A Clinically Translatable Ternary Platinum(IV) Prodrug for Synergistically Reversing Drug Resistance

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 IC50 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.