Design and Characterization of a Multifunctional pH-Triggered Peptide C8 for Selective Anticancer Activity

Area of Science:

• Biochemistry
• Materials Science
• Nanotechnology

Background:

• Current drug delivery systems often lack synergistic therapeutic actions.
• Targeting and on-demand strategies are common but rarely combined with inherent cytotoxicity.
• Developing multifunctional carriers is crucial for improved cancer treatment.

Purpose of the Study:

• To develop a cationic, pH-triggered anticancer peptide (C8) with self-assembly and drug delivery capabilities.
• To engineer a peptide that exhibits tunable cytotoxicity based on pH-dependent self-assembly.
• To investigate C8's potential as a selective anticancer agent and drug carrier.

Main Methods:

• Design of C8 peptide incorporating histidine-mediated pH-sensitivity, amphipathic helix, and amino acid pairing.
• Evaluation of C8's cytotoxicity on various cancer and non-cancerous cell lines.
• Liposome leakage assays and multiscale computer simulations to elucidate mechanisms of action.
• Complexation of C8 with ellipticine for drug delivery studies.

Main Results:

• C8 self-assembles into non-cytotoxic β-sheet fibers at high pH and cytotoxic, membrane-lytic monomers at low pH.
• Selective cytotoxicity of C8 was demonstrated against three cancer cell lines compared to two non-cancerous cell lines.
• Mechanisms of pore formation and selectivity were proposed, linked to lipid membrane composition and hydrogen bonding.
• C8 formed a nanocomplex with ellipticine, achieving pH-responsive, targeted delivery with enhanced efficacy and selectivity.

Conclusions:

• C8 represents a novel multifunctional self-assembling peptide with on-demand cytotoxicity.
• The peptide's pH-responsive nature allows for selective targeting of cancer cells.
• C8 shows significant potential as a therapeutic agent and a carrier for enhanced drug delivery in cancer treatment.