Modification of the plasma clearance and liver uptake of steroid ester-conjugated oligodeoxynucleotides by association with (lactosylated) low-density lipoprotein

Low-density lipoprotein (LDL) has been proposed as carrier for the selectiv e delivery of anticancer drugs to tumor cells. We reported earlier the asso ciation of several lipidic steroid-conjugated anticancer oligodeoxynucleoti des (ODNs) with LDL. In the present study, we determined the stability of t hese complexes. When the complexes were incubated with a mixture of high-de nsity lipoprotein and albumin, or with rat plasma, the oleoyl steroid-conju gated ODNs appeared to be more stably associated with LDL than the choleste ryl-conjugated ODN. Intravenously injected free lipid-ODNs were very rapidl y cleared from the circulation of rats. The area under the curve (AUC) of t he lipid-ODNs in plasma was <0.4 mu g.min/mL. After complexation with LDL, plasma clearance of the lipid-ODNs was delayed. This was most evident for O DN-5, the ODN conjugated with the oleoyl ester of lithocholic acid (AUC = 6 .82 +/- 1.34 mu g.min/mL). The AUC of ODN-4, a cholesteryl-conjugated ODN, was 1.49 +/- 0.37 mu g.min/mL. In addition, the liver uptake of the LDL-com plexed lipid-ODNs was reduced. The lipid-ODNs were also administered as a c omplex with lactosylated LDL, a modified LDL particle that is selectively t aken up by the liver. A high proportion of ODN-5 was transported to the liv er along with lactosylated LDL (69.1 +/- 8.1% of the dose at 15 min after i njection), whereas much less ODN-4 was transported (36.6 +/- 0.1% of the do se at 15 min after injection). We conclude that the oleoyl ester of lithoch olic acid is a more potent lipid anchor than the other steroid lipid anchor s. Because of the stable association, the oleoyl ester of lithocholic acid is an interesting candidate for tumor targeting of anticancer ODNs with lip oproteins. BIOCHEM PHARMACOL 59;11:1407-1416, 2000. (C) 2000 Elsevier Scien ce Inc.