Oxaliplatin Pt(IV) prodrugs conjugated to gadolinium-texaphyrin as potential antitumor agents
Menée sur des lignées de cellules cancéreuses et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence le potentiel antitumoral d'un médicament conjuguant gadolinium, texaphyrine et oxaliplatine Pt(IV)
Currently, cisplatin, carboplatin, and oxaliplatin are the only platinum agents approved by the US Food and Drug Administration for use in therapeutic regimens. While effective in select cancers, their clinical utility remains limited by intrinsic or acquired resistance. This is attributed, in part, to poor drug tumor localization and uptake. Additionally, one of the more formidable mechanisms of platinum resistance involves dysfunction of the tumor suppressor p53. Lack of wild-type p53 activation can translate to a significant reduction in the 5-y survival rate compared with mutant p53 in some cancers. The inability to overcome p53 dysfunction in concert with the dose-limiting toxicities and poor tumor-specific drug delivery of Pt provides an incentive to develop agents as described in this report.Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.
https://www.pnas.org/content/pnas/early/2020/03/12/1914911117 2020