Steric stabilization of fusogenic liposomes by a low-pH sensitive PEG--diortho ester--lipid conjugate.
We describe the synthesis and characterization of a pH-sensitive poly(ethylene glycol)-diortho ester-distearoyl glycerol conjugate (POD). POD was prepared by a one-step synthesis, and its acid sensitivity characterized by TLC. The conjugate was found to be stable at neutral pH for greater than 3 h but degraded completely within 1 h at pH 5. Liposomes composed of 10% of POD and 90% of a fusogenic lipid, dioleoyl phosphatidylethanolamine (DOPE) were readily prepared and remained stable for up to 12 h in neutral buffer as shown by photon correlation spectrometry and a liposome contents leakage assay. However, when POD/DOPE liposomes were incubated in acidic pH as mild as 5.5, they aggregated and released most of their contents within 30 min. The kinetics of content release from POD/DOPE liposomes consisted of two phases, a lag phase, and a burst phase. The lag phase is inversely correlated with pH and the logarithm of the length of lag phase showed a linear relationship with the buffer pH. When the POD/DOPE liposomes were incubated in 75% of fetal bovine serum at 37 degrees C, they remained as stable as traditional PEG-grafted liposomes for 12 h but released 84% of the encapsulated ANTS in the following 4 h. Upon intravenous administration into mice, liposomes composed of 10% POD and 90% DOPE were cleared from circulation by a one-compartment kinetics with a half-life of about 200 min. POD is an example for the design of a novel category of pH sensitive lipids composed of a headgroup, an acid-labile diortho ester linker and a hydrophobic tail. The uniquely fast degradation kinetics of POD at pH 5-6 and its ability to stabilize liposomes in serum make the conjugate suitable for applications for triggered drug release systems targeted to mildly acidic bio-environments such as endosomes, solid tumors, and inflammatory tissues.
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Departments of Pharmaceutical Chemistry and Biopharmaceutical Sciences, University of California at San Francisco, San Francisco, California 94143-0446, USA.
Szoka
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D000818:Animals; D004952:Esters / Q000737:chemistry; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D020404:Glycerophospholipids / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D015394:Molecular Structure; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D004952:Esters; D005456:Fluorescent Dyes; D020404:Glycerophospholipids; D007457:Iodine Radioisotopes; D008055:Lipids; D008081:Liposomes; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D005990:Glycerol