Topical Delivery of Rapamycin by Means of Microenvironment-Sensitive Core-Multi-Shell Nanocarriers: Assessment of Anti-Inflammatory Activity in an ex vivo Skin/T Cell Co-Culture Model

Autor: Rancan F, Guo X, Rajes K, Sidiropoulou P, Zabihi F, Hoffmann L, Hadam S, Blume-Peytavi U, Rühl E, Haag R, Vogt A
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: International Journal of Nanomedicine, Vol Volume 16, Pp 7137-7151 (2021)
ISSN: 1178-2013
Popis: Fiorenza Rancan,1 Xiao Guo,1 Keerthana Rajes,2 Polytimi Sidiropoulou,1 Fatemeh Zabihi,2 Luisa Hoffmann,1 Sabrina Hadam,1 Ulrike Blume-Peytavi,1 Eckart Rühl,3 Rainer Haag,2 Annika Vogt1 1Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 2Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany; 3Physical Chemistry, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, GermanyCorrespondence: Fiorenza RancanClinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charitéplatz 1, Berlin, 10117, GermanyTel +49 30 450 518 347Fax +49 30 450 518 952Email fiorenza.rancan@charite.deIntroduction: Rapamycin (Rapa) is an immunosuppressive macrolide that inhibits the mechanistic target of rapamycin (mTOR) activity. Thanks to its anti-proliferative effects towards different cell types, including keratinocytes and T cells, Rapa shows promise in the treatment of skin diseases characterized by cell hyperproliferation. However, Rapa skin penetration is limited due to its lipophilic nature (log P = 4.3) and high molecular weight (MW = 914 g/mol). In previous studies, new microenvironment-sensitive core multishell (CMS) nanocarriers capable of sensing the redox state of inflamed skin were developed as more efficient and selective vehicles for macrolide delivery to inflamed skin.Methods: In this study, we tested such redox-sensitive CMS nanocarriers using an inflammatory skin model based on human skin explants co-cultured with Jurkat T cells. Serine protease (SP) was applied on skin surface to induce skin barrier impairment and oxidative stress, whereas phytohaemagglutinin (PHA), IL-17A, and IL-22 were used to activate Jurkat cells. Activation markers, such as CD45 and CD69, phosphorylated ribosomal protein S6 (pRP-S6), and IL-2 release were monitored in activated T cells, whereas pro-inflammatory cytokines were measured in skin extracts and culture medium.Results: We found that alteration of skin barrier proteins corneodesmosin (CDSN), occludin (Occl), and zonula occludens-1 (ZO-1) as well as oxidation-induced decrease of free thiol groups occurred upon SP-treatment. All Rapa formulations exerted inhibitory effects on T cells after penetration across ex vivo skin. No effects on skin inflammatory markers were detected. The superiority of the oxidative-sensitive CMS nanocarriers over the other formulations was observed with regard to drug delivery as well as downregulation of IL-2 release.Conclusion: Overall, our results demonstrate that nanocarriers addressing features of diseased skin are promising approaches to improve the topical delivery of macrolide drugs.Keywords: redox-sensitive nanoparticles, sirolimus, psoriasis, stratum corneum barrier, dermatology, drug release
Databáze: OpenAIRE