In this study we report on experimental observations of giant unilamellar
liposomes composed of ternary mixtures of cholesterol (Chol), phospholipids
with relatively low Tmelt (DOPC, POPC, or DPoPC) and high
Tmelt (sphingomyelin (SM), or tetramyristoyl cardiolipin (TMCL)) and
their phase behaviors in the presence and absence of dipole modifiers. It was
shown that the ratios of liposomes exhibiting noticeable phase separation
decrease in the series POPC, DOPC, DPoPC regardless of any
high-Tmelt lipid. Substitution of SM for TMCL led to increased lipid
phase segregation. Taking into account the fact that the first and second cases
corresponded to a reduction in the thickness of the lipid domains enriched in
low- and high-Tmelt lipids, respectively, our findings indicate that
the phase behavior depends on thickness mismatch between the ordered and
disordered domains. The dipole modifiers, flavonoids and styrylpyridinium dyes,
reduced the phase segregation of membranes composed of SM, Chol, and POPC (or
DOPC). The other ternary lipid mixtures tested were not affected by the
addition of dipole modifiers. It is suggested that dipole modifiers address the
hydrophobic mismatch through fluidization of the ordered and disordered
domains. The ability of a modifier to partition into the membrane and fluidize
the domains was dictated by the hydrophobicity of modifier molecules, their
geometric shape, and the packing density of domain-forming lipids. Phloretin,
RH 421, and RH 237 proved the most potent among all the modifiers examined.