Drug targeting in antiviral chemotherapy: A chemically stable conjugate of 9-β-d-arabinofuranosyl-adenine 5'-monophosphate with lactosaminated albumin accomplishes a selective delivery of the drug to liver cells

Abstract With the aim of improving the chemotherapeutic index of 9-β- d -arabinofuranosyl-adenine 5' monophosphate (ara-AMP) in the treatment of chronic hepatitis B, this drug was conjugated with lactosaminated serum albumin ( l -SA), a neoglycoprotein which only enters into hepatocytes. We used a l -SA-ara-AMP conjugate which, in contrast to those previously employed, has the advantage of remaining soluble after lyophilization. We found in mice that: (I) this new conjugate was quite stable in the bloodstream where only a small part of ara-AMP was released; (II) after administration of the conjugate labelled in the drug moiety both acid insoluble and soluble radioactivities were several times higher in liver than in other organs; (III) in mice with Ectromelia virus hepatitis, the conjugate inhibited virus DNA synthesis in liver without affecting cellular DNA synthesis in intestine and bone marrow; (IV) the conjugate did not display any recognizable sign of acute toxicity even at doses several fold higher than those pharmacologically active; and (V) when prepared with homologous albumin it was not immunogenic.