Abstract
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.
Highlights
Preclinical disease models are essential tools for the evaluation of potential therapeutic targets, and for the assessment of novel pharmaceutical formulations
In order to assess the effects of the combined pretreatment on the skin explants, the skin barrier parameters typically measured in clinical trials were combined with histological evaluations as well as analyses of the mRNA expression and protein levels for inflammatory mediators in response to serine protease (SP) treatment and the topical application of two different DXM formulations
The overall observation of the combined SP treatment being a moderate inflammatory stimulus is in accordance with our own experiments using human keratinocyte cultures, which showed that the addition of low concentrations of trypsin and plasmin resulted in a mild-to-moderate radical formation, as assessed by electron paramagnetic resonance (EPR), while increasing IL-6 and IL-8 levels without impairing the overall cell viability [54]
Summary
Preclinical disease models are essential tools for the evaluation of potential therapeutic targets, and for the assessment of novel pharmaceutical formulations. The concept of reduction, refinement and replacement (3R) emphasizes the value of models derived from human skin cells and tissue to avoid unnecessary animal testing. The required experimental set-up, is usually time-consuming, and the value of these models for penetration studies that address penetration in diseased skin is limited, as they are typically hyperpermeable [10] and lack appendages and immune cells, all of which affect the tissue environment [11]. As newer generations of drug delivery systems can be equipped with elements that address specific features of diseased skin [13,14], a closer investigation of the interactions of drug formulations with skin barrier components could provide important guidance for the selection of the most promising candidates
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