A Highly Stable Photoactivatable Pt(IV) Prodrug with Lower Dark Cytotoxicity for Photochemotherapy

Photoactivation of Pt(IV) prodrugs to Pt(II) species at tumor sites is a promising strategy to reduce systemic toxicity of platinum-based antitumor drugs. An ideal Pt(IV) prodrug should remain stable in the dark and be rapidly activated upon irradiation. However, existing photoactivatable Pt(IV) prodrugs, based on carboxylato ligands, are gradually reduced in the dark and require long irradiation times for photoactivation. In this study, we developed a photoactivatable Ru(II)-Pt(IV) complex, RuOPt, by conjugating a Ru(II) Photosensitizer with an inert Pt(IV) moiety featuring an axial alkoxido ligand. Another complex, RuOOPt, with a carboxylato ligand, was also synthesized for comparison. RuOPt exhibited superior stability in the dark compared to RuOOPt. Both complexes were fully activated under 2 min of irradiation in the presence of ascorbate, releasing oxaliplatin. Additionally, both complexes underwent reduction and ligand substitution upon irradiation without electron donors. In Cancer cell assays, the two Ru(II)-Pt(IV) complexes exhibited similar photocytotoxicity, while RuOPt showed up to 4.6 times lower dark cytotoxicity than RuOOPt and demonstrated reduced dark toxicity in colony formation, Apoptosis, and tumor spheroid assays. This work provides a novel approach to enhance the stability and reduce dark cytotoxicity of photoactivatable Pt(IV) prodrugs using an axial alkoxido ligand.