Study On The Design, Synthesis And Targeting Capability Of Ligands For ASGP-R-mediated Liposomes

The hepatic diseases occur frequently in clinical practice. Many drugs used for hepatitis, liver fibrosis, cirrhosis and hepatoma clinically no organ selectivity, which lead to low drug concentration in liver. The hepatic targeted drug delivery system (HTDDS) selectively distributes drugs to the pathological parts of liver, so that it can reduce the poisonous side effects to normal organs and enhance bioavailability.On the surface of parenchymal cells, hepatocytes, exists an unique receptor protein, the galactose (Gal)- or N-acetylgalactosamine (GalNAc)-recognizing asialo-glycoprotein receptor (ASGP-R). In view of its exclusive and abundant presence on hepatocytes, and because of its high-affinity and high rate of internalization, the ASGP-R was considered a promising candidate target in many drug carrier studies.During the past more than 30 years, a lot of liver targeting conjugates mediated by ASGP-R have been prepared and reported. Antitumor drugs NGA-DNAQ was synthesized by coupling NGA to DNAQ as a targeting drug to liver via a butanediamide bridge. NGA were coupled with an antiviral drug ACV or primaquine to form NGA-ACV or NGA-PQ. The common characteristic of this structure is that all conjugates include three parts (galactosyl residue, protein carrier and drug molecule). Protein drugs or peptides could also been targeted to the liver cells by the ASGP-R if they are covalently coupled to some galactosyl residues. Under of the guidance of the idea, Gal-SOD, Gal-Interferon α₁ and Gal-Ant-CD₃mCaB-TIL were prepared and results of imaging in the rabbits and biodistribution of mice indicated that the liver uptake rates of Gal-SOD and Gal-Interferonα₁ were much higher than those in control.