Poly(ethylene glycol)‐lipid conjugates inhibit phospholipase C‐induced lipid hydrolysis, liposome aggregation and fusion through independent mechanisms

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Abstract
Poly(ethylene glycol)‐phosphatidylethanolamine (PEG‐PE) conjugates have been introduced in liposomal compositions. The resulting large unilamellar vesicles were subjected to the action of phospholipase C. Enzyme‐promoted vesicle aggregation and fusion were assayed in liposomes containing various proportions of PEG‐PE. At PEG‐PE concentrations above 1 mol% the rate of phospholipid hydrolysis decreases, perhaps because the PEG moiety hinders the enzyme from reaching the membrane surface. At concentrations above 0.1 mol% vesicle aggregation occurs at a slower rate, presumably because of the repulsive barrier properties or surface‐grafted PEG. Lipid mixing decreases in parallel with vesicle aggregation. Finally, liposomal fusion rates measured as mixing of vesicle aqueous contents are decreased at or even below 0.1 mol%. The latter inhibition is due, apart from the reduced rates of lipid hydrolysis, vesicle aggregation and lipid mixing, to a PEG‐PE‐based stabilization of the lipid bilayer structure. Thus the observed low rates of contents mixing arise from three combined and independent inhibitory effects of PEG‐PE.

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