Physicochemical and Computational Study of the Encapsulation of Resv-4′-LA and Resv-4′-DHA Lipophenols by Natural and HP-β-CDs

This study investigates the self-assembly and host-guest complexation behaviour of novel resveratrol-based lipophenols (LipoResv) – resveratrol-4’-linoleate (Resv-4’-LA) and resveratrol-4’-docosahexaenoate (Resv-4’-DHA) – with hydroxypropyl-β-cyclodextrins (HP-β-CDs). These amphiphilic molecules display surfactant-like properties, forming micellar aggregates in aqueous media. Fluorescence spectroscopy was used to determine the critical micelle concentration (CMC), revealing that LipoResv exhibit significantly lower CMC values than their free fatty acids, indicating higher hydrophobicity. The formation of inclusion complexes with HP-β-CDs was evaluated based on changes in CMC values and further confirmed by dynamic light scattering (DLS) and molecular modelling analyses. Resv-4’-LA formed 1:1 complexes (Kc= 720 M-1), while Resv-4’-DHA demonstrated 1:2 stoichiometry with lower affinity constants (K1= 17 M-1, K2= 0.18 M-1). Environmental parameters (pH, temperature and ionic strength) significantly modulated CMC and binding constants. Computational docking and molecular dynamics simulations supported the experimental findings by revealing key structural determinants of host-guest affinity and micelle stabilization. Ligand efficiency (LE) analysis further aligned with the experimental data, favouring the unmodified fatty acids. These results highlight the versatile encapsulation capacity of HP-β-CDs for bioactive amphiphiles molecules and support their potential applications in drug delivery and functional food systems.