title: Transferrin-bearing polypropylenimine dendrimer for targeted gene delivery to the brain.
abstract: The possibility of using genes as medicines to treat brain diseases is currently limited by the lack of safe and efficacious delivery systems able to cross the blood-brain barrier, thus resulting in a failure to reach the brain after intravenous administration. On the basis that iron can effectively reach the brain by using transferrin receptors for crossing the blood-brain barrier, we propose to investigate if a transferrin-bearing generation 3-polypropylenimine dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration. In vitro, the conjugation of transferrin to the polypropylenimine dendrimer increased the DNA uptake by bEnd.3 murine brain endothelioma cells overexpressing transferrin receptors, by about 1.4-fold and 2.3-fold compared to that observed with the non-targeted dendriplex and naked DNA. This DNA uptake appeared to be optimal following 2h incubation with the treatment. In vivo, the intravenous injection of transferrin-bearing dendriplex more than doubled the gene expression in the brain compared to the unmodified dendriplex, while decreasing the non-specific gene expression in the lung. Gene expression was at least 3-fold higher in the brain than in any tested peripheral organs and was at its highest 24h following the injection of the treatments. These results suggest that transferrin-bearing polypropylenimine dendrimer is a highly promising gene delivery system to the brain.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Sukrut
authors.initials: S
authors.lastname: Somani
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Blatchford
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Owain
authors.initials: O
authors.lastname: Millington
authors.affiliation: School of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: M Lynn
authors.initials: ML
authors.lastname: Stevenson
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. Electronic address: C.Dufes@strath.ac.uk.
authors.forename: Christine
authors.initials: C
authors.lastname: Dufès
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D050091:Dendrimers / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics; D011126:Polypropylenes / Q000737:chemistry / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050091:Dendrimers; D011126:Polypropylenes; D011990:Receptors, Transferrin; D014168:Transferrin; C443641:poly(propyleneimine); D004247:DNA
keywords: Blood–brain barrier; Brain delivery; Dendrimer; Gene delivery; Transferrin