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.

Recent Advances of Hyaluronan for Skin Delivery: From Structure to Fabrication Strategies and Applications.

Hyaluronan (HA) plays a fundamental role in maintaining the homeostasis on skin health. Furthermore, the effect of HA in skin inflammatory diseases is worth studying in the next future. HA and its conjugates change the solubility of active pharmaceutical ingredients, improve emulsion properties, prolong stability, reduce immunogenicity, and provide targeting. HA penetrates to deeper layers of the skin via several mechanisms, which depend on the macromolecular structure and composition of the formulation. The cellular and molecular mechanisms involved in epidermal dysfunction and skin aging are not well understood. Nevertheless, HA is known to selectively activate CD44-mediated keratinocyte signaling that regulates its proliferation, migration, and differentiation. The molecular size of HA is critical for molecular mechanisms and interactions with receptors. High molecular weight HA is used in emulsions and low molecular weight is used to form nanostructured lipid carriers, polymeric micelles, bioconjugates, and nanoparticles. In the fabrication of microneedles, HA is combined with other polymers to enhance mechanical properties for piercing the skin. Hence, this review aims to provide an overview of the current state of the art and last reported ways of processing, and applications in skin drug delivery, which will advocate for their broadened use in the future.

The Sphingosine and Acyl Chains of Ceramide [NS] Show Very Different Structure and Dynamics That Challenge Our Understanding of the Skin Barrier.

The lipid phase of the uppermost human skin layer is thought to comprise highly rigid lipids in an orthorhombic phase state to protect the body against the environment. By synthesizing sphingosine-d28 deuterated N-lignoceroyl-d-erythro-sphingosine (ceramide [NS]), we compare the structure and dynamics of both chains of that lipid in biologically relevant mixtures using X-ray diffraction, 2 H NMR analysis, and infrared spectroscopy. Our results reveal a substantial fraction of sphingosine chains in a fluid and dynamic phase state at physiological temperature. These findings prompt revision of our current understanding of the skin lipid barrier, where an extended ceramide [NS] conformation is preferred and a possible domain structure is proposed. Mobile lipid chains may be crucial for skin elasticity and the translocation of physiologically important molecules.