Vol. 301, Issue 2, 638-642, May 2002

Conjugates of Nucleoside Analogs with Lactosaminated Human Albumin to Selectively Increase the Drug Levels in Liver Blood: Requirements for a Regional Chemotherapy

Giuseppina Di Stefano, Marcella Lanza, Corrado Busi, Luigi Barbieri and Luigi Fiume

Department of Experimental Pathology, University of Bologna, Bologna, Italy

Nucleoside analogs (NAs) conjugated with galactosyl terminating peptides selectively enter hepatocytes via the asialoglycoprotein receptor and, after intracellular release from the carrier, partly exit from these cells into the bloodstream, resulting in higher concentrations in liver blood than in systemic circulation. Therefore, conjugates of anticancer NAs can be exploited to accomplish a loco-regional noninvasive treatment of liver micrometastases. In the present experiments we studied whether the enhancement of drug levels in liver blood achieved when NAs are given in the coupled form depends on the rate of drug elimination from the bloodstream. Three NAs, adenine arabinoside (ara-A), 5-fluoro-2'-deoxyuridine (FUdR), and 2',2'-difluorodeoxycytidine, were coupled with lactosaminated human albumin, a galactosyl terminating carrier. In rats that received an intravenous bolus injection of these conjugates, we compared the drug concentrations in liver blood to those in the systemic circulation. We found that enhanced levels of NAs in liver blood were only achieved by administering the conjugates of the drugs (ara-A and FUdR), which are rapidly cleared from the bloodstream. Increased drug levels also were obtained when ara-A and FUdR conjugates were slowly infused (a way of administration often used for anticancer drugs). The experiments also showed that galactosyl terminating conjugates of NAs might have the potential to produce a therapeutic effect only when the coupled drugs are active at low blood concentrations, since the amounts of drugs introduced into hepatocytes and released by these cells in the bloodstream cannot be increased when the receptor for the hepatic uptake of galactosyl terminating peptides is saturated.