Esterase-catalyzed dePEGylation of pH-sensitive vesicles modified with cleavable PEG-lipid derivatives

To make vesicles for the better controlled content release, we modified cholesteryl hemisuccinate (CHEMS)-derived vesicles with PEG-lipid derivatives. Two cholesterol analogs, cholesteryl hemisuccinate (CHEMS) and cholesteryl chloroformate (CHM), have been conjugated to the polyethylene glycol (PEG) via their ester bonds for the vesicle modifications, so the PEGs can be cleaved by esterases. The effects of PEG-lipid proportions, serum concentrations and the lipid types on the esterase-catalyzed cleavage of PEG polymer off the vesicles surface were determined. We observed that PEG cleavages decreased as the molar ratios of the PEG-lipids in vesicles increased; on the other hand, PEG cleavages gradually increased with the increased serum concentrations. In contrast to conventional long circulation materials mPEG-DSPE and mPEG-CHOL, the two new conjugates enabled higher degrees of PEG cleavages from modified vesicles. After incubation in the serum at acidic conditions, esterase-catalyzed dePEGylation destabilized these vesicles, increasing the mean particle sizes and promoting content releases. These results suggested that ester linkages between the PEG and lipid anchors allow faster content releases in the suitable conditions. Together, the two esterase cleavable PEG-lipid conjugations may be applied not only to stabilize vesicles and prolong their circulation time, but also to provide more efficient content releases by the esterase controlled dePEGylation.