Design and Synthesis of Novel Amphiphilic Dendritic Galactosides for Selective Targeting of Liposomes to the Hepatic Asialoglycoprotein Receptor

Abstract

A series of glycolipids have been prepared which contain a cluster galactoside moiety with high affinity for the hepatic asialoglycoprotein receptor and a bile acid ester moiety which mediates stable incorporation into liposomes. Loading of liposomes with these glycolipids at a ratio of 5% (w/w) resulted in efficient recognition and uptake of the liposomes by the liver. Preinjection with asialofetuin almost completely inhibited the uptake, establishing that the liposomes were selectively recognized and processed by the asialoglycoprotein receptor on liver parenchymal cells. In contrast, a glycolipid content of 50% (w/w) led to a liver uptake that could not be inhibited by preinjection with asialofetuin, indicating that the liposomes were now processed by the Gal/Fuc-recognizing receptor on liver macrophages. The results presented in this study are important for future targeting of water-soluble and amphiphilic drugs, enveloped in these glycolipid-laden liposomes, to parenchymal liver cells.

Glycosylation-mediated targeting of carriers

“…This corresponded with a report by Sliedregt et al [132]. These observations demonstrate the importance of the galactose density of galactosylated liposomes as well as the design of synthetic galactosylated lipids for hepatocyte-selective delivery.…”

Lipid Carrier Systems for Targeted Drug and Gene Delivery

“…Therefore, cholesterol was chosen as a hydrophobic anchor, which is stably associated with the liposomal membrane 36,37) and only mono-galactoside was introduced to the lipid as a ligand because the introduction of many hydrophilic galactose moieties to a lipid anchor would result in their removal from liposomes by interacting with lipoproteins and/or other lipid compartments under in vivo conditions. 38) We synthesized a novel galactosylated cholesterol derivative, i.e., cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)-amino)butyl) formamide (Gal-C4-Chol), to modify lipid carriers with galactose moieties for hepatocyte targeting. 39) When Gal-C4-Chol was added to O/W emulsions, a hydrophilic galactose moiety was fixed to the particle surface.…”

Synthesis of phospholipid-conjugated bile salts and interaction of bile salt-coated liposomes with cultured hepatocytes

“…Collagenase Worthington CLS II (specific activity of 220-230 U/mg protein) was obtained from Biochrom KG (Berlin, Germany). [1,[2][3] H]cholesterylhexadecylether (1.9 TBq/mmol) was from NEN Life Science Products GmbH (Frankfurt, Germany), and [ 3 H-(G)]CT was from Biotrend Chemikalien GmbH (Cologne, Germany). All other chemicals were of the highest quality available commercially.…”

“…Hepatocyte-specific targeting of liposomes has been achieved by covalently linking the ligand of a hepatocyte-specific receptor to a lipid moiety. The most prominent targeted receptor is the hepatic asialoglycoprotein receptor, which has been targeted by various galactosyllipids (1,2) or by asialofetuin, a glycoprotein (3). Glycyrrhizin (4) and a soybean-derived sterylglucoside mixture (5) have been used to target hepatocytes via receptors that have not yet been identified at the molecular level.…”