LIVER TARGETING OF ANTIVIRAL NUCLEOSIDE ANALOGS THROUGH THE ASIALOGLYCOPROTEIN RECEPTOR

In order to reduce the extrahepatic side-effects of antiviral nucleosi de analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl-terminating macromolecules. The conjuga tes selectively enter hepatocytes after interaction of the carrier gal actose 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 bet ween the carrier and the drug, allowing the latter to become concentra ted in the liver, The validity of this chemotherapeutic strategy has b een endorsed by a clinical study, Adenine arabinoside monophosphate (a ra-AMP), conjugated with lactosaminated human serum albumin (L-HSA) an d administered to hepatitis B virus (HBV)-infected patients for 28 day s, exerted an antiviral activity to the same extent as the free drug w ithout producing any clinical side-effects, including the severe neuro toxicity caused by the free drug, Preclinical studies are now underway with conjugates obtained using lactosaminated poly-l-lysine (Lac-poly (lys)) as the hepatotropic carrier, These new conjugates have some adv antages over those prepared with L-HSA: they can be administered by th e intramuscular route; they are obtained entirely by chemical synthesi s, thus eliminating the problems involved in the use of haemoderivativ es; they have a heavy drug load, which permits administration of small er quantities of conjugate that are more easily digested in lysosomes; and they enable higher quantities of drug to be introduced into hepat ocytes. The results of the experiments with two Lac-poly(Lys) conjugat es, one with ara-AMP and one with ribavirin, are reported in this revi ew.