Related Experiment Video
Updated: Aug 16, 2025
Facile Preparation and Photoactivation of Prodrug-Dye Nanoassemblies
Published on: February 17, 2023
Brd4 proteolysis-targeting chimera nanoparticles sensitized colorectal cancer chemotherapy
Yihong He1, Yan Ju2, Yuzhu Hu3
1Department of Pathophysiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China; Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Abstract:
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.
Insights
This study developed a novel nanoparticle (ARV-DOX/cRGD-P) to overcome doxorubicin (DOX) resistance in colorectal cancer (CRC). By targeting Bromodomain-Containing Protein 4 (BRD4), it enhances DOX efficacy and shows significant anti-tumor effects.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Bromodomain-Containing Protein 4 (BRD4) is upregulated in colorectal cancer (CRC) post-doxorubicin (DOX) treatment, contributing to DOX resistance.
- BRD4 plays a role in gene transcription and tumor progression, making it a potential therapeutic target in resistant cancers.
Purpose of the Study:
- To develop a tumor-targeting nanoparticle for co-delivery of DOX and a BRD4 degrader (ARV-825) to combat DOX-resistant CRC.
- To evaluate the synergistic anti-tumor effects and underlying mechanisms of the novel nanomedicine (ARV-DOX/cRGD-P).
Main Methods:
- Construction of a tumor-targeting copolymer (cRGD-PEG-PCL) for co-delivery of DOX and ARV-825.
- In vitro assessment of synergistic anti-tumor effects, including cell cycle arrest and apoptosis induction.
- In vivo evaluation in mouse models of subcutaneous and disseminated colorectal tumors.
Main Results:
- ARV-DOX/cRGD-P complexes demonstrated synergistic anti-tumor effects by inducing cell cycle arrest and apoptosis in vitro.
- Mechanism studies revealed regulation of proliferation- and apoptosis-related pathways.
- Significant suppression of tumor growth, promotion of apoptosis, and reduced angiogenesis were observed in vivo.
Conclusions:
- ARV-825 enhances DOX sensitivity in CRC, identifying BRD4 as a therapeutic target for DOX-resistant CRC.
- The developed ARV-DOX/cRGD-P nanomedicine exhibits potent anti-cancer effects and holds promise for future clinical application in colorectal cancer treatment.
