MMP-2-triggered, mitochondria-targeted PROTAC-PDT therapy of breast cancer and brain metastases inhibition
Fan Tong, Yufan Wang, Yanyan Xu, Yang Zhou, Siqin He, Yufan Du, Wenqin Yang, Ting Lei, Yujun Song, Tao Gong, Huile Gao
Abstract
Proteolytic targeting chimera (PROTAC) technology is a protein-blocking technique and induces antitumor effects, with potential advantages. However, its effect is limited by insufficient distribution and accumulation in tumors. Herein, a transformable nanomedicine (dBET6@CFMPD) with mitochondrial targeting capacity is designed and constructed to combine PROTAC with photodynamic therapy (PDT). In this work, we demonstrate that dBET6@CFMPD exhibits great biodistribution and retention, and can induce potent antitumor response to suppress primary and metastatic tumors, becoming a nanomedicine with potential in cancer combination therapy. Proteolytic targeting chimera (PROTAC) methodology is promising for cancer therapy but limited by the insufficient distribution and accumulation in most tumors. Here the authors assemble Ce6 and mitochondrial-targeting peptide into PROTAC agent dBET6 to achieve enhanced accumulation in tumor cells and subsequent BRD4 degradation, apoptosis induction thereby elicit its anti-cancer treatment.