Fluorocarbon Exposure Mode Markedly Affects Phospholipid Monolayer Behavior at the Gas/Liquid Interface: Impact on Size and Stability of Microbubbles.

Although most phospholipid-shelled microbubbles (MBs) investigated for medical applications are stabilized by a fluorocarbon (FC) gas, information on the interactions between the phospholipid and FC molecules at the gas/water interface remains scarce. We report that the procedure of introduction of perfluorohexane (F-hexane), that is, either in the gas phase above dimyristoylphosphatidylcholine (DMPC) or dipalmitoylphosphatidylcholine (DPPC) Langmuir monolayers, or in the aqueous subphase, radically affects the compression isotherms. When introduced in the gas phase, F-hexane is rapidly incorporated in the interfacial film, but is also readily desorbed upon compression and eventually totally expelled from the phospholipid monolayers. By contrast, when introduced in the aqueous phase, F-hexane remains trapped at the interface. These dissimilar outcomes demonstrate that the phospholipid monolayer acts as a barrier that effectively hinders the transfer of the FC across the interfacial film. F-hexane was also found to significantly accelerate the adsorption kinetics of the phospholipids at the gas/water interface and to lower the interfacial tension, as assessed by bubble profile analysis tensiometry. The extent of these effects is more pronounced when F-hexane is provided from the gas phase. The size and stability characteristics of DMPC- and DPPC-shelled microbubbles were also found to depend on how the FC is introduced. As compared to reference MBs prepared under nitrogen only, introduction of F-hexane always causes a decrease in MB mean radius. However, while for DMPC this decrease depends on the F-hexane introduction procedure, it is independent from the procedure and most pronounced (from ∼2.0 μm to ∼1.0 μm) for DPPC. Introducing the FC in the gas phase has the strongest effect on MB half-life (t1/2 = ∼1.8 and 6.8 h for DMPC and DPPC, respectively), as compared to when it is delivered through the aqueous phase (∼0.8 and ∼1.7 h). Fluorocarbonless reference DMPC and DPPC bubbles had a half-life of ∼0.5 and 0.8 h, respectively. The effects of F-hexane on MB characteristics are discussed with regard to the interactions between phospholipids and F-hexane and monolayer fluidization effect, as revealed by the Langmuir and tensiometric studies.