title: Biodistribution of the novel anticancer drug sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] KP-1339/IT139 in nude BALB/c mice and implications on its mode of action.
abstract: The ruthenium complex sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP-1339/IT139) has entered clinical trials as the more soluble alternative to the indazolium compound KP1019. In order to get insight into its distribution and accumulation throughout a living organism, KP-1339/IT139 was administered intravenously in non-tumor bearing nude BALB/c mice and the Ru content in blood cells and plasma, bone, brain, colon, kidneys, liver, lung, muscle, spleen, stomach and thymus was determined at several time points. The Ru concentration in blood cells and plasma was found to increase slightly within the first hours of analysis, with the Ru concentration being 3-times higher in plasma compared to blood cells. The plasma samples were subjected to analysis by capillary zone electrophoresis (CZE) and size exclusion/anion exchange chromatography (SEC-IC) both coupled to inductively coupled plasma-mass spectrometry (ICP-MS) and a large majority of the total Ru content was found attached to mouse serum albumin (MSA), confirming similar behavior to KP1019 in an in vivo setting. Within 1h, the peak ratio of approximately 1.2-1.5 Ru per albumin molecule was reached which declined to about 1 Ru per albumin molecule within 24h. Beside the MSA adduct a higher molecular weight species was observed probably stemming from MSA conjugates. In addition, the tissue samples were mineralized by microwave digestion and analyzed for their Ru content. The highest Ru levels were found in colon, lung, liver, kidney and notably in the thymus. The peak Ru concentrations in these tissues were reached 1-6h after administration and declined slowly over time.
authors.affiliation: University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, Austria.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Bytzek
authors.affiliation: University of Vienna, Faculty of Chemistry, Institute of Analytical Chemistry, Waehringer Str. 38, A-1090, Vienna, Austria.
authors.forename: Gunda
authors.initials: G
authors.lastname: Koellensperger
authors.affiliation: University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, Austria; University of Vienna, Research Platform 'Translational Cancer Therapy Research', Waehringer Str. 42, A-1090, Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, Austria; University of Vienna, Research Platform 'Translational Cancer Therapy Research', Waehringer Str. 42, A-1090, Vienna, Austria; University of Auckland, School of Chemical Sciences, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: c.hartinger@auckland.ac.nz.
authors.forename: Christian
authors.initials: C
authors.lastname: G Hartinger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D003106:Colon / Q000378:metabolism; D007191:Indazoles / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D012428:Ruthenium / Q000097:blood*; D017975:Ruthenium Compounds; D012709:Serum Albumin / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D012709:Serum Albumin; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D012428:Ruthenium
keywords: Cancer research; Capillary zone electrophoresis; Inductively coupled plasma mass spectrometry; Liquid chromatography; Ruthenium(III) complexes; Tissue distribution