Drug targeting in antiviral chemotherapy. A chemically stable conjugate of 9-beta-D-arabinofuranosyl-adenine 5'-monophosphate with lactosaminated albumin accomplishes a selective delivery of the drug to liver cells.
With the aim of improving the chemotherapeutic index of 9-beta-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.
Fiume
L
L
Bassi
B
B
Busi
C
C
Mattioli
A
A
Spinosa
G
G
D000818:Animals; D001088:Arabinonucleotides / Q000008:administration & dosage*; D001853:Bone Marrow / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005260:Female; D006509:Hepatitis B / Q000188:drug therapy; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D014677:Pharmaceutical Vehicles; D012709:Serum Albumin / Q000008:administration & dosage* / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D001084:Vidarabine Phosphate / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity
D001088:Arabinonucleotides; D014677:Pharmaceutical Vehicles; D012709:Serum Albumin; C046912:lactosaminated serum albumin; D001084:Vidarabine Phosphate; D004247:DNA; D013936:Thymidine