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

A A Legin,J Mayr,H P Varbanov,P Heffeter,S Reipert,W Berger,B K Keppler,A Schintlmeister,S Theiner,C R Kowol,M A Jakupec,M Wagner,M S Galanski

doi:10.1039/c5sc04383b

Abstract

Nano-scale secondary ion mass spectrometry (NanoSIMS) enables trace element and isotope analyses with high spatial resolution. This unique capability has recently been exploited in several studies analyzing the subcellular distribution of Au and Pt anticancer compounds. However, these studies were restricted to cell culture systems. To explore the applicability to the in vivo setting, we developed a combined imaging approach consisting of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), NanoSIMS and transmission electron microscopy (TEM) suitable for multi-scale detection of the platinum distribution in tissues. Applying this approach to kidney and tumor samples upon administration of selected platinum(iv) anticancer prodrugs revealed uneven platinum distributions on both the organ and subcellular scales. Spatial platinum accumulation patterns were quantitatively assessed by LA-ICP-MS in histologically heterogeneous organs (e.g., higher platinum accumulation in kidney cortex than in medulla) and used to select regions of interest for subcellular-scale imaging with NanoSIMS. These analyses revealed cytoplasmic sulfur-rich organelles accumulating platinum in both kidney and malignant cells. Those in the tumor were subsequently identified as organelles of lysosomal origin, demonstrating the potential of the combinatorial approach for investigating therapeutically relevant drug concentrations on a submicrometer scale.

Highlights

Platinum-based drugs play a pivotal role in cancer chemotherapy and are clinically used for treatment of a variety of solid tumors, including testicular, colorectal, bladder, ovarian, as well as head and neck cancer.[1]
To explore the applicability to the in vivo setting, we developed a combined imaging approach consisting of laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS), NanoSIMS and transmission electron microscopy (TEM) suitable for multi-scale detection of the platinum distribution in tissues
Kidney and liver were dissected in halves and the resulting parts were separately (i) shock-frozen for the ICP-MS platinum accumulation measurements and LA-ICP-MS imaging studies and (ii) xed for NanoSIMS investigations

Summary

Introduction

Platinum-based drugs play a pivotal role in cancer chemotherapy and are clinically used for treatment of a variety of solid tumors, including testicular, colorectal, bladder, ovarian, as well as head and neck cancer.[1]. To explore the applicability to the in vivo setting, we developed a combined imaging approach consisting of laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS), NanoSIMS and transmission electron microscopy (TEM) suitable for multi-scale detection of the platinum distribution in tissues.

Results

Conclusion