SYNTHESIS AND PHARMACOKINETICS OF A NEW LIVER-SPECIFIC CARRIER, GLYCOSYLATED CARBOXYMETHYL-DEXTRAN, AND ITS APPLICATION TO DRUG TARGETING

To develop a new carrier system for hepatic targeting, carboxymethyl-d extran (CMD) was modified with galactose and mannose residues (Gal-CMD , Man-CMD), and their disposition characteristics were studied in mice using C-14-labeled dextran. At a dose of 1 mg/kg, i.v.-injected Gal-C MD and Man-CMD rapidly accumulated in the liver parenchymal and nonpar enchymal cells, respectively, because of their preferential uptake via carbohydrate receptors in these cells. Pharmacokinetic analysis revea led that their uptake rates were sufficiently large for selective drug targeting. Targeting of cytosine beta-D-arabinoside (araC) was studie d using Gal-CMD as a specific carrier to the hepatocytes. From the con jugate of araC with Gal-CMD, araC was released with a half-life of 36 hr in phosphate buffer (pH 7.4) and 23 hr in plasma. An in vivo biodis tribution study demonstrated a disposition profile of the conjugated a raC similar to that of the carrier, and selective delivery to hepatocy tes of up to 80% of the dose was achieved. These findings suggest that glycosylated CMDs are carriers with a high affinity to liver parenchy mal or nonparenchymal cells without any affinity to other tissues.