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Mechanism of pH-Triggered Collapse of Phosphatidylethanolamine Liposomes Stabilized by an Ortho Ester Polyethyleneglycol Lipid

Xin Guo^*, J. Andrew MacKay and Francis C. Szoka, Jr.

^* Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California; Joint Graduate Group in Bioengineering, University of California at San Francisco and Berkeley, San Francisco, California; and Department of Biopharmaceutical Sciences, University of California at San Francisco, San Francisco, California

Correspondence: Address reprint requests to Francis C. Szoka, Jr., Dept. of Biopharmaceutical Sciences, HSE 1145, 513 Parnassus Ave., University of California, San Francisco, CA 94143-0446. Tel.: 415-476-3895; Fax: 415-476-0688; E-mail: szoka{at}cgl.ucsf.edu.

The mechanism of pH-triggered destabilization of liposomes composed of a polyethyleneglycol-orthoester-distearoylglycerol lipid (POD) and phosphatidyl ethanolamine (PE) has been studied using an ANTS/DPX leakage and a lipid-mixing assay. We developed a kinetic model that relates POD hydrolysis to liposome collapse. This minimum-surface-shielding model describes the kinetics of the pH-triggered release of POD/PE liposomes. In the model, when acid-catalyzed hydrolysis lowers the mole percentage of POD on the liposome surface to a critical level, intervesicular lipid mixing is initiated, resulting in a burst of contents release. Two phases of content leakage are observed: a lag phase and a burst phase. During the lag phase, less than 20% of liposomal contents are released and the leakage begins to accelerate when approaching to the transition point. During the burst phase, the leakage rate is dependent on interbilayer contact. The burst phase occurs when the surface density of the PEG lipid is 2.3 ± 0.6 mol%, regardless of the pH. Vesicles containing 4 mol% of a pH-insensitive PEG-lipid conjugate and 10% POD did not leak contents or collapse at any pH. These data are consistent with the stalk theory to describe the lamellar-to-inverted hexagonal phase transition and set a lower bound of 16 PE lipids on the external monolayer as the contact site required for lipid mixing between two bilayers.