RG108‐Conjugated Platinum(IV) Prodrugs: Enhanced Efficacy and Reduced Ototoxicity

Platinum-based chemotherapeutics remain clinically indispensable for treating various malignancies despite causing severe side effects, with ototoxicity being particularly limiting. This study reports the synthesis and evaluation of platinum(IV) prodrugs incorporating the hearing-protective ligand RG108. Among the synthesized mono- and di-substituted cisplatin and oxaliplatin derivatives, compound 4 exhibited exceptional antitumor activity with an IC₅₀ value of 0.07 ± 0.08 µM in FaDu cells. Mechanistic investigations revealed that the enhanced anti-tumor effect was primarily mediated via the EZH2/SLC47A2 regulatory axis. These prodrugs significantly mitigated ototoxicity, preserving cochlear hair cell viability, stabilizing auditory brainstem response thresholds, and maintaining cochlear basement membrane morphology. Our findings establish a framework for designing dual-functional platinum agents that synergize antitumor efficacy with organoprotective properties, addressing critical hearing loss limitations of conventional platinum chemotherapy while maintaining robust therapeutic outcomes.