Red-Light Photocatalytic Activation Of Pt(IV) Anticancer Prodrugs Using Methylene Blue

Abstract

Catalysis-based approaches offer versatile strategies for activating anticancer prodrugs, potentially allowing precise control over drug release and localization within tumor tissues, while reducing systemic toxicity. In this study, we explore the role of the phenothiazine dye methylene blue (MB+) as a photocatalyst in conjunction with biologically relevant electron donors to facilitate the red-light conversion of two Pt(IV) complexes, denoted as cis,cis,trans-[PtCl2(NH3)2(O2CCH2CH2COOH)2] (1) and trans-[Pt(O2CCH2CH2COOH)21R,2R-(DACH)(ox)] (2), into cisplatin and oxaliplatin, respectively. Combining spectroscopic techniques (NMR, UV-Vis, flash photolysis) with computational methods, we reveal that the doubly reduced MB+ (leucomethylene blue, LMB) triggers the reductive elimination of axial ligands in the two Pt(IV) precursors, generating the corresponding Pt(II) anticancer drugs. In vitro experiments conducted on the human cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV-16 genome, and on non-tumoral cells (HaCat) demonstrate that co-administration with Pt(IV) prodrugs improves MB+'s antiproliferative efficacy in cancer cells, particularly under red light exposure. This enhancement arises from the catalytic production of Pt(II) species within the cellular environment.