PDF(Pubmed)
Abstract：
Topical therapy remains a critical component in the management of immune‑mediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroid‑free therapeutic alternatives. Despite their potential for skin‑selective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrier‑based delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential anti‑inflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these \'hard‑to‑formulate\' macromolecules in the context of psoriasis and atopic dermatitis.
摘要：
局部治疗仍然是治疗免疫介导的炎症性皮肤病如银屑病和特应性皮炎的关键组成部分。在这个领域,大分子内酰胺免疫调节剂，包括钙调磷酸酶和哺乳动物雷帕霉素抑制剂，可以提供无类固醇的治疗替代方案。尽管与局部皮质类固醇相比，它们具有皮肤选择性治疗的潜力，这些化合物的物理化学性质，如高亲脂性和大的分子尺寸，不符合有效渗透皮肤的标准，尤其是传统的主题载体。因此，需要更复杂的方法来解决传统制剂的药代动力学局限性.在这方面,人们的兴趣越来越集中在纳米颗粒系统上,以优化渗透动力学并增强局部钙调磷酸酶和mTOR抑制剂在发炎皮肤中的疗效和安全性。已经探索了几种类型的纳米载体作为局部载体在银屑病和特应性皮肤中递送他克莫司，虽然在发炎的皮肤中基于纳米载体的局部西罗莫司的临床前数据也正在出现。鉴于有希望的初步结果和药物在发炎的皮肤上的输送的复杂性，需要进一步的研究将这些纳米疗法转化为炎症性皮肤病的临床环境。本综述概述了局部钙调磷酸酶和mTOR抑制剂的皮肤动力学特征，尤其是他克莫司,吡美莫司和西罗莫司,专注于它们在银屑病和特应性皮肤中的渗透动力学。它还总结了局部西罗莫司的潜在抗炎益处，并探索了研究皮肤应用纳米载体以评估和优化皮肤递送的新型临床前研究。在牛皮癣和特应性皮炎的背景下，这些难以配制的大分子的有效性和安全性。
