Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice.

Autor:	Kumar SA; Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK., Needham RJ; Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK., Abraham K; Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK., Bridgewater HE; Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK., Garbutt LA; Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK., Xandri-Monje H; Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK., Dallmann R; Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK., Perrier S; Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK., Sadler PJ; Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK., Lévi F; Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK.; UPR 'Chronotherapy, Cancers and Transplantation', Faculty of Medicine, Paris Saclay University, Campus CNRS, 7 rue Guy Moquet, 94800 Villejuif, France.; Hepato-Biliary Center, Paul Brousse Hospital, Assistance Publique-Hopitaux de Paris (AP-HP), 12-14 Avenue Paul-Vaillant Couturier, 94800 Villejuif, France.
Jazyk:	angličtina
Zdroj:	Metallomics : integrated biometal science [Metallomics] 2021 Feb 02; Vol. 13 (2).
DOI:	10.1093/mtomcs/mfaa003
Abstrakt:	The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1-6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6- counter-anion with chloride using a novel synthesis method. FY26⋅PF6 and FY26⋅Cl displayed similar in vitro cytotoxicity in two cancer cell models. We then show the moderate and late anticancer efficacy of FY26⋅PF6 and FY26⋅Cl in a subcutaneous murine hepatocarcinoma mouse model. Both efficacy and tolerability varied according to FY26 circadian dosing time in hepatocarcinoma tumour-bearing mice. Tumour and liver uptake of the drug were determined over 48 h following FY26⋅Cl administration at Zeitgeber time 6 (ZT6), when the drug is least toxic (in the middle of the light span when mice are resting). Our studies suggest the need to administer protracted low doses of FY26 at ZT6 in order to optimize its delivery schedule, for example through the use of chrono-releasing nanoparticles. (© The Author(s) 2020. Published by Oxford University Press.)
Databáze:	MEDLINE
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