Brd4 proteolysis-targeting chimera nanoparticles sensitized colorectal cancer chemotherapy

Bromodomain-Containing Protein 4 (BRD4) is a member of the BET family of bromodomains, which participates in gene transcription process and is closely related to tumor progression. We observed the up-regulated expression of BRD4 in colorectal cancer (CRC) after doxorubicin (DOX) treatment, which might be a potential mechanism for DOX resistance. This study constructed the tumor-targeting (cyclo (Arg-Gly-Asp-D-Phe-Lys)-poly(ethylene glycol)-poly(ε-caprolactone)) (cRGD-PEG-PCL) copolymer for co-delivery of DOX and BRD4 PROTAC degrader ARV-825 (ARV-DOX/cRGD-P) for CRC treatment. The ARV-DOX/cRGD-P complexes elicited synergistic anti-tumor effect via cell cycle arrest and the increased cell apoptosis, and mechanism studies implicated the regulation of proliferation- and apoptosis-related pathways in vitro. Moreover, the administration of ARV-DOX/cRGD-P significantly improved anti-tumor activity in subcutaneous colorectal tumors and colorectal intraperitoneal disseminated tumor models in mice by promoting tumor apoptosis, suppressing tumor proliferation and angiogenesis. Taken together, these data reveal that ARV-825 can heighten DOX sensitivity in CRC treatment and BRD4 is a potential therapeutic target for DOX-resistant CRC. The ARV-DOX/cRGD-P preparations have outstanding anti-cancer effects and may be used for clinical treatment of colorectal cancer in the future. Schematic illustration of the structure model about co-encapsulation of DOX and ARV-825 by cRGD-decorated nanoparticles (cRGD-P), and the processes of drug delivery in colorectal cancer-bearing mice. [Display omitted] •DOX induced upregulated expression of BRD4 in colorectal cancer cells.•The ARV-DOX/cRGD-P complexes inhibited tumor growth by blocking cell cycle and promoting cells apoptosis in vitro.•BRD4 degrading ARV sensitized anti-tumor effect of DOX.•cRGDfk peptides-modified nanoparticle improved anti-cancer effect in vivo.