Lipid Nanoparticles Loaded With Resveratrol And Glycyrrhetinic Acid As New Tool For Wound Healing

Skin and mucous membranes maintain the homeostasis of the full body and are the first barriers against microbial infections. Therefore, their integrity is crucial and any lesion or injury must be quickly treated. In healthy people, several steps, such as inflammation, production of pro-oxidative species, cells proliferation and remodelling, follow each other creating a cascade process that determine the total restoration of the injured tissue. However, even a single discrepancy in these phases can delay the wound healing or irreversibly compromise the tissue. A smart strategy to promote wound healing could be the administration of natural compounds such as polyphenols and triterpenoids which are characterized by strong antioxidant and anti-inflammatory activities, antimicrobial properties and low side effects. However, the beneficial effects of these molecules are limited by their disadvantageous physico-chemical properties (e.g., low solubility in water, degradation) that compromise their bioavailability and thereby their clinical use. Based on these considerations, the aim of this work was to prepare and characterize a novel drug delivery system in form of multicomponent lipid nanoparticles (LNPs) constituted by a complex mixture of PEGylated lipid, Glyceryl monoester and Menthol able to entrap the polyphenol Resveratrol (RSV) and the triterpenoid Glycyrrhetinic Acid (GA) in order to protect them from degradation and maximize their effectiveness so as to make them useful for the wound management. Following optimization of the lipid blend composition and excipient ratios, it resulted homogeneous, with a melting range temperature of 57-61°C and containing GA (2.73 ± 0.23%w/w) and RSV (4.56 ± 0.04%w/w) in the amorphous form. The LNPs, obtained by homogenization followed by high-frequency sonication, were characterized by DLS and SEM analyses resulting almost monodispersed (PDI: 0.267 ± 0.010), with spherical shape (by SEM), nanometric size (162.86 ± 3.12nm) and suitable Z-potential (-21.40 ± 7.33mV). The quantitative analyses showed high encapsulation efficiency for both RSV and GA having a suitable DR% (96.82 ± 1.34% and 99.6 ± 1.29%, respectively) and LE% (96.82 ± 1.34% and 97.15 ± 0.19%, respectively) values. RSV release studies highlighted a sustained and controlled pattern of discharge to different chemical environments simulating the wound conditions. Moreover, LNPs showed significant scavenger properties evaluated by the DPPH assay. Last, the biological evaluations (scratch assay) highlighted an enhanced fibroblasts proliferation and migration at extremely low doses (LNPs 22 μg/mL corresponding to RSV 5 μM). Furthermore, a promising antibiofilm effect against Staphilococcus aureus was observed in a dose-dependent manner. In conclusion, these novel multicomponent LNPs could represent a next generation carrier constituting a promising tool for wound healing purposes.