title: Altered organ accumulation of oligonucleotides using polyethyleneimine grafted with poly(ethylene oxide) or pluronic as carriers.
abstract: Passive targeting provides a simple strategy based on natural properties of the carriers to deliver DNA molecules to desired compartments. Polyethylenimine (PEI) is a potent non-viral system that has been known to deliver efficiently both plasmids and oligonucleotides (ODNs) in vitro. However, in vivo systemic administration of DNA/PEI complexes has encountered significant difficulties because these complexes are toxic and have low biodistribution in target tissues. This study evaluates PEI grafted with poly(ethylene oxide) (PEO(8K)-g-PEI(2K)) and PEI grafted with non-ionic amphiphilic block copolymer, Pluronic P85 (P85-g-PEI(2K)) as carriers for systemic delivery of ODNs. Following i.v. injection an antisense ODN formulated with PEO(8K)-g-PEI(2K) accumulated mainly in kidneys, while the same ODN formulated with P85-g-PEI(2K) was found almost exclusively in the liver. Furthermore, in the case of the animals injected with the P85-g-PEI(2K)-based complexes most of the ODN was found in hepatocytes, while only a minor portion of ODN was found in the lymphocyte/monocyte populations. The results of this study suggest that formulating ODN with PEO(8K)-g-PEI(2K) and P85-g-PEI(2K) carriers allows targeting of the ODN to the liver or kidneys, respectively. The variation in the tissue distribution of ODN observed with the two carriers is probably due to the different hydrophilic-lipophilic balance of the polyether chains grafted to PEI in these molecules. Therefore, polyether-grafted PEI carriers provide a simple way to enhance ODN accumulation in a desired compartment without the need of a specific targeting moiety.
authors.affiliation: Centre de recherche en santé humaine, INRS-Institut Armand-Frappier, Laval, Que., Canada.
authors.forename: B
authors.initials: B
authors.lastname: Ochietti
authors.forename: N
authors.initials: N
authors.lastname: Guérin
authors.forename: S V
authors.initials: SV
authors.lastname: Vinogradov
authors.forename: Y
authors.initials: Y
authors.lastname: St-Pierre
authors.forename: P
authors.initials: P
authors.lastname: Lemieux
authors.forename: A V
authors.initials: AV
authors.lastname: Kabanov
authors.forename: V Yu
authors.initials: VY
authors.lastname: Alakhov
mesh_terms: D000818:Animals; D001682:Biological Availability; D019556:COS Cells; D004337:Drug Carriers / Q000493:pharmacokinetics; D005260:Female; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000493:pharmacokinetics*; D009928:Organ Specificity; D011060:Poloxalene / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D011094:Polyethyleneimine / Q000493:pharmacokinetics*; D013873:Thionucleotides / Q000493:pharmacokinetics*
chemical_list: D004337:Drug Carriers; D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; C422648:pluronic block copolymer p85; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D011060:Poloxalene