SPECIFIC TARGETING OF A LIPOPHILIC PRODRUG OF IODODEOXYURIDINE TO PARENCHYMAL LIVER-CELLS USING LACTOSYLATED RECONSTITUTED HIGH-DENSITY-LIPOPROTEIN PARTICLES

We recently reported the conversion of the water-soluble antiviral dru g iododeoxyuridine (IDU) into the lipophilic prodrug dioleoyl-iododeox yuridine (IDU-Ol(2)). The prodrug was incorporated into reconstituted high-density lipoprotein (NeoHDL) particles with physical and biologic al properties similar to those of native HDL. We also found, in initia l experiments, that lactosylation of the prodrug-loaded NeoHDL increas es its liver uptake. Because this offers the attractive perspective of using these particles for the delivery of drugs to the liver, we now analyze the characteristics and biological fate of lactosylated IDU-Ol (2)-loaded NeoHDL. The particles (containing approximately 25 prodrug molecules) have the same size and charge as native HDL, indicating tha t lactosylation does not cause aggregation or oxidative modification. At 10 min after intravenous injection of lactosylated [H-3]IDU-Ol(2)-l oaded NeoHDL into rats, only 13.5 +/- 2.8% of the dose was left in pla sma and 75.9 +/- 2.4% of the dose was recovered in the liver. The rela tive specific uptake by the liver was 1-2 orders of magnitude higher t han that of any other tissue. The hepatic uptake of lactosylated [H-3] IDU Ol(2)-loaded NeoHDL was much higher than that of free [H-3]IDU (<2 0% of the dose). Both parenchymal liver cells and Kupffer cells expres s galactose-specific receptors. By isolating liver cells after injecti on of the prodrug-loaded particles, it was established that hepatic up take occurred mainly (for 84.4 +/- 3.8%) in parenchymal liver cells. P reinjection with asialofetuin substantially reduced the liver uptake o f lactosylated [H-3]IDU Ol(2)-loaded NeoHDL, which points to uptake by the asialoglycoprotein receptor. Subcellular fractionation of the liv er indicated that lactosylated [H-3]IDU-Ol(2)-loaded NeoHDL does not m erely associate to cells, but is internalized and delivered to the lys osomes. In conclusion, we show that IDU can be specifically targeted t o the parenchymal liver cell. Conversion of the water soluble parent d rug into a lipophilic prodrug that is incorporated into a lactosylated reconstituted HDL particle, is an approach that may also be used to d eliver other water-soluble drugs to the parenchymal liver cells. This may lead to more effective therapy for liver diseases such as hepatiti s B.