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

Hongye He; Feng Li; Rui Tang; Nianhong Wu; Ying Zhou; Yuting Cao; Can Wang; Li Wan; Yang Zhou; Hua Zhuang; Pan Li

doi:10.34133/bmr.0064

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

Biomater Res. 2024 Aug 13:28:0064. doi: 10.34133/bmr.0064. eCollection 2024.

Authors

Hongye He¹, Feng Li², Rui Tang¹, Nianhong Wu¹, Ying Zhou³, Yuting Cao¹, Can Wang⁴, Li Wan¹, Yang Zhou⁵, Hua Zhuang⁶, Pan Li¹

Affiliations

¹ Institute of Ultrasound Imaging & Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing 400010, China.
² Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
³ Department of Geriatrics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
⁴ Department of Ultrasound, The Third People's Hospital of Chengdu City, The Affiliated Hospital of Southwest Jiaotong University, Chengdu 610014, China.
⁵ Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, China.
⁶ Department of Ultrasound, The Ninth People's Hospital of Chongqing, Chongqing 400700, China.

Abstract

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.