Molecular Packing of Functionalized Fluorinated Lipids in Langmuir Monolayers

Abstract

Fluorinated amphipaths are a fascinating class of compounds, which, despite significant challenges associated with their syntheses, have found use across a number of areas of biotechnology. Applications range from the in vitro stabilization of membrane proteins to the development of enhanced stability intravenous drug and gene delivery systems. More recently, monolayer-forming fluorinated lipids have found use in the 2D crystallization of detergent-solubilized hydrophobic or partially hydrophobic proteins at the air-water interface. In this study, we investigate the surface properties of a novel suite of monolayer forming, partially fluorinated lipids. These modular lipid structures contain a densely fluorinated insertion in the hydrocarbon tail and a synthetically modifiable headgroup. Analyses of surface-pressure area isotherms and X-ray reflectometry profiles reveal that the lipids spread into fluid monolayers and are more compressible than their non-fluorinated counterparts. Furthermore, the data support a model whereby the partially fluorinated chains of the lipid tails form a film which is fundamentally incompatible with detergents and other destabilizing amphipaths.

Impact of the Spacer on the Condensing Effect of Fluorinated Chains Investigated by Grazing Incidence X-ray Diffraction on Ultrathin Langmuir Monolayers

“…Introducing a perfluoroalkyl chain ( F -chain) in the structure of an amphiphile strongly increases the stability of the monolayers and modifies their properties. , Recent studies of the monolayer behavior of (perfluoroalkyl)alkylated amphiphiles include those of highly fluorinated functionalized phospholipids, glycolipids, and anchor-shaped bolaamphiphiles . The case of semifluorinated alkanes (C n F 2 n +1 C m H 2 m +1 , FnHm diblocks), which are amphiphiles devoid of polar head, has also been investigated and their monolayers were shown to consist of arrays of large surface micelles. , …”

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

“…In the context of drug-carrying lipid assemblies, reduced permeability, tailored release (stability vs kinetics), increased bioavailability, and enhanced resistance to disorganizing biochemical species are some of the properties that fluorinated lipid analogues promise. 34,35 Recently, the stability of an α,α-difluoro ether phospholipid has been experimentally determined, 36 but the potential of both the α-fluoro and α,α-difluoro conjugates of a prodrug anticancer ether lipid (ProAEL; Figure 1) to serve as an efficient substrate for PLA 2 remains unexplored to our knowledge. In the present study, we investigate the PLA 2 -catalyzed degradation (Figure 2A) of ProAEL analogues partially and fully fluorinated at the α-position using well-established computational chemistry methods that include classical molecular dynamics (MD) simulations and quantum mechanics (QM)/density functional theory (DFT) calculations.…”

“…Partially fluorinated lipid analogues are compounds in which one or more hydrocarbons (CH n ) are replaced by fluorocarbons (partially, CH k F l , or completely, CF n ; n = k + l ), effectively changing the physical and chemical characteristics while retaining the hydrophobic property of the lipid. In the context of drug-carrying lipid assemblies, reduced permeability, tailored release (stability vs kinetics), increased bioavailability, and enhanced resistance to disorganizing biochemical species are some of the properties that fluorinated lipid analogues promise. , Recently, the stability of an α,α-difluoro ether phospholipid has been experimentally determined, but the potential of both the α-fluoro and α,α-difluoro conjugates of a prodrug anticancer ether lipid (ProAEL; Figure ) to serve as an efficient substrate for PLA 2 remains unexplored to our knowledge.…”

Comparison of Fluorinated and Nonfluorinated Lipids in Self-Adjuvanting Delivery Systems for Peptide-Based Vaccines

“…Multiple delivery systems have been reported to deliver peptide epitopes to the APCs, including lipopeptides, polymers, virus-like particles, and liposomes. , However, fluorinated amphiphiles have not yet been examined for this purpose. These compounds have biomedical applications as components of liposomal drug carriers, for ultrasound-mediated delivery of lipophilic drugs or for two-dimensional crystallization of histidine (His)-tagged membrane protein. − Fluorinated amphiphiles can form a third phase that is immiscible with aqueous and nonaqueous phases and thus self-assemble into nanoparticles . They also do not accumulate in lipid membranes .…”