1997 Volume 9 Issue 50 Pages 461-472
The aim of liver glycotargeting of antiviral nucleoside analogues (NAs) is to reduce the extrahepatic side effects of these drugs in the treatment of chronic viral hepatitis. For this purpose NAs are conjugated with galactosyl-terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with a lectin (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 majority of experiments of liver glycotargeting of NAs have been performed employing a conjugate of lactosaminated human albumin with adenine arabinoside monophosphate (ara-AMP), a phosphorylated NA active against hepatitis B virus. This conjugate, administered to patients with chronic hepatitis B, exerted the same antiviral activity as the free drug without producing any clinical side effect, including the severe neurotoxicity caused by free ara-AMP.
Pre-clinical studies are now underway with conjugates obtained using lactosaminated poly-L-lysine [Lac-poly(LYS)] as the hepatotropic carrier. These new conjugates have some advantages over those prepared with L-HSA: (a) they can be administered by the intramuscular route; (b) they are obtained entirely by chemical synthesis, thus eliminating the problems involved in the use of hemoderivatives; (c) they have a heavy drug load, enabling administration of smaller quantities of conjugate, more easily digested in lysosomes; (d) they allow higher quantities of drug to be introduced into hepatocytes. The results of experiments with two Lac-poly (LYS) conjugates, one with ara-AMP and one with ribavirin (a drug active in treatment of type C hepatitis), further support the validity of the liver targeting approach through the asialoglycoprotein receptor.
In conclusion, coupling to galactosyl-terminating carriers appears to be a way of obtaining higher concentrations of antiviral NAs within hepatocytes and permitting the administration of drugs, whose use would otherwise be prevented by extrahepatic side effects.
