Fluorinated Proteolysis Targeting Chimeras-Sorafenib Nanoassembly for Epigenetic Remodeling to Combat Multi-Pathway...

Area of Science:

• Oncology
• Nanomedicine
• Epigenetics

Background:

• Sorafenib is standard first-line therapy for hepatocellular carcinoma (HCC).
• Prolonged sorafenib use leads to drug resistance, driven by tumor hypoxia and immunosuppression.
• Targeting epigenetic programs and immune checkpoints offers potential to overcome resistance.

Purpose of the Study:

• To develop a novel nanoassembly for enhanced HCC therapy.
• To investigate the efficacy of a fluorinated PROTAC-sorafenib nanoassembly (FCP@SF/FPro) in overcoming drug resistance.
• To elucidate the mechanisms by which FCP@SF/FPro improves anti-tumor response.

Main Methods:

• Fabrication of a fluorinated PROTAC-sorafenib nanoassembly (FCP@SF/FPro) integrating a BRD4-targeting PROTAC (FPro) and sorafenib within a fluorinated polymer matrix.
• Evaluation of FCP@SF/FPro's ability to degrade bromodomain-containing protein 4 (BRD4).
• Assessment of FCP@SF/FPro's effects on hypoxia-inducible factor 1-α (HIF-1α), programmed death-ligand 1 (PD-L1), and tumor-associated macrophage (TAM) polarization.
• In vitro and in vivo studies to evaluate tumor growth and metastasis inhibition.

Main Results:

• FCP@SF/FPro effectively degrades BRD4, inducing apoptosis and down-regulating HIF-1α to mitigate hypoxia.
• The nanoassembly relieves immunosuppression by reducing PD-L1 expression and increasing the M1/M2 TAM ratio.
• FCP@SF/FPro demonstrated potent inhibition of HCC growth and metastasis in vitro and in vivo.
• The dual-payload platform combines epigenetic reprogramming with immune-checkpoint relief for synergistic anti-tumor effects.

Conclusions:

• The fluorinated PROTAC-sorafenib nanoassembly (FCP@SF/FPro) represents a promising strategy for treating drug-resistant HCC.
• Degrading BRD4 and modulating the tumor microenvironment are key mechanisms for FCP@SF/FPro's efficacy.
• This innovative combination therapy holds significant potential for advancing HCC treatment.