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Comparison of KP1019 and NAMI-A in Tumour-Mimetic Environments

Comparison of KP1019 and NAMI-A in Tumour-Mimetic Environments

Gemma K Gransbury, Peter Kappen, Chris J Glover, James N Hughes, Aviva Levina, Peter A Lay, Ian F Musgrave, Hugh H Harris

Metallomics. 2016 Aug 1;8(8):762-73.

PMID: 27460862

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP201653761	NAMI-A		201653-76-1	Price

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