Lactosylated low density lipoprotein: a potential carrier for the site-specific delivery of drugs to Kupffer cells.

Low density lipoprotein (LDL) is a spherical particle with a diameter of 22 nm. It consists of an apolipoprotein and a lipid moiety, in which a variety of lipophilic drugs and prodrugs can be incorporated. In the present study, lactose was coupled to the apolipoprotein of LDL by reductive amination (398 +/- 40 residues/LDL particle). After injection into rats, radioactively labeled lactosylated LDL was cleared rapidly from the plasma (half-life, less than 2 min). Ten minutes after injection, the liver contained about 90% of the dose, whereas only small amounts of radioactivity were found in other tissues. Preinjection of N-acetylgalactosamine completely blocked liver uptake, whereas N-acetylglucosamine was ineffective. This indicates that the hepatic recognition site is galactose specific. Subcellular fractionation of liver indicated that the recognition of lactosylated LDL is followed by internalization and degradation of the apolipoprotein in the lysosomes. In the liver, Kupffer cells are mainly responsible for uptake. At 10 min after injection, these cells contained a 70 and 7 times higher amount of lactosylated LDL per mg of cell protein than parenchymal and endothelial cells, respectively. After galactose-specific uptake in parenchymal cells was blocked with asialofetuin, the relative concentration in Kupffer cells was even higher. The hepatic uptake of the lipid moiety of lactosylated LDL, labeled with [3H]cholesteryl oleoyl ether, was identical to that of the 125I-labeled apolipoporotein, which indicates that the particle is taken up as a unit. Thus, lactosylated LDL is taken up rapidly and selectively by Kupffer cells, and it appears that it might be a very effective vehicle for the specific delivery of lipophilic drugs, e.g., immunomodulators, to these cells.