Ultrasound Controllable Release of Proteolysis Targeting Chimeras for Triple-Negative Breast Cancer Treatment

Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, which is highly aggressive and incurable. Here, we proposed an ultrasound activatable bromodomain-containing protein 4 (BRD4) proteolysis targeting chimera (PROTAC) release strategy for the first time for precisely controlled protein degradation in preclinical TNBC model. Through combination of PROTAC and ultrasound-targeted microbubble destruction (UTMD) technology, the present strategy also aims to concurrently solve the major limitations of poor loading capacity of microbubbles and undesirable targeting and membrane permeability of PROTAC. PROTAC (ARV-825)-encapsulated microbubbles, ARV-MBs, were developed for the efficacious treatment of TNBC in vitro and in vivo. The microbubbles we synthesized showed ultrasound-responsive drug release ability, which could effectively promote the penetration of PROTAC into tumor site and tumor cell. Under ultrasound, ARV-MBs could play an effective antitumor effect by potentiating the ubiquitination and degradation of BRD4 in tumor. The current study may provide a new idea for promoting clinical translation of drug-loaded microbubbles and PROTAC, and offer a new efficacious therapeutic modality for TNBC.