Acid-Triggered Release from Sterically Stabilized Fusogenic Liposomes via a Hydrolytic DePEGylation Strategy†

A novel acid-labile poly(ethylene glycol) (PEG)-conjugated lipid, (R)-1,2-di-O-(1‘Z,9‘Z-octadecadienyl)-glyceryl-3-(ω-methoxy-poly(ethylene glycolate, MW5000) (BVEP), a neutral PEG-derivatized analogue of diplasmenylcholine, has been used at low molar ratios to disperse the nonlamellar, fusogenic lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as unilamellar liposomes. It was anticipated that acid-catalyzed hydrolysis of the vinyl ether linkages would destabilize BVEP/DOPE liposomes by removal of the water-soluble, sterically stabilizing PEG layer, thereby promoting contents release and membrane−membrane fusion. This paper describes the hydrolysis rates, contents release rates, and fusion kinetics of BVEP-stabilized DOPE liposomes at 1:99, 3:97, and 5:95 molar ratios of BVEP/DOPE. Calcein leakage kinetics indicate that 3:97 BVEP/DOPE liposomes offer the best stability at pH 7.4 while retaining favorable leakage properties at pH 4.5 (t50%release ≈ 4 h). N-Rhodamine phosphatidylethanolamine/N-nit...