Ceramides (Cers) with α-hydroxylated acyl chains comprise about a third of all extractable skin Cers and are required for permeability barrier homeostasis. We have probed here the effects of Cer hydroxylation on their behavior in lipid models comprising the major SC lipids, Cer/free fatty acids (C 16-C 24)/cholesterol, and a minor component, cholesteryl sulfate. Namely, Cers with (R)-α-hydroxy lignoceroyl chains attached to sphingosine (Cer AS), dihydrosphingosine (Cer AdS), and phytosphingosine (Cer AP) were compared to their unnatural (S)-diastereomers and to Cers with non-hydroxylated lignoceroyl chains attached to sphingosine (Cer NS), dihydrosphingosine (Cer NdS), and phytosphingosine (Cer NP). By comparing several biophysical parameters (lamellar organization by X-ray diffraction, chain order, lateral packing, phase transitions, and lipid mixing by infrared spectroscopy using deuterated lipids) and the permeabilities of these models (water loss and two permeability markers), we conclude that there is no general or common consequence of Cer α-hydroxylation. Instead, we found a rich mix of effects, highly dependent on the sphingoid base chain, configuration at the α-carbon, and permeability marker used. We found that the model membranes with unnatural Cer (S)-AS have fewer orthorhombically packed lipid chains than those based on the (R)-diastereomer. In addition, physiological (R)-configuration decreases the permeability of membranes, with Cer (R)-AdS to theophylline, and increases the lipid chain order in model systems with natural Cer (R)-AP. Thus, each Cer subclass makes a distinct contribution to the structural organization and function of the skin lipid barrier.

• Klíčová slova
• biophysics, ceramides, hydroxylation, lipids, permeability, skin barrier, stratum corneum,
• MeSH
• acylace MeSH
• ceramidy chemie   MeSH
• hydroxylace MeSH
• kůže chemie   metabolismus   MeSH
• lidé MeSH
• permeabilita MeSH
• sfingosin analogy a deriváty   chemie   MeSH
• změna skupenství * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ceramidy MeSH
• phytosphingosine MeSH Prohlížeč
• safingol MeSH Prohlížeč
• sfingosin MeSH

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
• buněčná membrána metabolismus   MeSH
• ceramidy chemie   metabolismus   MeSH
• kůže metabolismus   MeSH
• membrány umělé * MeSH
• permeabilita MeSH
• voda metabolismus   MeSH
• změna skupenství MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ceramidy MeSH
• membrány umělé * MeSH
• voda 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.

• Klíčová slova
• galactoside, penetration enhancers, sugar, topical drug delivery, transdermal drug delivery,
• MeSH
• alkeny aplikace a dávkování   chemie   MeSH
• aplikace kožní MeSH
• cidofovir MeSH
• cytosin aplikace a dávkování   analogy a deriváty   chemie   MeSH
• epidermis metabolismus   MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• galaktosa analogy a deriváty   chemie   MeSH
• galaktosidy aplikace a dávkování   chemie   MeSH
• hydrokortison aplikace a dávkování   chemie   MeSH
• keratinocyty účinky léků   metabolismus   MeSH
• kožní absorpce účinky léků   MeSH
• kůže metabolismus   MeSH
• lidé MeSH
• lipidy chemie   MeSH
• organofosfonáty aplikace a dávkování   chemie   MeSH
• permeabilita MeSH
• theofylin aplikace a dávkování   chemie   MeSH
• uvolňování léčiv MeSH
• voda MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkeny MeSH
• cidofovir MeSH
• cytosin MeSH
• galaktosa MeSH
• galaktosidy MeSH
• hydrokortison MeSH
• lipidy MeSH
• organofosfonáty MeSH
• theofylin MeSH
• voda MeSH