CONJUGATION OF 5-FLUORO-2'-DEOXYURIDINE WITH LACTOSAMINATED POLY-L-LYSINE TO REDUCE EXTRAHEPATIC TOXICITY IN THE TREATMENT OF HEPATOCARCINOMAS

Background. The hepatocyte receptor for asialoglycoproteins ins, 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 antibla stic 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 o f solid tumours, but with toxic effects on intestine and bone marrow P oly-L-lysine is an galactosyl-terminating carrier which enables prepar ation of conjugates with very high drug load. We studied the pharmacol ogical 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 intes tine and heart of mice injected with free or conjugated [H-3]5-fluoro- 2'- deoxyuridine. Results. We found that poly-L-lysine-5-fluoro-2'-deo xyuridine enters into Hep G2 cells through the asialoglycoprotein rece ptor and after intracellular penetration, releases the drug in a pharm acologically active form. Administered to mice, the conjugate lends to enhanced accumulation of the drug in liver versus the intestine and t he heart. Conclusions, These data support conjugation with poly-L-lysi ne as a way to obtain drug targeting to those hepatocellular carcinoma s which maintain the asialoglycoprotein receptor.