Serine Protease-Mediated Cutaneous Inflammation: Characterization of an Ex Vivo Skin Model for the Assessment of Dexamethasone-Loaded Core Multishell-Nanocarriers
Janna Frombach,
Fiorenza Rancan,
Katharina Kübrich,
Fabian Schumacher,
Michael Unbehauen,
Ulrike Blume-Peytavi,
Rainer Haag,
Burkhard Kleuser,
Robert Sabat,
Kerstin Wolk,
Annika Vogt
Affiliations
Janna Frombach
Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Fiorenza Rancan
Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Katharina Kübrich
Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Fabian Schumacher
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany
Michael Unbehauen
Organic Chemistry, Institute of Chemistry and Biochemistry, Freie Universitaet Berlin, 14195 Berlin, Germany
Ulrike Blume-Peytavi
Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Rainer Haag
Organic Chemistry, Institute of Chemistry and Biochemistry, Freie Universitaet Berlin, 14195 Berlin, Germany
Burkhard Kleuser
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany
Robert Sabat
Psoriasis Research and Treatment Center, Department of Dermatology, Venerology and Allergy/Institute for Medical Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Kerstin Wolk
Psoriasis Research and Treatment Center, Department of Dermatology, Venerology and Allergy/Institute for Medical Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Annika Vogt
Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Standard experimental set-ups for the assessment of skin penetration are typically performed on skin explants with an intact skin barrier or after a partial mechanical or chemical perturbation of the stratum corneum, but they do not take into account biochemical changes. Among the various pathological alterations in inflamed skin, aberrant serine protease (SP) activity directly affects the biochemical environment in the superficial compartments, which interact with topically applied formulations. It further impacts the skin barrier structure and is a key regulator of inflammatory mediators. Herein, we used short-term cultures of ex vivo human skin treated with trypsin and plasmin as inflammatory stimuli to assess the penetration and biological effects of the anti-inflammatory drug dexamethasone (DXM), encapsulated in core multishell-nanocarriers (CMS-NC), when compared to a standard cream formulation. Despite a high interindividual variability, the combined pretreatment of the skin resulted in an average 2.5-fold increase of the transepidermal water loss and swelling of the epidermis, as assessed by optical coherence tomography, as well as in a moderate increase of a broad spectrum of proinflammatory mediators of clinical relevance. The topical application of DXM-loaded CMS-NC or DXM standard cream revealed an increased penetration into SP-treated skin when compared to untreated control skin with an intact barrier. Both formulations, however, delivered sufficient amounts of DXM to effectively suppress the production of interleukin-6 (IL-6), interleukin-8 (IL-8) and Thymic Stromal Lymphopoietin (TSLP). In conclusion, we suggest that the herein presented ex vivo inflammatory skin model is functional and could improve the selection of promising drug delivery strategies for anti-inflammatory compounds at early stages of development.
