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(ethyl ene glycol)-diortho ester-distearoyl glycerol conjugate (POD). POD was prep ared 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 b ut degraded completely within 1 h at pH 5. Liposomes composed of 10% of POD and 90% of a fusogenic lipid, dioleoyl phosphatidylethanolamine (DOPE) wer e readily prepared and remained stable for up to 12 h in neutral buffer as shown by photon correlation spectrometry and a liposome contents leakage as say. However, when POD/DOPE liposomes were incubated in acidic pH as mild a s 5.5, they aggregated and released most of their contents within 30 min. T he kinetics of content release from POD/DOPE liposomes consisted of two pha ses, 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 relati onship with the buffer pH. When the POD/DOPE liposomes were incubated in 75 % of fetal bovine serum at 37 degreesC, they remained as stable as traditio nal PEG-grafted liposomes for 12 h but released 84% of the encapsulated ANT S in the following 4 h. Upon intravenous administration into mice, liposome s composed of 10% POD and 90% DOPE were cleared from circulation by a one-c ompartment kinetics with a half-life of about 200 min. POD is an example fo r the design of a novel category of pH sensitive lipids composed of a headg roup, an acid-labile diortho ester linker and a hydrophobic tail. The uniqu ely fast degradation kinetics of POD at pH 5-6 and its ability to stabilize liposomes in serum make the conjugate suitable for applications for trigge red drug release systems targeted to mildly acidic bioenvironments such as endosomes, solid tumors, and inflammatory tissues.