Synthesis and self-assembling of hyaluronan grafted with ceramide NP for topical drug delivery.

In this work, amphiphilic hyaluronan was synthesized by grafting succinylated N-oleoyl-phytosphingosine via esters bonds. Succinylated N-oleoyl-phytosphingosine (sCER) was first prepared by esterification of hydroxyl moieties of the ceramide with succinic anhydride. The esterification of hyaluronan was governed by crowding effect. The oligomeric HA-sCER derivatives exhibited a strong self-aggregation as evidenced by a very low critical aggregation concentration (1.9 µg mL-1), higher pyrene binding constant (KB), and the smallest particle size (30 nm) in solution. The self-aggregation properties demonstrated to be a function of the substitution degree and molecular weight of HA. The prepared derivatives were non-cytotoxic towards cell lines NIH-3T3. Nanoparticles prepared using oligomeric HA-sCER derivatives improved the penetration of Nile red dye through the stratum corneum due to their smaller size (≤50 nm). The fluorescence intensity localized at the stratum corneum was higher for oligomeric HA-sCER. A significant inhibition of the pro-inflammatory cytokine interleukin-6 production was observed in vitro in macrophages differentiated from THP-1 cells. These findings showed that HA-sCER constituted a promising active ingredient for cosmetics use.

Structure and dynamics of the hyaluronan oligosaccharides and their solvation shell in water: organic mixed solvents.

Hyaluronan (HA) is a natural polysaccharide occurring ubiquitously in the connective tissues of vertebrates widely used in the cosmetic and pharmaceutic industries. In numerous applications HA oligosaccharides are being chemically modified using reactions incompatible with aqueous solutions, often carried out in water:organic mixed solvents. We carry out molecular-dynamics (MD) simulations of HA oligosaccharides in water:1,4-dioxane and water:tert-butanol mixtures of different compositions. HA molecule causes a separation of the solvent components in its surroundings, especially in tert-butanol containing solutions, constituting thus a solvation shell enriched by water. Furthermore, interactions with ions are stronger than in pure water and depend on the solvent composition. Consequently, the dynamics of the HA chain varies with the solvent composition and causes observable conformational changes of the HA oligosaccharide. Composition of mixed solvents thus enables us to modify the interaction of HA with other molecules as well as its reactivity.

Oleate-modified hyaluronan: Controlling the number and distribution of side chains by varying the reaction conditions.

In this work, low molecular weight hyaluronan was chemically modified by oleoyl moieties utilising mixed anhydrides methodology. The activation of oleic acid with benzoyl chloride in organic solvents miscible with water was followed by NMR spectroscopy. The product selectivity correlates with the solvent's Hildebrand solubility parameter. Furthermore, the effect of the solvent for the mixed anhydride formation was elucidated by density functional theory (DFT) and showed that the reactions are faster in acetonitrile or alcohols than in hexane. Furthermore, the solvent demonstrated to control the substituent distribution pattern along HA chain during esterification. An even distribution of substituents was observed in reactions performed in water mixed with ethers. The substituent distribution pattern clearly influenced the aggregation behaviour of amphiphilic HA, controlling the stability of the delivery system, while increasing the encapsulation capacity.