Development of a Novel Peptide-Caffeic Acid Conjugate with Enhanced Anti-Photoaging Properties: Efficacy, Transdermal Permeation, and Stability

Caffeoyl hexapeptide-9 (CH-9) is a novel cosmetic peptide designed by conjugating hexapeptide-9 (H-9), a known collagen-mimetic peptide with established skin anti-aging activity, with caffeic acid (CA) via an amide bond, leveraging peptide-drug conjugate (PDC) design principles. In ultraviolet (UV)-irradiated cellular and skin models, CH-9 outperformed H-9 in preserving cell viability, restoring collagen types I, III, and IV, and suppressing interleukin-6 and -8 secretion. Additionally, its direct antioxidant activity, absent in H-9, was demonstrated in vitro by scavenging of hydroxyl and peroxyl radicals. Molecular docking indicated CH-9 interacted with the catalytic domain of matrix metalloproteinase 2 (MMP2), a key enzyme in collagen degradation during photoaging, suggesting a potential inhibition of its activity. Molecular dynamics (MD) simulations revealed an improved insertion of CH-9 into a stratum corneum (SC) lipid bilayer compared to H-9, consistent with enhanced skin permeation in vivo. Moreover, CH-9 exhibited improved aqueous and cosmetic serum stability over CA. In a 28-day clinical study, topical application of CH-9 significantly improved skin elasticity and firmness compared to H-9. This work demonstrates that the PDC-based conjugate CH-9 combines enhanced anti-photoaging efficacy with improved transdermal permeation and stability, highlighting a promising strategy for the development of advanced cosmetic ingredients.