PMID- 34712046 OWN - NLM STAT- MEDLINE DCOM- 20211124 LR - 20220427 IS - 1178-2013 (Electronic) IS - 1176-9114 (Print) IS - 1176-9114 (Linking) VI - 16 DP - 2021 TI - 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. PG - 7137-7151 LID - 10.2147/IJN.S330716 [doi] AB - INTRODUCTION: 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. CI - (c) 2021 Rancan et al. FAU - Rancan, Fiorenza AU - Rancan F AUID- ORCID: 0000-0003-3903-3240 AD - Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, Germany. FAU - Guo, Xiao AU - Guo X AUID- ORCID: 0000-0002-0999-0261 AD - Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, Germany. FAU - Rajes, Keerthana AU - Rajes K AUID- ORCID: 0000-0002-0395-7495 AD - Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Sidiropoulou, Polytimi AU - Sidiropoulou P AUID- ORCID: 0000-0002-4987-2999 AD - Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, Germany. FAU - Zabihi, Fatemeh AU - Zabihi F AD - Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Hoffmann, Luisa AU - Hoffmann L AD - Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, Germany. FAU - Hadam, Sabrina AU - Hadam S AD - Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, Germany. FAU - Blume-Peytavi, Ulrike AU - Blume-Peytavi U AD - Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, Germany. FAU - Ruhl, Eckart AU - Ruhl E AD - Physical Chemistry, Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Haag, Rainer AU - Haag R AD - Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Vogt, Annika AU - Vogt A AD - Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, Germany. LA - eng PT - Journal Article DEP - 20211022 PL - New Zealand TA - Int J Nanomedicine JT - International journal of nanomedicine JID - 101263847 RN - 0 (Anti-Inflammatory Agents) RN - 0 (CDSN protein, human) RN - 0 (Drug Carriers) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 7S5I7G3JQL (Dexamethasone) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Administration, Cutaneous MH - Anti-Inflammatory Agents/metabolism MH - Coculture Techniques MH - Dexamethasone MH - Drug Carriers/metabolism MH - Humans MH - Intercellular Signaling Peptides and Proteins/metabolism MH - *Nanoparticles MH - Sirolimus MH - Skin/metabolism MH - *Skin Absorption PMC - PMC8548260 OTO - NOTNLM OT - dermatology OT - drug release OT - psoriasis OT - redox-sensitive nanoparticles OT - sirolimus OT - stratum corneum barrier COIS- Dr Fiorenza Rancan reports grants from Deutsche Forschungsgemeinschaft, during the conduct of the study. Ms Keerthana Rajes reports grants from Verein Chemischer Industrie, grants from Deutsche Forschungsgemeinschaft, during the conduct of the study. Prof. Dr. Ulrike Blume-Peytavi reports grants from Pfizer, personal fees from Galderma, personal fees from Sanofi Regeneron, personal fees from Vichy, personal fees from Boots Healthcare, outside the submitted work; The authors report no other conflicts of interest in this work. EDAT- 2021/10/30 06:00 MHDA- 2021/11/25 06:00 PMCR- 2021/10/22 CRDT- 2021/10/29 06:23 PHST- 2021/07/27 00:00 [received] PHST- 2021/09/09 00:00 [accepted] PHST- 2021/10/29 06:23 [entrez] PHST- 2021/10/30 06:00 [pubmed] PHST- 2021/11/25 06:00 [medline] PHST- 2021/10/22 00:00 [pmc-release] AID - 330716 [pii] AID - 10.2147/IJN.S330716 [doi] PST - epublish SO - Int J Nanomedicine. 2021 Oct 22;16:7137-7151. doi: 10.2147/IJN.S330716. eCollection 2021.