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 selective delivery of anticancer drugs to tumor cells. We reported earlier the association of several lipidic steroid-conjugated anticancer oligodeoxynucleotides (ODNs) with LDL. In the present study, we determined the stability of these complexes. When the complexes were incubated with a mixture of high-density lipoprotein and albumin, or with rat plasma, the oleoyl steroid-conjugated ODNs appeared to be more stably associated with LDL than the cholesteryl-conjugated ODN. Intravenously injected free lipid-ODNs were very rapidly cleared from the circulation of rats. The area under the curve (AUC) of the lipid-ODNs in plasma was <0.4 microg x min/mL. After complexation with LDL, plasma clearance of the lipid-ODNs was delayed. This was most evident for ODN-5, the ODN conjugated with the oleoyl ester of lithocholic acid (AUC = 6.82 +/- 1.34 microg x min/mL). The AUC of ODN-4, a cholesteryl-conjugated ODN, was 1.49 +/- 0.37 microg x min/mL. In addition, the liver uptake of the LDL-complexed lipid-ODNs was reduced. The lipid-ODNs were also administered as a complex with lactosylated LDL, a modified LDL particle that is selectively taken up by the liver. A high proportion of ODN-5 was transported to the liver along with lactosylated LDL (69.1 +/- 8.1% of the dose at 15 min after injection), whereas much less ODN-4 was transported (36.6 +/- 0.1% of the dose at 15 min after injection). We conclude that the oleoyl ester of lithocholic acid is a more potent lipid anchor than the other steroid lipid anchors. Because of the stable association, the oleoyl ester of lithocholic acid is an interesting candidate for tumor targeting of anticancer ODNs with lipoproteins.
Rump
E T
ET
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, P.O. Box 9503, 2300 RA, Leiden, The Netherlands.
de Vrueh
R L
RL
Manoharan
M
M
Waarlo
I H
IH
van Veghel
R
R
Biessen
E A
EA
van Berkel
T J
TJ
Bijsterbosch
M K
MK
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007785:Lactose / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D020319:Oligodeoxyribonucleotides, Antisense / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D013256:Steroids / Q000097:blood / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D020319:Oligodeoxyribonucleotides, Antisense; D012709:Serum Albumin; D013256:Steroids; D007785:Lactose