Application of ultrasound-mediated adapalene-coated lysozyme-shelled microbubbles in UVA-induced skin photoaging

Photoaging, the premature aging of skin induced by ultraviolet rays, is characterized by wrinkling, roughness, laxity, and pigmentary changes. Various natural and synthetic retinoids have been explored for the treatment of aging. Among retinoids, adapalene (Ada, 0.3%) is one of the most potent and widely used drugs to treat photoaging. However, it causes irritant reactions that limit its acceptance by patients. Several studies have shown the applicability of Lysozyme (Lys)-shelled microbubbles (MBs) for drug delivery through sonophoresis, and recently we have shown its efficiency to treat inflammatory skin disease. Here, we report the construction of novel Ada-LysMBs based on opposite electric charges for combined effects to treat photoaging. The Ada-LysMBs were self-assembled and had a mean diameter of 2857 nm. The maximum loading efficiency of Ada onto LysMBs was 13.99 ± 0.59%. An acoustic power density of 3 W/cm(2) for 1 min revealing maximum penetration depth of LysMBs was optimized for further in vitro and in vivo studies of Ada-LysMBs. It was observed that in vitro Ada release from Ada-LysMBs at 6 h after ultrasound (US) treatment was more rapid at pH 7.4 (82%) than at pH 5.5 (73%). Franz diffusion experiments on isolated porcine skin indicated that US approximately doubled Ada delivery by Ada-LysMBs and Ada + LysMBs at 12 h and six-fold Lys permeation by LysMBs at 6 h, compared to these treatments alone. A 5-week in vivo study in mice identified significant wrinkle reduction in animals treated with US plus Ada-LysMBs. Our findings indicate that US may be used with Ada-LysMBs in the water phase to treat photoaging by normalizing hyperkeratinization and promoting collagen synthesis.