Targeted disruption of the BCL9/β-catenin interaction by endosomal-escapable nanoparticles functionalized with an...

Area of Science:

• Oncology
• Nanotechnology
• Molecular Biology

Background:

• The Wnt/β-catenin signaling pathway is crucial in multiple cancers, driving tumor progression.
• Targeting this pathway presents a significant therapeutic opportunity for anticancer drug development.
• Existing peptide therapeutics face challenges like poor stability and cell penetration.

Purpose of the Study:

• To develop a potent and selective β-catenin antagonist using a peptide derived from E-cadherin region V (cECRV).
• To enhance the delivery and stability of cECRV using gold nanoparticles (AuNPs) for intracellular targeting.
• To evaluate the efficacy and safety of the nanoparticle-drug conjugate (pAuNP-cECRV) in cancer cells.

Main Methods:

• Design and synthesis of a gold nanoparticle (AuNP)-based nanocarrier for peptide delivery.
• Conjugation of the therapeutic peptide cECRV to AuNPs to form pAuNP-cECRV.
• Assessment of pAuNP-cECRV's cytotoxicity on normal cells and its effects on Wnt-hyperactive cancer cells, including cell cycle analysis and apoptosis assays.

Main Results:

• The developed nanoparticle, pAuNP-cECRV, demonstrated no cytotoxicity against normal peripheral blood mononuclear cells.
• pAuNP-cECRV successfully induced cell cycle arrest and apoptosis in Wnt-hyperactive cancer cells.
• The mechanism involved antagonizing β-catenin and inhibiting the Wnt signaling pathway.

Conclusions:

• pAuNP-cECRV effectively delivers the therapeutic peptide cECRV into cancer cells.
• This novel nanocarrier system overcomes peptide delivery limitations, showing significant potential for cancer therapy.
• The findings highlight pAuNP-cECRV as a safe and efficient vector for targeted anticancer treatment.