Comparison of KP1019 and NAMI-A in tumour-mimetic environments
Date
2016
Authors
Gransbury, G.
Kappen, P.
Glover, C.
Hughes, J.
Levina, A.
Lay, P.
Musgrave, I.
Harris, H.
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Journal article
Citation
Metallomics, 2016; 8(8):762-773
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Gemma K. Gransbury, Peter Kappen, Chris J. Glover, James N. Hughes, Aviva Levina, Peter A. Lay, Ian F. Musgravee and Hugh H. Harris
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Abstract
NAMI-A and KP1019 are RuIII-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to RuII. 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 mm). 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 RuIII to RuII 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.
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This journal is © The Royal Society of Chemistry 2016