Journal
FRONTIERS IN BIOSCIENCE
Volume 7, Issue -, Pages D717-D725Publisher
FRONTIERS IN BIOSCIENCE INC
DOI: 10.2741/wu2
Keywords
asialofetuin, asialoglycoprotein receptor; carbohydrate recognition domain; drug delivery; hepatocyte; gene therapy; liposome; liver; polymers; targeting therapy; review
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Funding
- NIAAA NIH HHS [AA-06386] Funding Source: Medline
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA006386] Funding Source: NIH RePORTER
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The asialoglycoprotein receptor (ASGP-R) on mammalian hepatocytes provides a unique means for the development of liver-specific carriers, such as liposomes, recombinant lipoproteins, and polymers for drug or gene delivery to the liver, especially to hepatocytes. The abundant receptors on the cells specifically recognize ligands with terminal galactose or N-acetylgalactosamine residues, and endocytose the ligands for an intracellular degradation process. The use of its natural ligand, i.e. asialofetuin, or synthetic ligands with galactosylated or lactosylated residues, such as galactosylated cholesterol, glycolipids, or galactosylated polymers has achieved significant targeting efficacy to the liver. There are several examples of successful targeted therapy for acute liver injury with asialofetuin-labeled and vitamin E-associated liposomes or with a caspase inhibitor loaded in sugar-carrying polymer particles, as well as for the delivery of a new antiviral agent, 9-(2-phosphonylmethoxyethyl) adenine. Liposome-mediated gene delivery to the liver is more difficult than to other organs, such as to lungs. It is still in its infancy due to difficulties in solving general issues, such as the circulatory stability of liposome-DNA complexes, and lysosomal or endosomal degradation of plasmid DNA. In spite of these existing concerns, several new approaches offer some reason for optimism, for example; intravenous injection of asialofetuin- or galactosylated cholesterol-labeled cationic liposomes has led to high transgene expression in the liver. In addition, specific antisense oligonucleotides against woodchuck hepatitis viruses incorporated into sialoorosomucoid-poly-L-lysine significantly inhibited viral replication in the liver. Finally, galactosylated polymers are promising for gene delivery, but require further studies to verify their potential applications.
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