Accelerated Mechanophore Activation and Drug Release in Network Core‐Structured Star Polymers Using High‐Intensity Focused Ultrasound

The ultrasound (US)‐induced activation of mechanophores embedded in linear polymers (LPs) is the most widely employed technique to realize chemical function by polymer mechanochemistry. However, the commonly used US frequency in this context is around 20 kHz, producing strong inertial cavitation limiting biomedical applicability. Herein, 20 kHz US and 1.5 MHz high‐intensity focused US (HIFU) are investigated to drive disulfide mechanophore activation and mechanochemical polymer chain scission in network core‐structured star polymers (NCSPs). It is found that the efficiency of activating disulfide mechanophores in NCSPs using 1.5 MHz HIFU irradiation is similar to the efficiency achieved with 20 kHz sonication. This is quantified by ‘turn on’ sensor molecules leveraging the Michael addition of the mechanochemically generated thiol groups and subsequent retro Diels–Alder reaction to release a fluorophore. Moreover, the anticancer drug doxorubicin (Dox) covalently loaded into NCSPs is efficiently released by 1.5 MHz HIFU. Finally, an in vitro study of drug release from NCSPs is performed, demonstrating the potential of HIFU‐activated polymer mechanochemistry for sonopharmacology.