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pH-dependent stability and fusion of liposomes combining protonatable double-chain amphiphiles with phosphatidylethanolamine.

We have prepared a series of novel double-chain amphiphiles with protonatable head groups, including acylated derivatives of various 2-substituted palmitic acids, amino acid conjugates of these species, and 1,2-dioleoyl-3-succinylglycerol. These species can be combined with phosphatidylethanolamine (PE) to prepare reverse-phase evaporation vesicles that are stable and trap hydrophilic solutes at pH 7. At weakly acidic pH values (as high as 6.5, depending on the titratable amphiphilic component), these pH-sensitive vesicles exhibit fusion, with a limited extent of contents mixing and extensive mixing of lipids, accompanied by leakage of aqueous contents. Protons and divalent cations show strong synergistic effects in promoting mixing of both lipids and aqueous contents between pH-sensitive vesicles prepared with any of a variety of double-chain titratable amphiphiles. Calorimetric results indicate that the relative stabilities of different types of pH-sensitive liposomes at low pH cannot be simply correlated with the propensity of the lipids to form a hexagonal II phase under these conditions. Fluorescence measurements demonstrate that single-chain fatty acids, but not double-chain titratable amphiphiles such as N-acyl-2-aminopalmitic acids, are rapidly removed from pH-sensitive vesicles in the presence of other lipid vesicles, serum albumin, or serum. Additionally, pH-sensitive liposomes containing double-chain titratable amphiphiles retain their aqueous contents better than do those containing single-chain amphiphiles in the presence of lipid membranes or albumin. Surprisingly, however, pH-sensitive vesicles of either type show retention of contents in the presence of serum that is comparable to that observed with vesicles composed purely of phospholipids. A model is proposed to explain these latter findings.