Modes of interaction between tapinarof and model lipid membranes mimicking stratum corneum lipid composition and related transdermal transport in human skin.

Tapinarof (3,5-dihydroxy-4-isopropylstilbene, TPN), structurally related to resveratrol, is a nonsteroidal agent that belongs to the class of naturally derived aryl hydrocarbon receptor (AhR) agonists. TPN is an active ingredient of a topical medication (1% cream, VTAMA®). The log Poctanol|water of 2.79 ± 0.08 confirms the relative lipophilic character of TPN. The confirmed hydrophobicity of TPN raises the question of how this drug interacts with model lipidic structures and cell membranes, providing information about its transport mechanisms in the skin. Based on a liposomal model (40 % (w/w) ceramide, 25 % cholesterol, 25 % lignoceric acid, and 10 % cholesterol sulphate), it was shown that TPN causes a significant increase in fluidity and possibly a disruption of the membrane. The investigated 50-100 nm unilamellar liposomes were strictly negatively charged (zeta potential approx. -85 mV) and mimic skin lipid composition of the stratum corneum. The disruption mechanism is discussed in terms of the intermolecular interactions between TPN molecules (aggregates) and the various lipids constituting the liposomal model. Molecular dynamic simulations revealed rapid insertion of TPN into the lipid bilayer at low concentrations, whereas higher concentrations promoted TPN self-association and membrane perturbation, characterized by decreased lipid order and membrane thickness together with increased area per lipid. Finally, we confirmed a dual behaviour of TPN ex vivo: it can accumulate in the human skin, but it is also sufficiently mobile to partially cross this barrier.