LA-ICP-MS imaging in multicellular tumor spheroids – a novel tool in the preclinical development of metal-based anticancer drugs

Abstract

A novel application of advanced elemental imaging offers cutting edge in vitro assays with more predictive power on the efficacy of anticancer drugs in preclinical development compared to two dimensional cell culture models. We propose LA-ICP-MS analysis of multicellular spheroids, which are increasingly being used as three dimensional (3D) models of tumors, for improving the in vitro evaluation of anticancer metallodrugs. The presented strategy is very well suited for screening drug–tumor penetration, a key issue for drug efficacy. A major advantage of tumor spheroid models is that they enable us to create a tissue-like structure and function. With respect to 2D culture on the one hand and in vivo models on the other, multicellular spheroids thus show intermediate complexity, still allowing high repeatability and adequate through-put for drug research. This strongly argues for the use of spheroids as bridging models in preclinical anticancer drug development. Probing the lateral platinum distribution within these tumor models allows visualizing the penetration depth and targeting of platinum-based complexes. In the present study, we show for the first time that spatially-resolved metal accumulation in tumor spheroids upon treatment with platinum compounds can be appropriately assessed. The optimized LA-ICP-MS setup allowed discerning the platinum localization in different regions of the tumor spheroids upon compound treatment at biologically relevant (low micromolar) concentrations. Predominant platinum accumulation was observed at the periphery as well as in the center of the spheroids. This corresponds to the proliferating outermost layers of cells and the necrotic core, respectively, indicating enhanced platinum sequestration in these regions.