title: Ethyl cellulose nanocarriers and nanocrystals differentially deliver dexamethasone into intact, tape-stripped or sodium lauryl sulfate-exposed ex vivo human skin - assessment by intradermal microdialysis and extraction from the different skin layers.
abstract: Understanding penetration not only in intact, but also in lesional skin with impaired skin barrier function is important, in order to explore the surplus value of nanoparticle-based drug delivery for anti-inflammatory dermatotherapy. Herein, short-term ex vivo cultures of (i) intact human skin, (ii) skin pretreated with tape-strippings and (iii) skin pre-exposed to sodium lauryl sulfate (SLS) were used to assess the penetration of dexamethasone (Dex). Intradermal microdialysis was utilized for up to 24h after drug application as commercial cream, nanocrystals or ethyl cellulose nanocarriers applied at the therapeutic concentration of 0.05%, respectively. In addition, Dex was assessed in culture media and extracts from stratum corneum, epidermis and dermis after 24h, and the results were compared to those in heat-separated split skin from studies in Franz diffusion cells. Providing fast drug release, nanocrystals significantly accelerated the penetration of Dex. In contrast to the application of cream and ethyl cellulose nanocarriers, Dex was already detectable in eluates after 6h when applying nanocrystals on intact skin. Disruption of the skin barrier further accelerated and enhanced the penetration. Encapsulation in ethyl cellulose nanocarriers delayed Dex penetration. Interestingly, for all formulations highly increased concentrations in the dialysate were observed in tape-stripped skin, whereas the extent of enhancement was less in SLS-exposed skin. The results were confirmed in tissue extracts and were in line with the predictions made by in vitro release studies and ex vivo Franz diffusion cell experiments. The use of 45kDa probes further enabled the collection of inflammatory cytokines. However, the estimation of glucocorticoid efficacy by Interleukin (IL)-6 and IL-8 analysis was limited due to the trauma induced by the probe insertion. Ex vivo intradermal microdialysis combined with culture media analysis provides an effective, skin-sparing method for preclinical assessment of novel drug delivery systems at therapeutic doses in models of diseased skin.
authors.affiliation: Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany; Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany. Electronic address: nadine.doege@charite.de.
authors.forename: Nadine
authors.initials: N
authors.lastname: Döge
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany. Electronic address: stefan.hoenzke@fu-berlin.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hönzke
authors.affiliation: Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany; Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany. Electronic address: fabian.schumacher@uni-potsdam.de.
authors.forename: Fabian
authors.initials: F
authors.lastname: Schumacher
authors.affiliation: College of Pharmacy, Freie Universität Berlin, Berlin, Germany. Electronic address: balzus@zedat.fu-berlin.de.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Balzus
authors.affiliation: College of Pharmacy, Freie Universität Berlin, Berlin, Germany. Electronic address: mcolombo@zedat.fu-berlin.de.
authors.forename: Miriam
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: sabrina.hadam@charite.de.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Hadam
authors.affiliation: Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: fiorenza.rancan@charite.de.
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Rancan
authors.affiliation: Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: ulrike.blume-peytavi@charite.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Blume-Peytavi
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany. Electronic address: monika.schaefer-korting@fu-berlin.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
authors.affiliation: Institute of Chemistry and Biochemistry - Physical and Theoretical Chemistry, Freie Universität Berlin, Berlin, Germany. Electronic address: anke.schindler@fu-berlin.de.
authors.forename: Anke
authors.initials: A
authors.lastname: Schindler
authors.affiliation: Institute of Chemistry and Biochemistry - Physical and Theoretical Chemistry, Freie Universität Berlin, Berlin, Germany. Electronic address: ruehl@zedat.fu-berlin.de.
authors.forename: Eckart
authors.initials: E
authors.lastname: Rühl
authors.affiliation: RefLab, Copenhagen, Denmark; Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: pss@reflab.dk.
authors.forename: Per Stahl
authors.initials: PS
authors.lastname: Skov
authors.affiliation: Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: M.K.Church@soton.ac.uk.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Church
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany. Electronic address: sarah.hedtrich@fu-berlin.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hedtrich
authors.affiliation: Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany. Electronic address: kleuser@uni-potsdam.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: College of Pharmacy, Freie Universität Berlin, Berlin, Germany. Electronic address: bodmeier@zedat.fu-berlin.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Bodmeier
authors.affiliation: Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: annika.vogt@charite.de.
authors.forename: Annika
authors.initials: A
authors.lastname: Vogt
mesh_terms: D000279:Administration, Cutaneous; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002482:Cellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D017551:Microdialysis; D053758:Nanoparticles; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D012871:Skin Diseases / Q000378:metabolism; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004337:Drug Carriers; D005938:Glucocorticoids; D012967:Sodium Dodecyl Sulfate; D003907:Dexamethasone; C013517:ethyl cellulose; D002482:Cellulose
keywords: Dexamethasone; Drug delivery systems; Microdialysis; Polymeric nanoparticles; Skin barrier disruption; Skin penetration