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

Swati A Kumar; Russell J Needham; Kristin Abraham; Hannah E Bridgewater; Lauren A Garbutt; Helena Xandri-Monje; Robert Dallmann; Sebastien Perrier; Peter J Sadler; Francis Lévi

doi:10.1093/mtomcs/mfaa003

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

Swati A Kumar, Russell J Needham, Kristin Abraham, Hannah E Bridgewater, Lauren A Garbutt, Helena Xandri-Monje, Robert Dallmann, Sebastien Perrier, Peter J Sadler, Francis Lévi

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Abstract

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.

Original language	English
Article number	mfaa003
Number of pages	11
Journal	Metallomics : integrated biometal science
Volume	13
Issue number	2
Early online date	11 Dec 2020
DOIs	https://doi.org/10.1093/mtomcs/mfaa003
Publication status	Published - 2 Feb 2021
Externally published	Yes

Bibliographical note

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press.

ASJC Scopus subject areas

Metals and Alloys
Chemistry (miscellaneous)
Biophysics
Biochemistry
Biomaterials

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/mtomcs/mfaa003Licence: CC BY

PublishedFinal published version, 1.67 MBLicence: CC BY

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Kumar, S. A., Needham, R. J., Abraham, K., Bridgewater, H. E., Garbutt, L. A., Xandri-Monje, H., Dallmann, R., Perrier, S., Sadler, P. J., & Lévi, F. (2021). Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice. Metallomics : integrated biometal science, 13(2), Article mfaa003. https://doi.org/10.1093/mtomcs/mfaa003

Kumar, SA, Needham, RJ, Abraham, K, Bridgewater, HE, Garbutt, LA, Xandri-Monje, H, Dallmann, R, Perrier, S, Sadler, PJ & Lévi, F 2021, 'Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice', Metallomics : integrated biometal science, vol. 13, no. 2, mfaa003. https://doi.org/10.1093/mtomcs/mfaa003

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abstract = "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.",

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

Abstract

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UN SDGs

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