Mass Spectrometry Imaging of Therapeutics from Animal Models to Three-Dimensional Cell Cultures

Liu, Xin; Hummon, Amanda B.

doi:10.1021/acs.analchem.5b00419

Cited by 62 publications

(63 citation statements)

References 127 publications

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“…MSI is a powerful technology that has been applied to visualize endogenous and exogenous molecules including peptides, proteins, lipids, drugs and metabolites 39,40 . In pharmaceutical research, label-free MALDI-MSI has been used to evaluate therapeutics.…”

Section: Resultsmentioning

confidence: 99%

MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids

Liu

Flinders

Mumenthaler

et al. 2017

J. Am. Soc. Mass Spectrom.

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Patient-derived colorectal tumor organoids (CTOs) closely recapitulate the complex morphological, phenotypic, and genetic features observed in in vivo tumors. Therefore, evaluation of drug distribution and metabolism in this model system can provide valuable information to predict the clinical outcome of a therapeutic response in individual patients. In this report, we applied matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to examine the spatial distribution of the drug irinotecan and its metabolites in CTOs from two patients. Irinotecan is a prodrug and is often prescribed as part of therapeutic regimes for patients with advanced colorectal cancer. Irinotecan shows a time-dependent and concentration-dependent permeability and metabolism in the CTOs. More interestingly, the active metabolite SN-38 does not co-localize well with the parent drug irinotecan and the inactive metabolite SN-38G. The phenotypic effect of irinotecan metabolism was also confirmed by a viability study showing significantly reduced proliferation in the drug treated CTOs. MALDI-MSI can be used to investigate various pharmaceutical compounds in CTOs derived from different patients. By analyzing multiple CTOs from a patient, this method could be used to predict patient-specific drug responses and help to improve personalized dosing regimens. Graphical Abstract ᅟ.

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Section: Resultsmentioning

confidence: 99%

MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids

Liu

Flinders

Mumenthaler

et al. 2017

J. Am. Soc. Mass Spectrom.

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“…13–14 Three-dimensional cell cultures or spheroids display pathophysiological gradients that are more complex than conventional two-dimensional cell cultures and are higher throughput than animal models. 17–18 These cultures have naturally occurring layers of cellular populations that are comparable to in vivo tumors. The physiological layers form in response to decreasing nutrient and oxygen concentrations from the exterior of the spheroid to the core.…”

Section: Introductionmentioning

confidence: 99%

Analyzing Liposomal Drug Delivery Systems in Three-Dimensional Cell Culture Models Using MALDI Imaging Mass Spectrometry

2017

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Cancer chemotherapeutics often fail to reach all diseased cells. To help solve this problem, researchers are investigating novel drug delivery systems. Liposomes are an attractive option due to their low toxicity, high biocompatibility, and potential to carry a large amount of a drug to the tumor site, all while avoiding being eliminated from the body. This study evaluates the penetration of doxorubicin-encased liposomes into three-dimensional cell cultures, or spheroids. Liposomes composed of lipids containing head groups of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cholesterol were created by extrusion. Doxorubicin is encapsulated within the hydrophilic core of the liposome. The drug is actively released in the spheroid as the lipids bind to cellular lipid bilayers. Spheroids were dosed with liposomal doxorubicin, free doxorubicin, or media control to assess drug distribution over the course of seventy-two hours. Drug penetration was visualized Matrix-Assisted Laser Desorption/IonizationImaging Mass Spectrometry (MALDI-IMS) with confirmation by steady state fluorescence microscopy, creating a comprehensive picture of drug distribution. This technique is able to identify both free and liposomal doxorubicin throughout the spheroid after just twelve hours of treatment. Additionally, MALDI-IMS is able to detect three metabolites of doxorubicin, indicating that cells actively metabolize the drug during treatment. Steady state fluorescence microscopy cannot distinguish the drug from its metabolites as they have the same emission spectra. This report summarizes the first study to use MALDI-IMS to analyze drug penetration of a liposomal drug carrier as well as its metabolites.

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“…Single-cell mass spectrometry (MS) provides label-free detection, qualitative–quantitative information, and capability for targeted or untargeted (discovery) operation. Single-cell MS technologies include but are not limited to secondary ion MS (SIMS) for lipids in mating bacteria 21 and single Xenopus embryos 22 , matrix-assisted 23–25 and matrix-free 26, 27 laser desorption ionization for endogenous metabolites and drugs in animal, plant, or microbial cells and cell cultures. Additionally, single-cell MS can be performed under atmospheric-pressure conditions.…”

Section: Introductionmentioning

confidence: 99%

Single-cell mass spectrometry with multi-solvent extraction identifies metabolic differences between left and right blastomeres in the 8-cell frog (Xenopus) embryo

Onjiko

Morris

Moody

et al. 2016

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Single-cell metabolic mass spectrometry enables the discovery (untargeted) analysis of small molecules in individual cells. Using single-cell capillary electrophoresis high-resolution mass spectrometry (CE-HRMS), we recently uncovered small-molecule differences between embryonic cells located along the animal–vegetal and dorsal–ventral axes of the 16-cell frog (Xenopus laevis) embryo, raising the question whether metabolic cell heterogeneity also exists along the left–right body axis. To address this question, we here advance single-cell CE-HRMS for identifying and quantifying metabolites in higher analytical sensitivity, and then use the methodology to compare metabolite production between left and right cells. Our strategy utilizes multiple solvents with complementary physicochemical properties to extract small molecules from single cells and improve electrophoretic separation, increasing metabolite ion signals for quantification and tandem HRMS. As a result, we were able to identify 55 different small molecules in D1 cells that were isolated from 8-cell embryos. To quantify metabolite production between left and right cells, we analyzed n = 24 different D1 cells in technical duplicate–triplicate measurements. Statistical and multivariate analysis based on 80 of the most repeatedly quantified compounds revealed 10 distinct metabolites that were significantly differentially accumulated in the left or right cells (p < 0.05 and fold change ≥ 1.5). These metabolites were enriched in the arginine–proline metabolic pathway in the right, but not the left D1 cells. Besides providing analytical benefits for single-cell HRMS, this work provides new metabolic data on the establishment of normal body asymmetry in the early developing embryo.

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Mass Spectrometry Imaging of Therapeutics from Animal Models to Three-Dimensional Cell Cultures

Cited by 62 publications

References 127 publications

MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids

MALDI Mass Spectrometry Imaging for Evaluation of Therapeutics in Colorectal Tumor Organoids

Analyzing Liposomal Drug Delivery Systems in Three-Dimensional Cell Culture Models Using MALDI Imaging Mass Spectrometry

Single-cell mass spectrometry with multi-solvent extraction identifies metabolic differences between left and right blastomeres in the 8-cell frog (Xenopus) embryo

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