Theoretical Assessment of Fluorinated Phospholipids in the Design of Liposomal Drug-Delivery Systems.

Abstract

Fluorinated phospholipid analogues are investigated as potential substrates for phospholipase A2 (PLA2) using classical molecular dynamics simulations and quantum mechanics/density functional theory calculations. The fluorinated phospholipid analogues are α-fluoro (HF-ProAEL) and α,α-difluoro (F2-ProAEL) conjugates of (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phoshocholineglycerol (ProAEL). Our results provide a theoretical assessment of the potential usefulness of these fluorinated lipids in the rational design of liposomal drug-delivery systems. The α-fluorine-substituted phospholipid analogues are found to be substrates for secretory PLA2, with sufficient accessibility of water to the active site to allow for enzymatic hydrolysis. Because of the inherently less stable nature of HF-ProAEL and F2-ProAEL when compared to that of ProAEL, the hydrolytic reaction is predicted to occur at a progressively faster rate; the more electronegative substituent at the α-position effectively lowers the energy barrier for hydrolysis. We conclude that the partially fluorinated phospholipid analogues facilitate rational design of liposomal vesicles of phospholipid mixtures with desirable physicochemical properties and that are still subjects for important and pharmaceutically proven drug-delivery mechanisms.