Tumor microenvironment in focus: LA-ICP-MS bioimaging of a preclinical tumor model upon treatment with platinum(iv)-based anticancer agents

Abstract

The selection of drug candidates for entering clinical development relies on in vivo testing in (solid) tumor animal models. However, the heterogeneity of tumor tissue (e.g. in terms of drug uptake or tissue composition) is rarely considered when testing novel drug candidates. Therefore, we used the murine colon cancer CT-26 tumor model to study the spatially-resolved drug distribution in tumor tissue upon repetitive treatment of animals over two weeks with three investigational platinum(IV)-based anticancer agents, oxaliplatin or satraplatin. A quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method revealed a heterogeneous platinum distribution, which correlated well with the histologic features of the tumor and surrounding tissue at the microscopic level. In most of the cases, higher amounts of intratumoral platinum were found in the surrounding tissue than in the malignant parts of the sample. This indicates that determination of average platinum amounts (e.g. by microwave-assisted digestion of the sample followed by analysis with ICP-MS) might overestimate the drug uptake in tumor tissue causing misleading conclusions. In addition, we studied the platinum distribution in the kidneys of treated animals to probe if accumulation in the cortex and medulla predict potential nephrotoxicity. A 10-fold increase of platinum in the cortex of the kidney over the medulla was observed for oxaliplatin and satraplatin. Although these findings are similar to those in the platinum distribution of the nephrotoxic anticancer drug cisplatin, treatment with the compounds of our study did not show signs of nephrotoxicity in clinical use or clinical trials (oxaliplatin, satraplatin) and did not result in the alteration of renal structures. Thus, predicting the side effects based on bioimaging data by LA-ICP-MS should be considered with caution. To the best of our knowledge, this is the first LA-ICP-MS study on spatially-resolved platinum accumulation in tissues after repetitive platinum-based anticancer drug treatment of mice bearing a preclinical tumor model.

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

“…The finding of predominant cortical localization of platinum from compound 1 is in good accordance with previous LA-ICP-MS studies in kidney sections upon treatment with cisplatin, oxaliplatin, and satraplatin. 9 , 29 , 31 , 32 …”

“…Laser ablation was performed as described previously. 9 Data were recorded by using a Triple Quadrupole ICP-MS Agilent 8800 instrument (Agilent Technologies, Tokyo, Japan) and processed with the Agilent MassHunter software package (Workstation Software, Version B.01.03, 2013). The software Igor Pro (Wavemetrics, Igor Pro 6.34A) together with its add-on Iolite (Iolite Version 2.5) was used for further data processing and generation of platinum distribution maps.…”

Accurate quantification of modified cyclic peptides without the need for authentic standards

“…For HPLC-ICP-MS quantification, interferences were efficiently removed in the ICP-MS/MS with selection of dual m/z, for sulfur quantification, by measuring S, m/z 32 and 34 were obtained as 32 66 . Cyclic peptides 6-10 were extracted from chemoenzymatic reaction mixtures using SPE and subsequently identified and quantified by HPLC-ICPMS/ESMS.…”

“…[26][27] For these reasons it has become a significant and complementary technique in bioanalysis for the determination of biomolecules and quantification of therapeutic agents. [28][29][30][31][32][33][34][35][36] Application of ICPMS allows the quantification of elements independent of their molecular form, hence the analyte retains its original form during quantification. Coupled with molecular information obtained from ESI-MS or MALDI enables the compound identification simultaneously with its quantification.…”

Analysis of small molecule antibody–drug conjugate catabolites in rat liver and tumor tissue by liquid extraction surface analysis micro‐capillary liquid chromatography/tandem mass spectrometry

“…The concentration of a drug within specific tissues is conventionally determined using analytical methods such as quantitative whole body autoradiography (QWBA) requiring a radiolabeled entity or by analysis of tissue homogenates using liquid chromatography/tandem mass spectrometry (LC/MS/MS) where spatial resolution is lost . In recent years, mass spectrometry imaging (MSI) technologies have been introduced to track simultaneously molecules and their metabolites in single or multiple tissues using matrix‐assisted laser desorption ionization mass spectrometry (MALDI‐MS), nanospray desorption electrospray ionization mass spectrometry (nDESI‐MS), inductively coupled plasma mass spectrometry (ICP‐MS) hyphenated to laser ablation (LA), mass cytometry or liquid extraction surface analysis mass spectrometry (LESA‐MS) . Besides the general difficulties in quantitative MSI described in recent reviews, one challenge specifically associated with MSI is the preparation of homogeneous and reproducible calibration standards (Cs) and quality control (QC) samples for tissue analysis.…”