Nanozyme-Mediated PROTACs Delivery for Targeted Protein Degradation and Ferroptosis Sensitization in Prostate Cancer

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Castration-resistant prostate cancer (CRPC) presents significant treatment challenges due to therapy resistance.
• Current androgen receptor (AR)-targeted therapies are often ineffective against CRPC.
• Proteolysis-targeting chimeras (PROTACs) offer potential but face delivery limitations.

Purpose of the Study:

• To develop a nanoengineered PROTAC platform for improved delivery and efficacy of ARV-771 in CRPC.
• To create a dual-action synergistic mechanism combining PROTAC-mediated degradation and ferroptosis induction.
• To evaluate the therapeutic potential of the nano-PROTAC system in preclinical CRPC models.

Main Methods:

• Fabrication of a nanoengineered PROTAC platform (ARV@MIL-HA-ss-HA) using MIL-101 nanoparticles and HA-ss-HA hydrogel.
• Utilizing MIL-101 as a nanozyme and HA-ss-HA for CD44-mediated tumor targeting and GSH-triggered release.
• Investigating the synergistic mechanism involving BRD4 degradation, ferroptosis induction via H2O2 conversion, and GSH depletion.

Main Results:

• The nano-PROTAC system demonstrated enhanced delivery and pharmacokinetics of ARV-771.
• Efficient BRD4 degradation and significant ferroptotic cell death were observed in CRPC models.
• Superior antitumor efficacy with minimal systemic toxicity was achieved in vitro and in vivo.

Conclusions:

• The developed nano-PROTAC platform effectively overcomes delivery challenges for PROTAC drugs.
• This dual-mechanism strategy synergistically enhances therapeutic efficacy against CRPC.
• The nano-PROTAC approach represents a promising new avenue for treating resistant prostate cancers.