Tumor-targeted dual-action NSAID-platinum(iv) anticancer prodrugs

Abstract

Platinum(IV) prodrugs are a promising class of anticancer agents designed to overcome the limitations of conventional platinum(II) therapeutics. In this work, we present oxaliplatin(IV)-based complexes, which upon reduction, release acetylsalicylic acid (aspirin), known for its antitumor activity against colon cancer and currently investigated in combination with oxaliplatin in a phase III clinical study. Comparison with a recently reported cisplatin analog (asplatin) revealed a massive increase in reduction stability for the oxaliplatin complex in mouse serum. This was in line with the cell culture data indicating the desired prodrug properties for the newly synthesized complex. For in vivo studies, a new derivative containing an albumin-binding maleimide unit was synthesized. Indeed, distinctly longer plasma half-life as well as higher tumor accumulation in comparison to asplatin and oxaliplatin were observed, also leading to significantly higher antitumor activity and overall survival of CT26 tumor-bearing mice.