Multi-scale imaging of anticancer platinum(<scp>iv</scp>) compounds in murine tumor and kidney

Legin, Anton A.; Theiner, Sarah; Schintlmeister, Arno; Reipert, Siegfried; Heffeter, Petra; Jakupec, Michael A.; Mayr, Josef; Varbanov, Hristo P.; Kowol, Christian R.; Galanski, Markus; Berger, Walter; Wagner, Michael; Keppler, Bernhard K.

doi:10.1039/c5sc04383b

Cited by 36 publications

(35 citation statements)

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“…NanoSIMS allows high spatial resolution imaging (B100 nm) of the metal centre and when used in tandem with isotopic labelling, provides valuable information on the ligands surrounding the metal centre. 17,18 In recent years, NanoSIMS has been used to study cellular distribution of metallodrugs based on Au, 19 Ru 17 and Pt, [20][21][22] with the cellular distribution of cisplatin being reported in colon cancer cells. Despite the high spatial resolutions of this technique, as far as we are aware no comparative study has been done to analyse with high spatial resolution differences in the distribution of Pt between cancer cells that are sensitive and resistant to the drug.…”

Section: Introductionmentioning

confidence: 99%

Differences in cisplatin distribution in sensitive and resistant ovarian cancer cells: a TEM/NanoSIMS study

et al. 2017

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Cisplatin is a widely used anti-cancer drug, but its effect is often limited by acquired resistance to the compound during treatment. Here, we use a combination of transmission electron microscopy (TEM) and nanoscale-secondary ion mass spectrometry (NanoSIMS) to reveal differences between cisplatin uptake in human ovarian cancers cells, which are known to be susceptible to acquired resistance to cisplatin. Both cisplatin sensitive and resistant cell lines were studied, revealing markedly less cisplatin in the resistant cell line. In cisplatin sensitive cells, Pt was seen to distribute diffusely in the cells with hotspots in the nucleolus, mitochondria, and autophagosomes. Inductively coupled plasma mass spectrometry (ICP-MS) was used to validate the NanoSIMS results.

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Section: Introductionmentioning

confidence: 99%

Differences in cisplatin distribution in sensitive and resistant ovarian cancer cells: a TEM/NanoSIMS study

et al. 2017

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“…31 P is typically most abundant in the nucleus, which can be further segmented into the 32 Sintense nucleolus and 32 S-sparse nucleoplasm. Within the cytoplasm, 32 S is enriched in some (but not all) lysosomes, providing some definition for intracellular vesicles (Legin et al, 2014(Legin et al, , 2016Narendra et al, 2020). Additionally, in some tissues, such as the heart…”

Section: Narendra and Steinhausermentioning

confidence: 99%

Metabolic Analysis at the Nanoscale with Multi‐Isotope Imaging Mass Spectrometry (MIMS)

Narendra

Steinhauser

2020

CP Cell Biology

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Incorporation of a stable‐isotope metabolic tracer into cells or tissue can be followed at submicron resolution by multi‐isotope imaging mass spectrometry (MIMS), a form of imaging secondary ion microscopy optimized for accurate isotope ratio measurement from microvolumes of sample (as small as ∼30 nm across). In a metabolic MIMS experiment, a cell or animal is metabolically labeled with a tracer containing a stable isotope. Relative accumulation of the heavy isotope in the fixed sample is then measured as an increase over its natural abundance by MIMS. MIMS has been used to measure protein turnover in single organelles, track cellular division in vivo, visualize sphingolipid rafts on the plasma membrane, and measure dopamine incorporation into dense‐core vesicles, among other biological applications. In this article, we introduce metabolic analysis using NanoSIMS by focusing on two specific applications: quantifying protein turnover in single organelles of cultured cells and tracking cell replication in mouse tissues in vivo. These examples illustrate the versatility of metabolic analysis with MIMS. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Metabolic labeling for MIMS Basic Protocol 2: Embedding of samples for correlative transmission electron microscopy and MIMS with a genetically encoded reporter Alternate Protocol: Embedding of samples for correlative light microscopy and MIMS Support Protocol: Preparation of silicon wafers as sample supports for MIMS Basic Protocol 3: Analysis of MIMS data

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“…[301] Recently, the use of nanoscale secondary ion mass spectrometry (nanoSIMS), which consists in a nanoscopic scale resolution imaging technique, was reported to localise Au-and Pt-based metallodrugs in tumors. [302,303] Keppler et al first reported the use of a combined LA-ICP-MS and nanoSIMS approach in complex biological systems (kidney and tumour samples) after treatment with Pt(IV) pro-drugs. [303] The results revealed that uneven platinum distribution was occurring in both the organ and subcellular fractions.…”

Section: Ms Analyses Of Metallodrugs In Complex Biological Systemsmentioning

confidence: 99%

“…[302,303] Keppler et al first reported the use of a combined LA-ICP-MS and nanoSIMS approach in complex biological systems (kidney and tumour samples) after treatment with Pt(IV) pro-drugs. [303] The results revealed that uneven platinum distribution was occurring in both the organ and subcellular fractions.…”

Section: Ms Analyses Of Metallodrugs In Complex Biological Systemsmentioning

confidence: 99%

“…The malignant organelles taking up the drug were found of lysosomal origin, demonstrating the potential of this combinatorial approach in complex biological systems. [303] Finally, nanoSIMS was also described in combination with EFTEM (Energy Filtered Transmission Electron Microscopy) to visualise a gold(I) phosphine complex in tumour cells. [302] This approach allowed the identification of sulfur-rich regions in the nucleus and in the cytoplasm to be the preferential binding sites of gold, supporting the hypothesis that the mechanism of action of such Au(I) anticancer agents is based in the inhibition of thiol-containing protein families such as TrxR.…”

Section: Ms Analyses Of Metallodrugs In Complex Biological Systemsmentioning

confidence: 99%

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Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Wenzel

Casini

2017

Coordination Chemistry Reviews

107

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Metal-based compounds form a promising class of therapeutic agents, whose mechanisms of action still need to be elucidated, and that are in general prone to undergo extensive speciation in physiological environment. Thus, determination of the fate of the metal compounds in complex biological systems, contributing to their overall pharmacological and toxicological profiles, is important to develop more rationalised and targeted metal-based drugs. To these aims, a number of spectroscopic and biophysical methods, as well as analytical techniques, are nowadays extensively applied to study the reactivity of metal complexes with different biomolecules (e.g. nucleic acids, proteins, buffer components). Among the various techniques, molecular mass spectrometry (MS) has emerged in the last decade as a major tool to characterise the interactions of metallodrugs at a molecular level. In this review, we present an overview of the information available on the reactivity of various families of therapeutic metallodrugs (mainly anticancer compounds based on Pt, Ru, Au and As) with biomolecules studied by different MS techniques, including high-resolution ESI-, MALDI-and ion mobility-MS among others. Representative examples on the potential of the MS approach to study non-covalent interactions are also discussed. The review is organized to present results obtained on samples with different degrees of complexity, from the interactions of metal compounds with small model nucleophiles (amino acids and nucleobases), model peptides/oligonucleotides, target proteins/nucleic acids, to the analysis of serum, cell extracts and tissue samples. The latter requiring combination of proteomic methods with advanced MS techniques. Correlations between molecular reactivity of metallodrugs and biological activity are hard to establish, but differences in the reactivity of metallodrugs to biomolecules and their different adducts, as revealed by MS methods, may indicate differences in their modes of action. Overall, the knowledge offered by MS methods on metallodrugs speciation is invaluable to establish new rules and define new trends in the periodic table aimed at rationalizing the behavior of metal compounds in complex living systems. Keywordsmetal-based drugs; proteins; nucleic acids; mass spectrometry; metallomics. Corresponding Author Angela Casini Corresponding Author's InstitutionCardiff University To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. Order of Authors 1 Answers to Reviewers Reviewer 1 The authors have made some effort to answer suggestions and the manuscript is improved. Since it is a review, there is, strictly, no new information but nevertheless the compilation of data and references could be useful.Answer: no further comments. Liu et al." in place of "Lu et al." iv) Some symbols in the PDF file are not correctly displayed. Reviewer Answer:We have inserted all the minor modifications requested by this rev...

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Multi-scale imaging of anticancer platinum(iv) compounds in murine tumor and kidney

Abstract: A NanoSIMS, LA-ICP-MS and TEM combinatorial approach was applied to analyze the distribution of platinum(iv) prodrugs in murine tissue samples.

Cited by 36 publications

References 65 publications

Differences in cisplatin distribution in sensitive and resistant ovarian cancer cells: a TEM/NanoSIMS study

Differences in cisplatin distribution in sensitive and resistant ovarian cancer cells: a TEM/NanoSIMS study

Metabolic Analysis at the Nanoscale with Multi‐Isotope Imaging Mass Spectrometry (MIMS)

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

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