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.
Mass spectrometry imaging is being increasingly used in metal-based anticancer drug development to study elemental and/or molecular drug distributions in different biological systems. The main analytical tools employed are SIMS (especially nanoSIMS), LA-ICP-MSI and MALDI-MSI as well as a combination of complementary imaging techniques. Main challenges are appropriate sample preparation methods, reliable and validated quantification strategies and a trade-off between sensitivity and spatial resolution. So far, research has mostly focused on the development of analytical methods for imaging with the long term goal to study drug uptake into tumor tissue and toxicity affected organs and to identify cellular targets of metal-based drugs. In this review we cover the technological features of the mass spectrometry imaging methods used and give an overview of the applications in metal-based anticancer drug research as well as some future perspectives.
Metallodrug-protein interactions contribute to their therapeutic effect (even when DNA is the dominant target), side-effects and are implicit in drug resistance. Here, we provide mass spectrometric-based evidence to show that metallodrug interactions with proteins are considerably more complex than current literature would suggest. Using native-like incubation and electrospray conditions together with an automated tool we designed for exhaustive mass spectra matching, the promiscuity of binding of cisplatin to ubiquitin is revealed, with 14 different binding sites observed. There is a binding preference to negatively charged sites on the protein, consistent with the cationic nature of the cisplatin adduct following aquation. These results have implications in metallodrug development and beyond to the toxicological effects of metal ions more generally.
The in vitro inter- and intra-cellular distribution of an isotopically labelled ruthenium(II)-arene (RAPTA) anti-metastatic compound in human ovarian cancer cells was imaged using nano-scale secondary ion mass spectrometry (NanoSIMS). Ultra-high resolution isotopic images of (13)C, (15)N, and Ru indicate that the phosphine ligand remains coordinated to the ruthenium(II) ion whereas the arene detaches. The complex localizes mainly on the membrane or at the interface between cells which correlates with its anti-metastatic effects.
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