Effects of replacement of the hydroxyl group of cholesterol and tocopherol on the thermotropic behavior of phospholipid membranes

Abstract

The role of the hydroxyl groups of cholesterol and tocopherol in mediating their interaction with phospholipid bilayers has been a subject of considerable interest. We have examined this question by using derivatives of cholesterol and tocopherol in which the hydroxyl group is esterified to succinate. The hemisuccinate esters of cholesterol and alpha-tocopherol can be readily incorporated into phospholipid membranes and in fact can by themselves form closed membrane vesicles as demonstrated by the encapsulation of [3H]sucrose. The thermotropic behavior of mixtures containing each succinate ester and phospholipid was studied by differential scanning calorimetry. The effect of cholesteryl hemisuccinate on the thermotropic properties of dipalmitoylphosphatidylcholine and dimyristoylphosphatidylethanolamine is very similar to that of cholesterol. This indicates that the 3 beta-OH is not required for the formation of a cholesterol-phospholipid complex. In mixtures of tocopherol acid succinate and phospholipids the peak transition temperature is progressively shifted to lower temperatures as the mole fraction of alpha-tocopherol succinate is increased, while the enthalpy of the transition is only slightly affected. At a tocopherol succinate/phospholipid molar ratio of 9/1 a phase transition is still detectable. A comparison between tocopherol succinate and tocopherol indicates that the substitution of the hydroxyl group reduces the interaction of tocopherol with phospholipids to a small but measurable extent. Thus, the hydroxyl group of tocopherol is more important than the hydroxyl group of cholesterol in influencing their interactions with phospholipids.

On the formulation of pH-sensitive liposomes with long circulation times

“…The cone shape of PE molecules favors the establishment of strong intermolecular interactions between the amine and phosphate groups of the polar headgroups, justifying the strong tendency of these molecules to acquire the inverted hexagonal phase above the phase transition temperature (T H ) (for DOPE the T H is 10 jC). Intercalation of amphiphilic molecules containing a protonatable acidic group (negatively charged at physiological pH) among PE molecules favors electrostatic repulsion and allows the formation of bilayer structures, leading to liposome formation at physiological pH and temperature [22,23]. This latter approach constitutes the basis for the biophysical mechanisms underlying the pH-sensitivity exhibited by PE-containing liposomes.…”

Tocopheryl Succinate—Versatile Functions due to Its Unique Physicochemical Properties

“…The physicochemical effects of TS on lipid membranes are reported to be significantly different from that of ␣ -T [23][24][25]. Because the terminal carboxylic moiety of TS is ionized at physiological pH, TS incorporated in lipid membranes increases their negative charge, while ␣ -T does not affect their surface charge [ 25 ].…”

A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery

“…The cone shape favors the formation of inverted hexagonal phase above the phase transition temperature due to interaction of amine and phosphate groups of the polar head group. When we intercalate amphiphilic molecules containing a protonatable acidic group in PE, it will form a bilayer structure stable at physiological pH (Lai et al, 1985). Although stable liposomes are formed at physiological pH, on acidification, protonation of the acidic groups of the amphiphiles leads to the destabilization of liposomes (Torchilin et al, 1993).…”

“…Several laboratories exploited pH-sensitive liposomes for the delivery of therapeutic macromolecule (Connor et al, 1984;Duzgunes et al, 1985). The pH-sensitive liposomes containing herpes simplex virus thymidine kinase gene released content into the cytoplasm and delivered DNA expressed efficiently in the cells (Wang & Huang, 1986).…”

“…Mechanistically, the pH-sensitive liposomes undergo rapid destabilization in acidic environments such as endosomes. They are generally composed of a neutral coneshaped lipid dioleoylphosphatidyl-ethanolamine (DOPE) and a weakly acidic amphiphile, such as cholesteryl hemisuccinate (CHEMS) (Lai et al, 1985). The fusogenic behavior of these liposomes is due to the DOPE present in its lipid layer, which does not form bilayer structure when dispersed in aqueous media but form hexagonal structure.…”