Ultrasound-Triggered Activation of <i>p</i>-Azidobenzyloxycarbonyl-Based Prodrugs via Radical-Mediated Cascade Elimination

Selective prodrug activation at tumor sites through noninvasive external stimuli represents a promising strategy in enhancing the therapeutic index. Here, we report a <i>p</i>-azidobenzyloxycarbonyl (PAzBC)-based prodrug platform activated by physiotherapy-grade ultrasound (2.0 W/cm², 1 MHz) through radical-mediated cascade elimination. Mechanistic studies reveal that ultrasound initiates single-electron-transfer (SET) and hydrogen-atom-transfer (HAT) processes, enabling efficient azide-to-amine reduction. This activation is further amplified by superoxide anion radicals generated via acoustic sensitizers, as confirmed by DFT calculations and radical trapping experiments. The PAzBC platform demonstrates broad applicability with diverse drug functionalities (amino, hydroxyl, sulfhydryl), achieving >99% azide reduction efficiency and approximately 40% active drug release under optimized sonication conditions. Cellular studies reveal a 4.1-115.5-fold reduction in prodrug toxicity and a 11.9-169.5-fold enhancement in selective activation, highlighting its potential for clinical translation. This work establishes a robust platform for spatiotemporally controlled drug delivery, advancing the field of ultrasound-mediated precision cancer therapy.