Efficacy of topically applied rapamycin-loaded redox-sensitive nanocarriers in a human skin/T cell co-culture model

Rapamycin, also known as Sirolimus, is a promising anti-proliferative drug, but its therapeutic use for the topical treatment of inflammatory, hyperproliferative skin disorders is limited by insufficient penetration rates due to its high molecular weight (MW of 914.172 g/mol) and high lipophilicity. We have shown that core multi-shell (CMS) nanocarriers sensitive to oxidative environment can improve drug delivery to the skin. In this study, we investigated the mTOR inhibitory activity of these oxidation-sensitive CMS (osCMS) nanocarrier formulations in an inflammatory ex vivo human skin model. In this model, features of inflamed skin were introduced by treating the ex vivo tissue with low-dose serine protease (SP) and lipopolysaccharide (LPS), while phorbol 12-myristate 13-acetate and ionomycin were used to stimulate IL-17A production in the co-cultured SeAx cells. Furthermore, we tried to elucidate the effects of rapamycin on single cell populations isolated from skin (ker-atinocytes, fibroblast) as well as on SeAx cells. Further, we measured possible effects of the rapamycin formu-lations on dendritic cell (DC) migration and activation. The inflammatory skin model enabled the assessment of biological readouts at both the tissue and T cell level. All investigated formulations successfully delivered rapamycin across the skin as revealed by reduced IL-17A levels. Nevertheless, only the osCMS formulations reached higher anti-inflammatory effects in the skin compared to the control formulations with a significant downregulation of mTOR activity. These results indicate that osCMS formulations could help to establish rapamycin, or even other drugs with similar physico-chemical properties, in topical anti-inflammatory therapy.

Automated summary

Rapamycin, a potential anti-proliferative drug, has limitations in topical treatment of skin disorders due to its high molecular weight and lipophilicity. This study demonstrated that oxidation-sensitive CMS nanocarriers improved drug delivery to the skin and showed mTOR inhibitory activity in an inflammatory ex vivo human skin model. The osCMS formulations achieved higher anti-inflammatory effects and downregulated mTOR activity, suggesting their potential use in topical anti-inflammatory therapy.