Tumor-Specific Protein Induced in Situ Self-Assembly of Peptide Drugs for Synergistic Mitochondria Disruption

Area of Science:

• Biochemistry
• Nanotechnology
• Oncology

Background:

• Mitochondria-targeted cancer therapy shows promise but faces challenges from tumor cell repair mechanisms.
• Tumor cells possess repair pathways that counteract mitochondrial damage induced by therapies.

Purpose of the Study:

• To design a peptide nanomaterial (RC-K-FX) utilizing intracellular self-assembly to overcome mitochondrial repair mechanisms in cancer cells.
• To investigate the therapeutic potential of inhibiting MUC1-C dimerization and mitochondrial repair simultaneously.

Main Methods:

• Development of RC-K-FX, a peptide nanomaterial designed for intracellular self-assembly.
• Inhibition of MUC1-C dimerization and mitochondrial repair pathways within tumor cells.
• Evaluation of anti-tumor effects, including mitochondrial destruction, redox balance disruption, and inhibition of NF-κB and EMT pathways.
• Assessment of in vivo anti-tumor activity and survival in tumor-bearing mice after intravenous administration.

Main Results:

• RC-K-FX self-assembles into a stable structure upon binding to MUC1-C, inhibiting its function and blocking mitochondrial repair.
• The peptide induces mitochondrial damage, disrupts redox balance, increases reactive oxygen species (ROS), and inhibits the NF-κB pathway and epithelial-mesenchymal transition (EMT).
• Intravenous administration of RC-G-FX demonstrated accumulation at tumor sites, enhanced anti-tumor effects, and prolonged survival in mice.

Conclusions:

• The combination of in situ self-assembly of peptide drugs and targeting mitochondrial repair offers a potent strategy for cancer therapy.
• This approach effectively targets tumor cells by disrupting essential cellular processes and overcoming resistance mechanisms.