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ORIGINAL ARTICLE

Optimized Targeting of Polyethylene Glycol-Stabilized Anti-Intercellular Adhesion Molecule 1 Oligonucleotide/Lipid Particles to Liver Sinusoidal Endothelial Cells

Groningen University Institute for Drug Exploration (GUIDE), Department of Cell Biology (M.B., A.H.W.-K., H.W.M.M., G.L.S., J.A.A.M.K.), Pathology and Laboratory Medicine/Medical Biology (H.W.M.M., S.A.A., J.A.A.M.K.), Pharmacokinetics and Drug Delivery (D.K.F.M.), University of Groningen, The Netherlands; and the Department of Pharmaceutical Technology, University of Freiburg, Germany (A.K., R.S.).

Abstract

We prepared polyethylene glycol (PEG)-stabilized antisense oligonucleotide (ODN)/lipid particles from a lipid mixture including the positively charged amphiphile 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and anti-intercellular adhesion molecule 1 (ICAM-1) antisense ODN by an extrusion method in the presence of 40% ethanol. These particles were targeted to scavenger receptors on liver endothelial cells by means of covalently coupled polyanionized albumin. Two types of such targeted particles were prepared, one with the albumin coupled to a maleimide group attached to the particle's lipid bilayer and the other with the protein coupled to a maleimide group attached at the distal end of added bilayer-anchored PEG chains. Upon intravenous injection, the ODN particles with bilayer-coupled albumin were cleared from the blood circulation at the same low rate as untargeted particles (<5% in 30 min). By contrast, the distal-end coupled particles were very rapidly cleared from the blood and preferentially taken up by the endothelial cells of the hepatic sinusoid (55% of injected dose after 30 min). Despite this substantial endothelial targeting, no consistent inhibition of ICAM-1 expression could be demonstrated in this cell type, either in vivo or in vitro. However, in J774 cells that also express scavenger receptors and ICAM-1, significant down-regulation of ICAM-1 mRNA was achieved with distal-end targeted lipid particles, as determined with real-time RT-PCR. It is concluded that massive delivery of ODN to cell types that express scavenger receptors can be achieved if lipid particles are provided with negatively charged albumin distally attached to bilayer anchored PEG chains.

Address correspondence to: Jan A. A. M. Kamps, University of Groningen, Department Pathology and Laboratory Medicine/Medical Biology Section - Endothelial Cell Research and Vascular Drug Targeting, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: j.a.a.m.kamps{at}med.rug.nl