Glucosylated Derivatives of Semifluorinated Surfactants for Intravenous Delivery of Sevoflurane: Synthesis, Physicochemical Characterization, and Immunogenicity Studies.

摘要

Intravenous delivery of fluorinated anesthetics has a number of potential advantages when compared with inhalation delivery. In principle, direct injection of emulsified anesthetics into the bloodstream eliminates the equilibration time between the anesthetics and the lungs; as a result, the anesthetic induction is more rapid as compared with inhaled anesthetics.;In this project, we first synthesized a series of linear mPEG-PFC diblock copolymers with different length of mPEG and perfluoroalkyl chains and determined their critical micelle concentration (CMC), particle size, and morphology in aqueous medium. Secondly, we proposed two approaches to reduce the immunogenicity associated with the previous formulation. We replaced PEG MW 5000 by PEG MW 1100 in the hydrophilic block of the original polymer, or coated the PEG surface by glucose, a non-immunogenic monosaccharide, to reduce the recognition of the PEG corona by immune system components. Therefore, we designed, synthesized, and characterized novel perfluoroalkylated PEG surfactants in which either one or three glucose moieties had been conjugated at the PEG (MW 1000) terminus. We characterized the physicochemical properties and the hemolytic activity of these novel polymers as well as the physical stability of their sevoflurane nanoemulsions. The 20% v/v sevoflurane nanoemulsions containing these novel polymers and 10% v/v perfluorooctyl bromide successfully induced anesthesia in rats from which recovery was smooth and rapid. For each formulation, a dose-response curve was established and the ED50 value was determined. The immunogenic and anesthetic effects of sevoflurane nanoemulsions were investigated in dogs (beagles). When injected intravenously, these formulations were able to induce general anesthesia in dogs. The sevoflurane nanoemulsions containing glucose-functionalized polymers were associated with allergic-like responses, while the sevoflurane nanoemulsion containing the mPEG (MW 1100)-PFC polymer was able to reduce the allergic-like response in dogs compared to the original formulation comprising the mPEG (MW 5000)-PFC polymer.;In a further study, we designed, synthesized, and characterized a novel fluorinated alpha-cyclodextrin to evaluate its ability as a semifluorinated amphiphile to emulsify fluorinated anesthetic sevoflurane. Our results demonstrated that a mixture of novel fluorinated alpha-cyclodextrin and mPEG (MW 1100)-PFC polymer was able to emulsify 20% v/v of sevoflurane and form a stable anesthetic formulation.