Impact of α-tocopherol derivatives on the structural and functional properties of model lipid nanocarriers: A...

While α-tocopherol is widely studied for its antioxidant role in membranes, its potential as a functional component of liposomal carriers remains underexplored, despite their range of interesting biological activities and growing use in nanocarrier systems. This study systematically evaluates how three tocopherol derivatives - α-tocopherol phosphate (TP), α-tocopherol succinate (TS), and α-tocopherol polyethylene glycol succinate (TPGS)-affect nanoliposomes, focusing on colloidal stability, encapsulation efficiency, and fundamental membrane properties such as fluidity, hydration, and thermotropic behavior. Results showed that all α-tocopherol derivatives significantly altered membrane properties, inducing structural changes in both the lipid chain and polar regions of the liposome bilayer. TS enhanced membrane rigidity and reduced permeability, while TP increased fluidity and promoted payload release. TPGS, with its bulky PEG chain, stabilized liposomes but induced phase heterogeneity. Additionally, all derivatives lowered the lipid main phase transition temperature and altered its thermotropic behavior. Despite these disruptions, the derivatives preserved nanoscale vesicle sizes (∼100 nm) and monodisperse distributions (PDI < 0.3) over extended storage. These experimental observations were further supported by molecular dynamics simulations, which confirmed differences in membrane affinity among the derivatives, with TS showing the strongest binding affinity. The simulations also revealed that the derivatives' positioning within the bilayer and their interactions-mainly hydrogen bonding and hydrophobic contacts-contribute to their distinct effects on membrane structure and dynamics. Collectively, these findings demonstrate that α-tocopherol derivatives distinctly modulate liposomal membrane architecture and behavior in a structure-dependent manner, offering promising tools for tuning nanocarrier performance in pharmaceutical applications.