A Clinically Translatable Ternary Platinum(IV) Prodrug for Synergistically Reversing Drug Resistance
Ying Liu, Dun Wang, Hongbing Liu, Li Liu, Shuang Li, Zongtao Zhou, Linyin Lu, Xuyue Liu, Lifang He, Dongxiu He, Cui‐Yun Yu, Hua Wei
Abstract
Scalable production of a clinically translatable formulation with enhanced therapeutic efficacy against cisplatin-resistant tumors without the use of any clinically unapproved reagents and additional manipulation remains a challenge. For this purpose, we report herein the construction of TPP-Pt- acetal -CA based on all commercially available, clinically approved reagents consisting of a cinnamaldehyde (CA) unit for reactive oxygen species generation, a mitochondrially targeted triphenylphosphonium (TPP)-modified Pt(IV) moiety for mitochondrial dysfunction, and an intracellular acidic pH-cleavable acetal link between these two moieties. The resulting self-assembled, stabilized TPP-Pt- acetal -CA nanoparticles mediated an IC 50 value approximately 6-fold lower than that of cisplatin in A549/DDP cells and a tumor weight reduction 3.6-fold greater than that of cisplatin in A549/DDP tumor-bearing BALB/c mice with insignificant systematic toxicity due to the synergistic mitochondrial dysfunction and markedly amplified oxidative stress. Therefore, this study presents the first example of a clinically translatable Pt(IV) prodrug with enhanced efficiency for synergistically reversing drug resistance.