Ultrasound-triggered prodrug activation via sonochemically induced cleavage of a 3,5-dihydroxybenzyl carbamate scaffold.

Spatiotemporal control of drug release in deep tissues is crucial for targeted treatment precision and minimized systemic side effects. Ultrasound is a non-invasive and clinically safe stimulus capable of deep-tissue penetration without requiring optical transparency. Here, we introduce an innovative strategy for controlling cargo release via ultrasound-triggered sonochemical cleavage of a 3,5-dihydroxybenzyl carbamate (DHBC) prodrug platform. We demonstrate that low-intensity therapeutic ultrasound (LITUS) effectively generates hydroxyl radicals in aqueous solutions, which hydroxylate DHBC to initiate spontaneous cleavage and cargo release. Using a prototype chemotherapy prodrug (ProDOX) as a proof-of-concept, we show that LITUS irradiation triggers doxorubicin release to kill cancer cells in vitro. Remarkably, this sonochemical activation was successfully achieved through 2 cm of chicken breast, highlighting the deep-penetrating capability of our approach. Extending this strategy, we developed ProR848, a sono-activable prodrug of the Toll-like receptors (TLR) agonist R848, enabling remotely triggered, on-demand immune cell activation. Collectively, our results establish a novel and versatile sonochemical cleavage platform for ultrasound-targeted prodrug activation, offering significant potential for applications including controlled therapeutic release and responsive biomaterials.