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

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–Universitätsmed...

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Autores principales:	Rancan F, Guo X, Rajes K, Sidiropoulou P, Zabihi F, Hoffmann L, Hadam S, Blume-Peytavi U, Rühl E, Haag R, Vogt A
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	redox-sensitive nanoparticles sirolimus psoriasis stratum corneum barrier dermatology drug release Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/2a08026e4d67461d9410043d7230818d
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spelling	oai:doaj.org-article:2a08026e4d67461d9410043d7230818d2021-12-02T18:37:21ZTopical 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 Model1178-2013https://doaj.org/article/2a08026e4d67461d9410043d7230818d2021-10-01T00:00:00Zhttps://www.dovepress.com/topical-delivery-of-rapamycin-by-means-of-microenvironment-sensitive-c-peer-reviewed-fulltext-article-IJNhttps://doaj.org/toc/1178-2013Fiorenza 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 releaseRancan FGuo XRajes KSidiropoulou PZabihi FHoffmann LHadam SBlume-Peytavi URühl EHaag RVogt ADove Medical Pressarticleredox-sensitive nanoparticlessirolimuspsoriasisstratum corneum barrierdermatologydrug releaseMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 7137-7151 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	redox-sensitive nanoparticles sirolimus psoriasis stratum corneum barrier dermatology drug release Medicine (General) R5-920
spellingShingle	redox-sensitive nanoparticles sirolimus psoriasis stratum corneum barrier dermatology drug release Medicine (General) R5-920 Rancan F Guo X Rajes K Sidiropoulou P Zabihi F Hoffmann L Hadam S Blume-Peytavi U Rühl E Haag R Vogt A 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
description	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
format	article
author	Rancan F Guo X Rajes K Sidiropoulou P Zabihi F Hoffmann L Hadam S Blume-Peytavi U Rühl E Haag R Vogt A
author_facet	Rancan F Guo X Rajes K Sidiropoulou P Zabihi F Hoffmann L Hadam S Blume-Peytavi U Rühl E Haag R Vogt A
author_sort	Rancan F
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/2a08026e4d67461d9410043d7230818d
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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

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