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https://hdl.handle.net/2440/102464
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Type: | Journal article |
Title: | Comparison of KP1019 and NAMI-A in tumour-mimetic environments |
Author: | Gransbury, G. Kappen, P. Glover, C. Hughes, J. Levina, A. Lay, P. Musgrave, I. Harris, H. |
Citation: | Metallomics: integrated biometal science, 2016; 8(8):762-773 |
Publisher: | Royal Society of Chemistry |
Issue Date: | 2016 |
ISSN: | 1756-5901 1756-591X |
Statement of Responsibility: | Gemma K. Gransbury, Peter Kappen, Chris J. Glover, James N. Hughes, Aviva Levina, Peter A. Lay, Ian F. Musgravee and Hugh H. Harris |
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. |
Keywords: | Spheroids, Cellular Tumor Cells, Cultured Humans Neuroblastoma Ruthenium Ruthenium Compounds Organometallic Compounds Dimethyl Sulfoxide Indazoles Antineoplastic Agents X-Ray Absorption Spectroscopy Tumor Microenvironment Hypoxia |
Rights: | This journal is © The Royal Society of Chemistry 2016 |
DOI: | 10.1039/c6mt00145a |
Grant ID: | http://purl.org/au-research/grants/arc/DP140100176 http://purl.org/au-research/grants/arc/DP130103566 |
Published version: | http://dx.doi.org/10.1039/c6mt00145a |
Appears in Collections: | Aurora harvest 3 Chemistry publications |
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