Conjugation of 5-fluoro-2'-deoxyuridine with lactosaminated poly-l-lysine to reduce extrahepatic toxicity in the treatment of hepatocarcinomas

Abstract

Background: The hepatocyte receptor for asialoglycoproteins, which binds and internalizes galactosyl-terminating peptides, was found to be expressed also on the cells of well differentiated hepatocarcinomas.

Aims: We explored the possibility of obtaining a delivery of antiblastic drugs to hepatocarcinoma cells through this receptor.

Methods: We conjugated 5-fluoro-2'-deoxyuridine (FUDR) with lactosaminated poly-L-lysine. 5-fluoro-2'-deoxyuridine is an active drug in the treatment of solid tumours, but with toxic effects on intestine and bone marrow. Poly-L-lysine is an galactosyl-terminating carrier which enables preparation of conjugates with very high drug load. We studied the pharmacological activity of poly-L-lysine-5-fluoro-2'-deoxyuridine conjugate on in vitro proliferation of Hep G2 cells, a human hepatocarcinoma cell line. Moreover, we compared the levels of radioactivity in liver, intestine and heart of mice injected with free or conjugated [3H]5-fluoro-2'-deoxyuridine.

Results: We found that poly-L-lysine-5-fluoro-2'-deoxyuridine enters into Hep G2 cells through the asialoglycoprotein receptor and, after intracellular penetration, releases the drug in a pharmacologically active form. Administered to mice, the conjugate leads to enhanced accumulation of the drug in liver versus the intestine and the heart.

Conclusions: These data support conjugation with poly-L-lysine as a way to obtain drug targeting to those hepatocellular carcinomas which maintain the asialoglycoprotein receptor.