Biodistribution of cisplatin revealed by imaging mass cytometry identifies extensive collagen binding in tumor and normal tissues

Vladimir I Baranov,Rita Straus,David W Hedley,Iram Siddiqui,Olga I Ornatsky,Qing Chang

doi:10.1038/srep36641

Abstract

Imaging mass cytometry was used for direct visualization of platinum localization in tissue sections from tumor and normal tissues of cisplatin-treated mice bearing pancreas cancer patient-derived xenografts. This recently-developed technology enabled simultaneous detection of multiple markers to define cell lineage, DNA damage response, cell proliferation and functional state, providing a highly detailed view of drug incorporation in tumor and normal tissues at the cellular level. A striking and unanticipated finding was the extensive binding of platinum to collagen fibers in both tumor and normal mouse tissues. Time course experiments indicated the slow release of stroma-bound platinum, although it is currently unclear if released platinum retains biological activity. Imaging mass cytometry offers a unique window into the in vivo effects of platinum compounds, and it is likely that this can be extended into the clinic in order to optimize the use of this important class of agent.

Highlights

Previous studies have used bulk assays to measure the amount of Pt in tissues obtained from patients following cisplatin treatment[17], with little information available about the localization of cisplatin within the tumor microenvironment and in normal tissues
We exploited the unique potential of IMC to image the cellular content of platinum in BRCA-mutant and wild-type patient-derived pancreatic cancer xenograft-bearing mice treated with cisplatin, and in key normal host tissues
The free drug is rapidly cleared through the kidneys, it is extensively protein bound[21,23] which is consistent with our observation that Pt levels in formalin-fixed, Antibody/Reagent γH2AX p53 Vimentin *E-cadherin EF5 VEGF *Pan-Keratin CK7 β-catenin Ki-67 #Collagen I BRCA1 #αSMA Histone H3 *Intercalator IdU

Summary

Introduction

Previous studies have used bulk assays to measure the amount of Pt in tissues obtained from patients following cisplatin treatment[17], with little information available about the localization of cisplatin within the tumor microenvironment and in normal tissues. Mass cytometry is able to detect elements in the mass range 75–209, and we have previously described its use to measure the uptake of platinum-based drugs in cell suspensions from human tumor xenografts[18]. We used IMC to study the tissue distribution and quantitation of cisplatin in conjunction with multiple biomarkers in pancreatic cancer patient-derived xenografts. These studies revealed extensive binding of cisplatin to collagen fibers in the tumor stroma, as well as in normal tissues including kidney, intestine and skin

Methods

Results

Conclusion