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, which binds and internalizes galactosyl-terminating peptides, was found to be expressed also on the cells of well differentiated hepatocarcinomas.


OBJECTIVE
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.
Department of Experimental Pathology, University of Bologna, Italy.
G
G
Di Stefano
C
C
Busi
M
M
Derenzini
D
D
Trerè
L
L
Fiume
D000606:Amino Sugars / Q000008:administration & dosage; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D004195:Disease Models, Animal; D004337:Drug Carriers; D004355:Drug Stability; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D006321:Heart / Q000187:drug effects*; D007422:Intestines / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D011107:Polylysine / Q000008:administration & dosage* / Q000737:chemistry; D012016:Reference Values; D014018:Tissue Distribution
D000606:Amino Sugars; D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D005467:Floxuridine; C032233:lactosamine; D011107:Polylysine