Dually functionalized dendrimer for stimuli-responsive release of active ingredients into the skin

Abstract

The skin, our largest organ, protects against environmental dangers but is vulnerable to various conditions like infections, eczema, dermatitis, psoriasis, skin cancer, and age-related collagen and elastin degradation. Its outer layer, the water-impermeable epidermis, presents challenges for passive drug delivery to the lower living layers of the skin. An ideal dermal delivery system should penetrate the epidermis and release treatments over time. We report a stimuli-activated nanocarrier that slowly releases active ingredients under skin-specific conditions. Using a fourth-generation polyamidoamine (PAMAM), dendrimer functionalized with poly(2-ethyl-2-oxazoline) and palmitoyl pentapeptide-4, we show a controlled release of biologically active therapeutics into the dermis of the skin for 24 h. Ex vivo studies demonstrate that our nanocarrier system delivers cargo to the dermis and is non-toxic to skin fibroblasts. As a proof of principle, we demonstrate a system that effectively enhances collagen production in human dermal fibroblasts by co-delivering all-trans retinol and palmitoyl pentapeptide-4. Our nanosystem surpasses the effects of individual components. This nanocarrier offers a promising approach for targeted dermal delivery, potentially improving treatment efficacy for various skin conditions while minimizing adverse effects associated with traditional formulations.

Statement of Significance

In this manuscript we introduce a stimuli-responsive nanocarrier based on a G4-PAMAM dendrimer functionalized with poly(2-ethyl-2-oxazoline) (POZ) and palmitoyl pentapeptide-4, designed to deliver biomolecules specifically to the skin. The nanocarrier enables controlled, stimuli-triggered release under skin-specific conditions (pH 5, 37 °C), enhancing dermal penetration and minimizing release at neutral pH or lower temperatures. This work improves traditional dendrimer systems by reducing toxicity through POZ, ensuring controlled delivery without invasive techniques like iontophoresis, and co-delivering both a small molecule (all-trans-retinol) and a collagen-stimulating peptide for enhanced therapeutic effects. This system addresses major drug delivery challenges, sets a new precedent for safer, multifunctional nanomaterials, and advances dendrimer chemistry, opening new possibilities in targeted therapies, skin treatments, and materials science.