PROTAC-based nanoassemblies targeting BRD4 for potentiate FLASH radiosensitization therapy.

Area of Science:

• Oncology
• Nanomedicine
• Radiotherapy

Background:

• Ultrahigh dose-rate radiotherapy (FLASH-RT) offers normal tissue sparing but faces challenges with tumor radioresistance.
• Targeted protein degradation presents a novel strategy to overcome treatment resistance in cancer therapy.

Purpose of the Study:

• To develop a redox-responsive nanoplatform (APF) for targeted delivery of a PROTAC (ARV-771) to enhance FLASH-RT efficacy.
• To investigate the mechanism of APF in sensitizing tumors to FLASH-RT through BRD4 degradation and disruption of DNA repair pathways.

Main Methods:

• Self-assembly of folate-conjugated PEG2000-ARV-771 into APF nanoparticles.
• FA-mediated tumor cell targeting and endocytic uptake, followed by glutathione-triggered release of ARV-771.
• Assessment of APF-assisted FLASH-RT efficacy in vitro and in vivo, including apoptosis, necrosis, ROS generation, and DNA damage analysis.

Main Results:

• APF nanoparticles successfully delivered ARV-771, leading to proteasomal degradation of BRD4.
• BRD4 degradation disrupted the BRD4-c-Myc-RAD51AP1 pathway and suppressed DNA repair genes, sensitizing tumors to FLASH-RT.
• APF@FLASH-RT combination therapy demonstrated significant tumor inhibition with reduced systemic toxicity and enhanced cancer cell killing.

Conclusions:

• The novel APF nanoplatform effectively overcomes tumor radioresistance by targeting BRD4 degradation.
• APF enhances FLASH-RT efficacy through ROS generation and DNA damage, offering a promising strategy for improved cancer treatment.
• This nanomedicine approach holds potential for advancing FLASH radiotherapy in clinical oncology.