A Targeted Redox-Active Dual-Action Pt(IV)-Mn(II) Prodrug Displays Enhanced In Vivo Anticancer Activity

Abstract

As FDA-approved platinum (Pt) anticancer drugs (e.g. cisplatin, oxaliplatin and carboplatin) grapple with clinical challenges including chemoresistance and systemic side-effects, Pt(IV) prodrugs have emerged as potent alternative chemotherapies. In this work, a novel bimetallic dual-action Pt(IV) prodrug bearing a manganese (Mn) superoxide dismutase mimic (SODm) is presented, demonstrating high stability in solution. The prodrug displays intrinsic antisuperoxide properties and in vitro comparable cytotoxic activities to that of oxaliplatin in 2- and 3D colorectal cancer cellular models, as well as an increase in intracellular reactive oxygen species (ROS) production. The prodrug is further evaluated in an in vivo mice model for colorectal cancer, demonstrating a similar performance to that of oxaliplatin. Additionally, a total tumor remission is reached with a PEGylated micellar encapsulation of the prodrug. This novel formulation increases the lifetime of the prodrug and therefore its tumoral uptake and plasma content with respect to the unencapsulated drug. This enhanced activity suggests the therapeutic potential of said formulation.

Keywords: SOD mimics; drug discovery; nanoformulation; oxaliplatin; oxidative stress; platinum prodrugs.