Supramolecular Deep Eutectic Solvent for Transdermal Drug Delivery: Mechanisms of Solubilization and Permeation Enhancement

Supramolecular deep eutectic solvents (SUPRADESs) as novel biomaterials are attracting increasing attention. However, their application to transdermal drug delivery has not yet been fully explored. This study aimed to investigate the internal mechanism and applicability. First, SUPRADESs composed of six cyclodextrins (CDs) and levulinic acid (Lev) were prepared and characterized. Resveratrol (RES) was used as a model drug. A series of experiments combined with molecular dynamics simulations indicated that SUPRADES remarkably enhanced the solubility of RES compared to only CD and Lev, whose solubilizing ability was contrary to the initial binding strength of the host-guest. The thermodynamic parameters and intermolecular interactions confirmed that the complexation formation in SUPRADES was driven by a favorable enthalpy decrease and a larger unfavorable entropy reduction. When the initial entropy contribution of the host-guest binding was smaller (the weak binding strength), the Gibbs free energy change became smaller in SUPRADES, and the solubilization ability of SUPRADES on drug was further increased. Skin penetration studies showed that, compared to RES/CD complexes, SUPRADES significantly enhanced the penetration and retention of RES in the skin. Thermodynamic calculations and molecular interactions studies revealed that the penetration enhancement was related to the improved skin wettability, the denaturation of the α-helix structure of keratin, and the increased skin hydration. Additionally, SUPRADES enhanced the stability and bioactivity of RES and exhibited low cytotoxicity and skin irritation. Overall, our study reveals the molecular mechanisms of SUPRADES-mediated solubility and permeation enhancement, guides the design of drug-SUPRADES formulations, and extends their pharmaceutical applications.