peptide melanotan II.
B. Chen, et al., Analytica Chimica Acta, (2020).
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Pharmacokinetics and dynamics: Melanotan II PK/PD in multiple organs in mice.
Bruker product: solariX MRMS.
Sample: Full body mouse.
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Peptide therapeutics occupies an important pharmaceutical niche due to its natural advantages of high selectivity, efficacy and safety compared to small molecules and larger biologics. Research in this therapeutics sphere has been accelerated in recent years and analytical techniques have been developed or adapted to study peptide therapeutics PK/PD.
MALDI MS, especially TOF instruments are well suited to analyzing peptides. Here, MALDI-imaging is used to study melanotan II's PK/PD in mice. Melanotan II and two of its metabolites were successfully detected spatially in entire mice body imaging, across multiple organs showing that MALDI-imaging is a versatile and generalized technique for pre-clinical screening of peptide therapeutics.
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DOI: 10.1016/j.aca.2020.05.050
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