Liver targeting of antiviral nucleoside analogues through the asialoglycoprotein receptor

Summary. In order to reduce the extrahepatic side‐effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl‐terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with the asialoglycoprotein receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The validity of this chemotherapeutic strategy has been endorsed by a clinical study. Adenine arabinoside monophosphate (ara‐AMP), conjugated with lactosaminated human serum albumin (L‐HSA) and administered to hepatitis B virus (HBV)‐infected patients for 28 days, exerted an antiviral activity to the same extent as the free drug without producing any clinical side‐effects, including the severe neurotoxicity caused by the free drug. Preclinical studies are now underway with conjugates obtained using lactosaminated poly‐L‐lysine (Lacpoly(Lys)) as the hepatotropic carrier. These new conjugates have some advantages over those prepared with L‐HSA: they can be administered by the intramuscular route; they are obtained entirely by chemical synthesis, thus eliminating the problems involved in the use of haemoderivatives; they have a heavy drug load, which permits administration of smaller quantities of conjugate that are more easily digested in lysosomes; and they enable higher quantities of drug to be introduced into hepatocytes. The results of the experiments with two Lac‐poly(Lys) conjugates, one with ara‐AMP and one with ribavirin, are reported in this review.