SPECIFIC TARGETING OF THE ANTIVIRAL DRUG 5-IODO 2'DEOXYURIDINE TO THEPARENCHYMAL LIVER-CELL USING LACTOSYLATED POLY-L-LYSINE

In this study, we describe the development and characterization of lac tosylated poly-L-lysine as a potential carrier for targeting anti-vira l drugs to the parenchymal liver cell: Poly-L-lysine (M(r) 38 000) was modified with 2 to 130 lactose residues per molecule poly-L-lysine. I n vitro competition studies for the asialoglycoprotein receptor on par enchymal liver cells using I-125-asialoorosomucoid as radioligand reve aled that mild modification of poly-L-lysine with only five lactose re sidues was sufficient for high affinity competition. In vivo studies s howed that, after injection of poly-L-lysine modified with at least fi ve lactose residues, about 70-80% of the injected dose was taken up by the liver. Preinjection of N-acetyl galactosamine almost completely b locked the hepatic uptake of lactosylated poly-L-lysine, indicating th at galactose-recognizing receptors are involved. At 10 min following i njection, the contribution of the various liver cell types to the hepa tic uptake of lactosylated poly-L-lysine was determined; the parenchym al cell appeared to be responsible for more than 98% of the total live r uptake. To assess the applicability of lactosylated poly-L-lysine as an anti-viral drug carrier, it was derivatized with 4 to 15 residues of the antiviral drug 5-iodo 2'-deoxyuridine, 5'-monophosphate per mol ecule poly-L-lysine (4-16% by weight) via an acid-labile phosphamide b ond. Maximally 0.7% of the conjugated 5-iodo 2'-deoxyuridine 5'-monoph osphate was released after 1 h incubation of the drug/carrier conjugat e with serum at 37 degrees C, thus establishing the stability of the c onjugate in serum. The drug-carrier conjugate was rapidly cleared from the bloodstream within 1. min. Approximately 90% of the injected dose could be recovered in the liver. The parenchymal liver cell was respo nsible for 97% of the hepatic uptake. lit vitro studies on the kinetic s of endocytosis of lactosylated poly-L-lysine, derivatized with 5-iod o 2'-deoxyuridine 5'-monophosphate, by parenchymal liver cells reveale d that the ligand was immediately internalized and, after a 10-min lag phase, deacetylated. Internalization and degradation did not occur in the presence of 100 mM N-acetyl galactosamine. In conclusion, the bio availability of 5-iodo 2'-deoxyuridine 5'-monophosphate to the parench ymal liver cell is dramatically enhanced as a result of the conjugatio n of the anti-viral drugs to lactosylated poly-L-lysine. Accordingly, lactosylated poly-L-lysine constitutes a suitable carrier for targetin g anti-viral drugs to the parenchymal liver cell. It is suggested that 5-iodo 2'-deoxyuridine 5'-monophosphate, conjugated to lactosylated p oly-L-lysine might constitute effective therapy against viral infectio ns such as chronic hepatitis B, which involve the parenchymal liver ce ll. (C) Journal of Hepatology.