The stability and tissue distribution of lipid vesicles modified at the surface by the incorporation ofeither a galactosyl ceramide (GalCer)'or a galactosyl'cholesterol (GalChol) glycoconjugate have been studied in. mice by measuring the release of vesicle-entrapped "'1In. Although the tissue distributions of both vesicle types were similar, the GalCer-containing vesicles were markedly less stable than those. prepared with GalChol, whether administered orally or by intraperitoneal injection. Physical characterization of the vesicles in vitro suggests that the increased disruption rate for GalCer vesicles in vivo is related to. structural instabilities induced by the cerebroside, which can then result in either an increased rate of vesicle uptake by tissues or a greater susceptibility to lysis. These studies demonstrate the importance ofthe nonpolar anchoring groups in determining the fate of surface-modified vesicles in vivo.The targeting ofencapsulated agents, such as drugs or enzymes, to specific tissues is one of the goals in the development of liposomes as exogenous delivery systems. To achieve this result, a number of strategies have been attempted, including the addition ofcharged lipids to neutral vesicles (1), the covalent binding of antibodies to vesicle surfaces (2), and the use oflocalized hyperthermia to induce phase transitions in synthetic liposomes (3). The finding that mammalian hepatocyte surfaces contain a galactose-specific glycoprotein binding site (4) has led to studies on the usefulness ofcarbohydrate-modified vesicles in targeting encapsulated materials (5-7). Initial work has shown great promise (7), leading to further investigation ofvariables that can affect the system. Due to the amphiphilic nature of vesicle bilayers, it is convenient to incorporate polar carbohydrate molecules by attaching them to nonpolar lipid groups. In view' of the importance of lipid shape to vesicle structure (8), it is likely that the choice of lipid conjugate or anchoring group will, in addition to the type of carbohydrate used, affect the fate of modified vesicles in vivo. In the present communication; we report studies of carbohydrate-modified vesicles containing glycolipids differing in the structure oftheir nonpolar group. The results, comparing the effects of N-stearoyl-DL-dihydrogalactocerebroside (galactosyl ceramide, GalCer, II) with those of 6-(5-cholesten-3f-yloxy)hexyl-l-thio-(3-D-galactopyranoside (galactosyl cholesterol, GalChol, I) demonstrate the importance of the carbohydrate anchoring group in maintaining stable vesicles in vivo.