Guanidinium-rich scyllo-inositol molecular transporter enables enhanced transdermal and intracellular delivery of vitagen.

Transdermal drug delivery (TDD) is a non-invasive and painless drug delivery method, making it a compelling alternative to conventional methods, such as oral intake and intravenous injection. Although TDD holds promise, it faces challenges owing to the complex structure of the human skin. In particular, the stratum corneum (SC) serves as a significant barrier to drug absorption, hindering the passage of larger molecules. The TDD of vitagen, a stable L-ascorbic acid derivative with antioxidant properties, remains challenging because of its limited skin permeability. To address this issue, we prepared an ionic complex between vitagen and a synthesized guanidine-rich molecular transporter, scyllo-inositol-G6 (scyllo-G6), as a permeation enhancer (vitagen/scyllo-G6). This ionic complex showed improved skin permeability compared to vitagen alone with negligible cytotoxicity, indicating that the molecular transporter is biocompatible. Franz cell diffusion experiments demonstrated that scyllo-G6 exhibited a higher penetration coefficient with vitagen than other common penetration enhancers, such as oleic acid and menthol. Additionally, our findings revealed that the vitagen/scyllo-G6 complex had a notably greater inhibition effect on intracellular reactive oxygen species (ROS) than when vitagen was complexed to other permeation enhancers. Furthermore, FITC-labelled vitagen (FITC-vitagen) complexed with scyllo-G6 (FITC-vitagen/scyllo-G6) exhibited improved cellular uptake and penetrated deeper into tissue sections in a mouse model than FITC-vitagen conjugated to an arginine hexamer (Arg6), indicating that scyllo-G6 is a more effective skin penetration enhancer than Arg6. These findings suggest that utilizing scyllo-G6 as molecular transporter to enhance the skin permeability of vitagen is a promising strategy for TDD of vitagen.