Massive and selective delivery of lipid-coated cationic lipoplexes of oligonucleotides targeted in vivo to hepatic endothelial cells.
OBJECTIVE
Previously we reported on massive uptake of liposomes surface-modified with negatively charged aconitylated albumin (AcoHSA) by liver sinusoidal endothelial cells (EC) in vivo. In the present work we applied this principle for the in vivo delivery of antisense oligonucleotides (ODN) to these cells.


METHODS
Anti ICAM-1 ODN was complexed with the cationic lipid DOTAP and the complex was coated by an excess of neutral lipids including a lipid-anchored poly(ethylene glycol). Aco-HSA was coupled to the coated cationic lipoplexes (CCLs). Plasma disappearance, organ and intrahepatic distribution of Aco-HSA modified CCLs were determined in rats, using [3H]-cholesteryl oleyl ether and 32P-labeled ODN as markers.


RESULTS
The Aco-HSA coupled CCLs were <160 nm in size, contained 1.03+/-0.35 nmol ODN and 54+/-18 microg Aco-HSA per micromol total lipid. These CCLs were rapidly eliminated from plasma, about 60% the injected dose of 3H- or 32P-label being recovered in the liver after 30 min. Within the liver, the EC accounted for two thirds of total liver uptake. Control non-targeted CCLs were eliminated very slowly: after 30 min still >90% of the particles was in the blood.


CONCLUSIONS
Our results demonstrate efficient targeting of antisense ODN to EC in vivo, employing plasma-stable coated cationic lipoplexes, surface modified with negatively charged albumin. 40% of the injected ODN was delivered to the target cells within 30 min.
Bartsch
Martin
M
Groningen University, Institute of Drug Exploration, The Netherlands.
Weeke-Klimp
Alida H
AH
Meijer
Dirk K F
DK
Scherphof
Gerrit L
GL
Kamps
Jan A A M
JA
D000156:Aconitic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D004337:Drug Carriers; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D007275:Injections, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D008055:Lipids; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D012709:Serum Albumin / Q000737:chemistry; D000075462:Serum Albumin, Human; D014018:Tissue Distribution
D004337:Drug Carriers; D008055:Lipids; D016376:Oligonucleotides, Antisense; D012709:Serum Albumin; C108785:polyaconitylated human serum albumin; D018799:Intercellular Adhesion Molecule-1; D000156:Aconitic Acid; D000075462:Serum Albumin, Human