Synthesis of the dioleoyl derivative of iododeoxyuridine and its incorporation into reconstituted high density lipoprotein particles.

We investigated the potential use of reconstituted HDL particles (NeoHDL) as a carrier for lipophilic (pro)drugs. The antiviral drug iododeoxyuridine (IDU) was used as model compound. [3H]-IDU was derivatized with two oleoyl residues to dioleoyl[3H]iododeoxyuridine ([3H]IDU-Ol2), and the lipophilic prodrug was incorporated into NeoHDL by cosonication of [3H]IDU-Ol2 with lipids and HDL apoproteins. NeoHDL particles with the same density, size, and electrophoretic mobility as native HDL were obtained, which contained 7.3 +/- 0.8% (w/w) [3H]IDU-Ol2 (about 30 molecules of prodrug per particle). NeoHDL-associated [3H]IDU-Ol2 was stable during 2 h of incubation with human plasma; the prodrug was not appreciably hydrolyzed, nor exchanged with LDL. After intravenous injection of [3H]-IDU-Ol2-loaded 125I-NeoHDL into rats, [3H]IDU-Ol2 disappeared more rapidly from the circulation than the 125I-apoproteins (78.0 +/- 8.0% vs 30.1 +/- 4.5% of the dose cleared from plasma in 60 min, respectively). The hepatic association of the prodrug was higher than that of the apoproteins (21.6 +/- 0.5 vs 5.2 +/- 1.0% of the dose at 10 min after injection, respectively). As selective clearance and uptake of lipid esters is also observed with native HDL, this suggests that, in vivo, prodrug-loaded NeoHDL may be subject to physiological HDL-specific processing. Lactosylated [3H]IDU-Ol2-loaded 125I-NeoHDL, which contains galactose residues that can be recognized by galactose receptors on parenchymal liver cells, was rapidly cleared from plasma.(ABSTRACT TRUNCATED AT 250 WORDS)