Aurisin A Complexed with 2,6-Di-O-methyl-β-cyclodextrin Enhances Aqueous Solubility, Thermal Stability, and Antiproliferative Activity against Lung Cancer Cells

Aurisin A (AA), an aristolane dimer sesquiterpene isolated from the luminescent mushroom Neonothopanus nambi, exhibits various biological and pharmacological effects. However, its poor solubility limits its use for further medicinal applications. This study aimed to improve the water solubility of AA via complexation with beta-cyclodextrin (beta CD) and its derivatives (2,6-di-O-methyl-beta CD (DM beta CD) and 2-hydroxypropyl-beta CD (HP beta CD). A phase solubility analysis demonstrated that the solubility of AA linearly enhanced with increasing concentrations of beta CDs (ranked in the order of AA/DM beta CD > AA/HP beta CD > AA/beta CD). Notably, beta CDs, especially DM beta CD, increased the thermal stability of the inclusion complexes. The thermodynamic study indicated that the complexation between AA and beta CD(s) was a spontaneous endothermic reaction, and AA/DM beta CD possesses the highest binding strength. The complex formation between AA and DM beta CD was confirmed by means of FT-IR, DSC, and SEM. Molecular dynamics simulations revealed that the stability and compactness of the AA/DM beta CD complex were higher than those of the DM beta CD alone. The encapsulation of AA led to increased intramolecular H-bond formations on the wider rim of DM beta CD, enhancing the complex stability. The antiproliferative activity of AA against A549 and H1975 lung cancer cells was significantly improved by complexation with DM beta CD. Altogether, the satisfactory water solubility, high thermal stability, and enhanced antitumor potential of the AA/DM beta CD inclusion complex would be useful for its application as healthcare products or herbal medicines.