Direct S,S Coordination Suppresses Pt(II)-Thiol Reactivity to Mitigate Nephrotoxicity and Enable Chemo-Photodynamic Therapy against Metastatic Triple-Negative Breast Cancer.

Platinum chemotherapy is limited by the thiol reactivity of Pt(II), which promotes interactions with sulfur-containing biomolecules, causing nephrotoxicity and drug deactivation while providing limited efficacy against metastatic disease. Here, we show that direct S,S coordination suppresses Pt(II)-thiol reactivity, mitigating nephrotoxicity while enabling chemo-photodynamic therapy. Three Pt(II) complexes (Pt1-Pt3) containing a dithiolene ligand were designed to pre-satisfy the sulfur affinity of Pt(II). The lead complex, Pt3, resists glutathione binding, exhibits cytotoxicity toward 4T1 triple-negative breast cancer cells (IC50 = 6.05 μM), and shows a 2.6-fold enhancement under 660 nm red-light irradiation (IC50 = 2.29 μM) through singlet oxygen-mediated apoptosis, while remaining minimally toxic to HEK-293 normal kidney cells (IC50 > 100 μM). In an orthotopic 4T1 tumor model, Pt3 demonstrated potent in vivo antitumor activity with reduced nephrotoxicity and suppressed lung metastasis relative to cisplatin and oxaliplatin, establishing direct S,S coordination as a medicinal design strategy for safer Pt(II) chemotherapeutics.