The cell glycocalyx is an attractive model for surface modification of liposomes, because its hydrated oligosaccharide layer inhibits nonspecific protein adsorption and can provide specificity towards desired sites. Here, we report on the use of lactose as a model saccharide to modify the liposome surface and examine the vesicle size and stability. Two kinds of lactosyl lipids, including lactosyl ether-lipid (6a) and lactosyl ester-lipid (6b), which contain octadecyl and octadecanoyl as the lipid tails, respectively, were synthesized and their liposomes were prepared by the extrusion method. The effects of glycolipid structure, concentration, and the pore size of the extrusion membrane on vesicle size and stability were investigated at room temperature by photon correlation spectroscopy (PCS). All liposomes with 5 or 10 mol% of lactosyl lipids had a narrow size distribution and remained stable at room temperature for at least one month, which is comparable to 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)- and poly(ethylene glycol) (PEG)-liposomes. The maximum incorporation of lactosyl ester-lipid into liposomes was 15 mol%, compared with only 10 mol% for the lactosyl ether-lipid. The lactosyl ester-liposomes had better stability and exhibited less size change than the lactosyl ether-liposomes at 15 or 20 mol% of lactosyl lipids incorporated. This may be attributed to the better structural compatibility of lactosyl ester-lipid with DSPC. The PCS results show that the glycolipid structure and concentrations are major factors that affect vesicle stability, while the pore size of extrusion membranes has no influence. (c) 2005 Elsevier Inc. All rights reserved.