Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy

Area of Science:

• Biochemistry
• Materials Science
• Oncology

Background:

• Metal-based chemotherapeutics, like cisplatin, are crucial in cancer treatment but cause side effects.
• Redox-active copper (Cu) complexes are explored as alternatives, facing challenges in solubility and delivery.
• Previous work established a Cu(II) scaffold with reactive oxygen species (ROS)-mediated cytotoxicity.

Purpose of the Study:

• To enhance the anticancer activity of a Cu(II) scaffold by functionalization.
• To improve aqueous solubility and intracellular delivery without altering the ROS-generating Cu(II) center.
• To investigate structure-activity relationships for redox-active metal-based anticancer agents.

Main Methods:

• Synthesis and characterization of sulfonate, arginine, and cell-penetrating peptide (CPP) derivatives of a Cu(II) complex.
• In vitro cytotoxicity assays across multiple cancer cell lines.
• Immunofluorescence microscopy to track intracellular localization.

Main Results:

• All derivatives maintained the parent Cu(II) core and redox capabilities.
• Solubility-enhancing modifications (sulfonate, arginine) did not improve cytotoxicity.
• CPP-conjugation significantly enhanced anticancer activity and intracellular copper delivery.
• Cu(II) peptide-conjugates showed cytosolic distribution, avoiding lysosomal entrapment.

Conclusions:

• Cell-penetrating peptide conjugation is a viable strategy to improve the efficacy of redox-active Cu(II) anticancer agents.
• Targeted intracellular delivery via CPPs potentiates ROS-mediated cytotoxicity.
• Understanding structure-activity relationships guides the rational design of improved metal-based cancer therapies.