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 drug iododeoxyuridine (IDU) into the lipophilic prodrug dioleoyl-iododeoxyuridine (IDU-Ol2). The prodrug was incorporated into reconstituted high-density lipoprotein (NeoHDL) particles with physical and biological properties similar to those of native HDL. We also found, in initial experiments, that lactosylation of the prodrug-loaded NeoHDL increases 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-Ol2-loaded NeoHDL. The particles (containing approximately 25 prodrug molecules) have the same size and charge as native HDL, indicating that lactosylation does not cause aggregation or oxidative modification. At 10 min after intravenous injection of lactosylated [3H]IDU-Ol2-loaded NeòHDL into rats, only 13.5 +/- 2.8% of the dose was left in plasma and 75.9 +/- 2.4% of the dose was recovered in the liver. The relative specific uptake by the liver was 1-2 orders of magnitude higher than that of any other tissue. The hepatic uptake of lactosylated [3H]IDU-Ol2-loaded NeoHDL was much higher than that of free [3H]IDU ( < 20% of the dose). Both parenchymal liver cells and Kupffer cells express galactose-specific receptors. By isolating liver cells after injection of the prodrug-loaded particles, it was established that hepatic uptake occurred mainly (for 84.4 +/- 3.8%) in parenchymal liver cells. Preinjection with asialofetuin substantially reduced the liver uptake of lactosylated [3H]IDU-Ol2-loaded NeoHDL, which points to uptake by the asialoglycoprotein receptor. Subcellular fractionation of the liver indicated that lactosylated [3H]IDU-Ol2-loaded NeoHDL does not merely associate to cells, but is internalized and delivered to the lysosomes. In conclusion, we show that IDU can be specifically targeted to the parenchymal liver cell. Conversion of the water-soluble parent drug into a lipophilic prodrug that is incorporated into a lactosylated reconstituted HDL particle, is an approach that may also be used to deliver other water-soluble drugs to the parenchymal liver cells. This may lead to more effective therapy for liver diseases such as hepatitis B.