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. [H-3]- IDU was derivatized with two oleoyl residues to dioleoyl[H-3]iododeoxyuridine ([H-3]IDU-Ol(2)), and the lipophilic prodrug was incorporated into NeoHDL by cosonication of [H-3]IDU-Ol(2) 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) [H-3]IDU-Ol(2) (about 30 molecules of prodrug per particle). NeoHDL-associated [H-3]IDU-Ol(2) was stable during 2 h of incubation with human plasma; the prodrug was not appreciably hydrolyzed, nor exchanged with LDL. After intravenous injection of [H-3]IDU-Ol(2)-loaded I-125-NeoHDL into rats, [H-3]IDU-Ol(2) disappeared more rapidly from the circulation than the I-125-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 [H-3]IDU-Ol(2)-loaded I-125-NeoHDL, which contains galactose residues that can be recognized by galactose receptors on parenchymal liver cells, was rapidly cleared from plasma. At 10 min after injection, only about 10% of the injected I-125-apoprotein and H-3-prodrug was left in plasma, and approximately 75% of the injected amount of both labels was recovered in the liver. We conclude that it is possible to convert a hydrophilic drug, like IDU, into a lipophilic prodrug that can be efficiently incorporated into a reconstituted HDL particle with similar properties as native HDL. The same approach may be applied for other water-soluble drugs. In particular, with lactosylated NeoHDL, an efficient delivery system to the liver can be achieved, which allows a more effective treatment of diseases like hepatitis B.