title: Comparison of KP1019 and NAMI-A in tumour-mimetic environments.
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.
authors.affiliation: Department of Chemistry, The University of Adelaide, SA 5005, Australia. hugh.harris@adelaide.edu.au.
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Gransbury
authors.affiliation: Australian Synchrotron, Clayton, VIC 3168, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kappen
authors.affiliation: Australian Synchrotron, Clayton, VIC 3168, Australia.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Glover
authors.affiliation: Department of Molecular and Cellular Biology, The University of Adelaide, SA 5005, Australia.
authors.forename: James N
authors.initials: JN
authors.lastname: Hughes
authors.affiliation: School of Chemistry, The University of Sydney, NSW 2006, Australia.
authors.forename: Aviva
authors.initials: A
authors.lastname: Levina
authors.affiliation: School of Chemistry, The University of Sydney, NSW 2006, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lay
authors.affiliation: School of Medical Sciences, The University of Adelaide, SA 5005, Australia.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Musgrave
authors.affiliation: Department of Chemistry, The University of Adelaide, SA 5005, Australia. hugh.harris@adelaide.edu.au.
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Harris
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology*; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D017975:Ruthenium Compounds; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects; D056928:X-Ray Absorption Spectroscopy
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D012428:Ruthenium; D004121:Dimethyl Sulfoxide