Ultrasound-induced Activation of Tetravalent Platinum Polyglutamate Nanoprodrug Accelerated by Coumarin Derivatives

Given that platinum-based drugs are widely used clinically as chemotherapeutic agents, their severe toxic side effects have attracted significant attention. Consequently, the development of novel nanoprodrugs based on low-toxicity tetravalent platinum (Pt(IV)) complexes holds substantial research value. Herein, we discovered that coumarin derivatives exhibit inherent antitumor efficacy and significantly enhance superoxide anion radicals (•O 2 − ) generation in aqueous solutions under ultrasound (US) irradiation. Given that •O 2 − is known to mediate the reduction of Pt(IV) to divalent platinum (Pt(II)), we engineered an US-responsive dual-drug nanoprodrug (P-cisPt(IV)@5-MOP). This nanoprodrug was prepared by covalently conjugating Pt(IV) and methoxy polyethylene glycol hydroxyl (mPEG-OH) to a poly( l -glutamic acid) (PLG) carrier, followed by encapsulating coumarin derivatives. Under low-intensity US irradiation (1.5 W/cm 2 , 1 MHz, 10 min), P-cisPt(IV)@5-MOP achieved a Pt(IV) reduction rate of 91.4%. Furthermore, upon US exposure, its half-maximal inhibitory concentration (IC 50 ) against 4T1 breast cancer cells decreased dramatically from 25.7 µmol/L to 0.1 µmol/L. Remarkably, this system combined with US therapy yielded a tumor inhibition rate of 90.9%, with 40% of tumor-bearing mice achieving complete eradication of tumors, while exhibiting low systemic toxicity. Collectively, this work not only identifies a novel sonosensitizer capable of generating •O 2 − but also develops a new class of ultrasound-activatable Pt(IV) nanoprodrug.