Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergology, Charité - Universitätsmedizin Berlin, Germany.
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
Int Immunopharmacol. 2023 Apr;117:109903. doi: 10.1016/j.intimp.2023.109903. Epub 2023 Feb 27.
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 (keratinocytes, fibroblast) as well as on SeAx cells. Further, we measured possible effects of the rapamycin formulations 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.
雷帕霉素，也称为西罗莫司，是一种有前途的抗增殖药物，但由于其分子量（914.172 g/mol）高且亲脂性高，导致渗透速率不足，限制了其在治疗炎症性、过度增生性皮肤病方面的应用。我们已经证明，对氧化环境敏感的核心多壳（CMS）纳米载体可以改善药物向皮肤的传递。在这项研究中，我们研究了这些氧化敏感 CMS（osCMS）纳米载体配方在炎症性离体人皮肤模型中的 mTOR 抑制活性。在该模型中，通过用低剂量丝氨酸蛋白酶（SP）和脂多糖（LPS）处理离体组织来引入炎症皮肤的特征，同时用佛波醇 12-肉豆蔻酸 13-乙酸酯和离子霉素刺激共培养的 SeAx 细胞中 IL-17A 的产生。此外，我们试图阐明雷帕霉素对从皮肤（角质形成细胞、成纤维细胞）分离的单细胞群以及 SeAx 细胞的影响。此外，我们测量了雷帕霉素制剂对树突状细胞（DC）迁移和激活的可能影响。炎症皮肤模型能够在组织和 T 细胞水平上评估生物学读出值。所有研究的配方都成功地将雷帕霉素递送到皮肤中，这表现为 IL-17A 水平降低。然而，只有 osCMS 配方在皮肤中达到了比对照配方更高的抗炎效果，mTOR 活性显著下调。这些结果表明，osCMS 配方可能有助于将雷帕霉素甚至其他具有类似物理化学性质的药物应用于局部抗炎治疗。
