Comparison of KP1019 and NAMI-A in tumour-mimetic environments

  • Metallomics. 2016 Aug 1;8(8):762-73. doi: 10.1039/c6mt00145a.
Gemma K Gransbury  1 ,  Peter Kappen  2 ,  Chris J Glover  2 ,  James N Hughes  3 ,  Aviva Levina  4 ,  Peter A Lay  4 ,  Ian F Musgrave  5 ,  Hugh H Harris  1
Affiliations
  • 1. Department of Chemistry, The University of Adelaide, SA 5005, Australia. [email protected].
  • 2. Australian Synchrotron, Clayton, VIC 3168, Australia.
  • 3. Department of Molecular and Cellular Biology, The University of Adelaide, SA 5005, Australia.
  • 4. School of Chemistry, The University of Sydney, NSW 2006, Australia.
  • 5. School of Medical Sciences, The University of Adelaide, SA 5005, Australia.
PMID: 27460862 DOI: 10.1039/c6mt00145a
Abstract

NAMI-A and KP1019 are Ru(III)-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to Ru(II). The potential reduction of NAMI-A and KP1019 in the hypoxic environment of a tumour model of neuroblastoma was examined. Normoxic, hypoxic and necrotic tumour tissues were modelled by multicellular spheroids of SH-SY5Y human neuroblastoma cells of various diameters (50-800 μm). The variation in spheroid environment was confirmed with pimonidazole staining. Laser-ablation inductively-coupled plasma mass spectrometry showed KP1019 and NAMI-A penetration into the spheroid hypoxic region. XANES showed that the speciation of NAMI-A biotransformation products did not change significantly as hypoxia levels increased. KP1019 metabolites showed a correlation between the degree of spheroid hypoxia and the Ru K-edge energy consistent with either partial reduction of Ru(III) to Ru(II) in tumour microenvironments, increased S/Cl coordination or a reduced fraction of polynuclear Ru species. EXAFS spectroscopy was undertaken in an attempt to distinguish between these scenarios but was inconclusive.

Products