Ceramides (Cer) are essential components of the skin permeability barrier. To probe the role of Cer polar head groups involved in the interfacial hydrogen bonding, the N-lignoceroyl sphingosine polar head was modified by removing the hydroxyls in C-1 (1-deoxy-Cer) or C-3 positions (3-deoxy-Cer) and by N-methylation of amide group (N-Me-Cer). Multilamellar skin lipid models were prepared as equimolar mixtures of Cer, lignoceric acid and cholesterol, with 5 wt% cholesteryl sulfate. In the 1-deoxy-Cer-based models, the lipid species were separated into highly ordered domains (as found by X-ray diffraction and infrared spectroscopy) resulting in similar water loss but 4-5-fold higher permeability to model substances compared to control with natural Cer. In contrast, 3-deoxy-Cer did not change lipid chain order but promoted the formation of a well-organized structure with a 10.8 nm repeat period. Yet both lipid models comprising deoxy-Cer had similar permeabilities to all markers. N-Methylation of Cer decreased lipid chain order, led to phase separation, and improved cholesterol miscibility in the lipid membranes, resulting in 3-fold increased water loss and 10-fold increased permeability to model compounds compared to control. Thus, the C-1 and C-3 hydroxyls and amide group, which are common to all Cer subclasses, considerably affect lipid miscibility and chain order, formation of periodical nanostructures, and permeability of the skin barrier lipid models.

• MeSH
• Cell Membrane metabolism   MeSH
• Ceramides chemistry   metabolism   MeSH
• Skin metabolism   MeSH
• Membranes, Artificial * MeSH
• Permeability MeSH
• Water metabolism   MeSH
• Phase Transition MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Ceramides MeSH
• Membranes, Artificial * MeSH
• Water MeSH

Ceramides (Cers) with ultralong (∼32-carbon) chains and ω-esterified linoleic acid, composing a subclass called omega-O-acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ∼10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability. The model membrane systems contained six to nine Cer subclasses as well as fatty acids, cholesterol, and cholesterol sulfate; acylCer content-namely, acylCers containing sphingosine (Cer EOS), dihydrosphingosine (Cer EOdS), and phytosphingosine (Cer EOP) ranged from zero to 30 mol%. Systems with normal physiologic concentrations of acylCer mixture mimicked the permeability and nanostructure of human skin lipids (with regard to LPP, chain order, and lateral packing). The models also showed that the sphingoid base in acylCer significantly affects the membrane architecture and permeability and that Cer EOP, notably, is a weaker barrier component than Cer EOS and Cer EOdS. Membranes with diminished or missing acylCers displayed some of the hallmarks of diseased skin lipid barriers (i.e., lack of LPP, less ordered lipids, less orthorhombic chain packing, and increased permeability). These results could inform the rational design of new and improved strategies for the barrier-targeted treatment of skin diseases.

• Keywords
• acylceramide, ceramides, disease models, epidermis, extracellular matrix, membrane nanostructure, membranes/model, permeability, sphingolipids,
• MeSH
• Ceramides analysis   metabolism   MeSH
• Skin Diseases metabolism   MeSH
• Skin chemistry   metabolism   MeSH
• Humans MeSH
• Membrane Lipids chemistry   metabolism   MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Ceramides MeSH
• Membrane Lipids MeSH

PURPOSE: To study new skin penetration/permeation enhancers based on amphiphilic galactose derivatives. METHODS: Two series of alkyl and alkenyl galactosides were synthesized and evaluated for their enhancing effect on transdermal/topical delivery of theophylline (TH), hydrocortisone (HC) and cidofovir (CDV), reversibility of their effects on transepidermal water loss (TEWL) and skin impedance, interaction with the stratum corneum using infrared spectroscopy, and cytotoxicity on keratinocytes and fibroblasts. RESULTS: Initial evaluation identified 1-(α-D-galactopyranosyl)-(2E)-pentadec-2-ene A15 as a highly potent enhancer - it increased TH and HC flux through human skin 8.5 and 5 times, respectively. Compound A15 increased the epidermal concentration of a potent antiviral CDV 7 times over that reached by control and Span 20 (an established sugar-based enhancer). Infrared spectroscopy of human stratum corneum indicated interaction of A15 with skin barrier lipids but not proteins. These effects of A15 on the skin barrier were reversible (both TEWL and skin impedance returned to baseline values within 24 h after A15 had been removed from skin). In vitro toxicity of A15 on HaCaT keratinocytes and 3T3 fibroblasts was acceptable, with IC50 values over 60 μM. CONCLUSIONS: Galactosyl pentadecene A15 is a potent enhancer with low toxicity and reversible action.

• Keywords
• galactoside, penetration enhancers, sugar, topical drug delivery, transdermal drug delivery,
• MeSH
• Alkenes administration & dosage   chemistry   MeSH
• Administration, Cutaneous MeSH
• Cidofovir MeSH
• Cytosine administration & dosage   analogs & derivatives   chemistry   MeSH
• Epidermis metabolism   MeSH
• Fibroblasts drug effects   metabolism   MeSH
• Galactose analogs & derivatives   chemistry   MeSH
• Galactosides administration & dosage   chemistry   MeSH
• Hydrocortisone administration & dosage   chemistry   MeSH
• Keratinocytes drug effects   metabolism   MeSH
• Skin Absorption drug effects   MeSH
• Skin metabolism   MeSH
• Humans MeSH
• Lipids chemistry   MeSH
• Organophosphonates administration & dosage   chemistry   MeSH
• Permeability MeSH
• Theophylline administration & dosage   chemistry   MeSH
• Drug Liberation MeSH
• Water MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alkenes MeSH
• Cidofovir MeSH
• Cytosine MeSH
• Galactose MeSH
• Galactosides MeSH
• Hydrocortisone MeSH
• Lipids MeSH
• Organophosphonates MeSH
• Theophylline MeSH
• Water MeSH

PURPOSE: Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin. METHODS: To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of D-glucose derivatives, both hydrophilic and amphiphilic. RESULTS: Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6-amino-6-deoxy-α-D-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin. CONCLUSIONS: Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids.

• Keywords
• penetration enhancers, sugar, topical drug delivery, transdermal drug delivery,
• MeSH
• Antiviral Agents administration & dosage   metabolism   MeSH
• Administration, Cutaneous MeSH
• Administration, Topical MeSH
• Cell Line MeSH
• Cidofovir MeSH
• Cytosine administration & dosage   analogs & derivatives   metabolism   MeSH
• Epidermis drug effects   metabolism   MeSH
• Chemistry, Pharmaceutical MeSH
• Glucosides chemical synthesis   pharmacology   MeSH
• Hexoses pharmacology   MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Keratinocytes drug effects   metabolism   MeSH
• Skin Absorption MeSH
• Skin drug effects   metabolism   MeSH
• Drug Delivery Systems MeSH
• Humans MeSH
• Lipids physiology   MeSH
• Organophosphonates administration & dosage   metabolism   MeSH
• Permeability MeSH
• Theophylline administration & dosage   metabolism   MeSH
• Cell Survival MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents MeSH
• Cidofovir MeSH
• Cytosine MeSH
• Glucosides MeSH
• Hexoses MeSH
• Lipids MeSH
• Organophosphonates MeSH
• sorbitan monolaurate MeSH Browser
• Theophylline MeSH

Mutations in the filaggrin (FLG) gene are strongly associated with common dermatological disorders such as atopic dermatitis. However, the exact underlying pathomechanism is still ambiguous. Here, we investigated the impact of FLG on skin lipid composition, organization, and skin acidification using a FLG knockdown (FLG-) skin construct. Initially, sodium/hydrogen antiporter (NHE-1) activity was sufficient to maintain the acidic pH (5.5) of the reconstructed skin. At day 7, the FLG degradation products urocanic (UCA) and pyrrolidone-5-carboxylic acid (PCA) were significantly decreased in FLG- constructs, but the skin surface pH was still physiological owing to an upregulation of NHE-1. At day 14, secretory phospholipase A2 (sPLA2) IIA, which converts phospholipids to fatty acids, was significantly more activated in FLG- than in FLG+. Although NHE-1 and sPLA2 were able to compensate the FLG deficiency, maintain the skin surface pH, and ensured ceramide processing (no differences detected), an accumulation of free fatty acids (2-fold increase) led to less ordered intercellular lipid lamellae and higher permeability of the FLG- constructs. The interplay of the UCA/PCA and the sPLA2/NHE-1 acidification pathways of the skin and the impact of FLG insufficiency on skin lipid composition and organization in reconstructed skin are described.

• MeSH
• Dermatitis, Atopic metabolism   pathology   MeSH
• Filaggrin Proteins MeSH
• Group II Phospholipases A2 metabolism   MeSH
• Gene Knockdown Techniques MeSH
• Hydrogen-Ion Concentration MeSH
• Skin cytology   metabolism   MeSH
• Pyrrolidonecarboxylic Acid metabolism   MeSH
• Urocanic Acid metabolism   MeSH
• Fatty Acids, Nonesterified metabolism   MeSH
• Acids metabolism   MeSH
• Humans MeSH
• Lipid Metabolism physiology   MeSH
• Sodium-Hydrogen Exchangers metabolism   MeSH
• Permeability MeSH
• Intermediate Filament Proteins deficiency   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Filaggrin Proteins MeSH
• FLG protein, human MeSH Browser
• Group II Phospholipases A2 MeSH
• growth factor-activatable Na-H exchanger NHE-1 MeSH Browser
• Pyrrolidonecarboxylic Acid MeSH
• Urocanic Acid MeSH
• Fatty Acids, Nonesterified MeSH
• Acids MeSH
• Sodium-Hydrogen Exchangers MeSH
• Intermediate Filament Proteins MeSH