Kumar Swati A, Needham Russell J, Abraham Kristin, Bridgewater Hannah E, Garbutt Lauren A, Xandri-Monje Helena, Dallmann Robert, Perrier Sebastien, Sadler Peter J, Lévi Francis
Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK.
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
Metallomics. 2021 Feb 2;13(2). doi: 10.1093/mtomcs/mfaa003.
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.
有机锇配合物[OsII(ɳ6-p-异丙基苯)(苯基偶氮吡啶-NMe2)I]+（FY26）对小鼠肝癌Hepa1-6及其他小鼠或人类癌细胞系表现出有前景的体外抗肿瘤活性。在此，我们通过一种新颖的合成方法用氯离子取代PF6-抗衡阴离子，大幅提高了FY26的水溶性。FY26⋅PF6和FY26⋅Cl在两种癌细胞模型中表现出相似的体外细胞毒性。然后我们展示了FY26⋅PF6和FY26⋅Cl在皮下小鼠肝癌模型中的中晚期抗癌疗效。在荷肝癌小鼠中，疗效和耐受性均随FY26昼夜给药时间而变化。在授时时间6（ZT6）给予FY26⋅Cl后48小时内测定药物在肿瘤和肝脏中的摄取情况，此时药物毒性最小（在小鼠休息的光照时段中间）。我们的研究表明，有必要在ZT6给予长时间低剂量的FY26以优化其给药方案，例如通过使用缓释纳米颗粒。
