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

Triple-negative breast cancer (TNBC) is a highly aggressive and currently incurable subtype of breast cancer. In this study, we introduce, for the first time, an ultrasound-activatable strategy to release bromodomain-containing protein 4 (BRD4) proteolysis targeting chimera (PROTAC) for precise and controlled protein degradation in a preclinical TNBC model. By integrating PROTAC with ultrasound-targeted microbubble destruction (UTMD) technology, this approach addresses two major challenges: the limited drug-loading capacity of microbubbles and the suboptimal targeting and membrane permeability of PROTACs.

We developed PROTAC (ARV-825)-encapsulated microbubbles, termed ARV-MBs, for the effective treatment of TNBC both in vitro and in vivo. These microbubbles demonstrated ultrasound-responsive drug release, facilitating the targeted delivery and enhanced penetration of PROTAC into tumor sites and tumor cells. Upon ultrasound activation, ARV-MBs significantly enhanced BRD4 ubiquitination and degradation in tumor cells, exerting potent antitumor effects. This study provides a novel approach for advancing the clinical translation of drug-loaded microbubbles and PROTACs, offering a promising therapeutic strategy for TNBC.