title: A peptide-based vector for efficient gene transfer in vitro and in vivo.
abstract: Finding suitable nonviral delivery vehicles for nucleic acid-based therapeutics is a landmark goal in gene therapy. Cell-penetrating peptides (CPPs) are one class of delivery vectors that has been exploited for this purpose. However, since CPPs use endocytosis to enter cells, a large fraction of peptides remain trapped in endosomes. We have previously reported that stearylation of amphipathic CPPs, such as transportan 10 (TP10), dramatically increases transfection of oligonucleotides in vitro partially by promoting endosomal escape. Therefore, we aimed to evaluate whether stearyl-TP10 could be used for the delivery of plasmids as well. Our results demonstrate that stearyl-TP10 forms stable nanoparticles with plasmids that efficiently enter different cell-types in a ubiquitous manner, including primary cells, resulting in significantly higher gene expression levels than when using stearyl-Arg9 or unmodified CPPs. In fact, the transfection efficacy of stearyl-TP10 almost reached the levels of Lipofectamine 2000 (LF2000), however, without any of the observed lipofection-associated toxicities. Most importantly, stearyl-TP10/plasmid nanoparticles are nonimmunogenic, mediate efficient gene delivery in vivo, when administrated intramuscularly (i.m.) or intradermally (i.d.) without any associated toxicity in mice.
authors.affiliation: Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Tartu, Estonia. tlehto@ut.ee
authors.forename: Taavi
authors.initials: T
authors.lastname: Lehto
authors.forename: Oscar E
authors.initials: OE
authors.lastname: Simonson
authors.forename: Imre
authors.initials: I
authors.lastname: Mäger
authors.forename: Kariem
authors.initials: K
authors.lastname: Ezzat
authors.forename: Helena
authors.initials: H
authors.lastname: Sork
authors.forename: Dana-Maria
authors.initials: DM
authors.lastname: Copolovici
authors.forename: Joana R
authors.initials: JR
authors.lastname: Viola
authors.forename: Eman M
authors.initials: EM
authors.lastname: Zaghloul
authors.forename: Per
authors.initials: P
authors.lastname: Lundin
authors.forename: Pedro M D
authors.initials: PM
authors.lastname: Moreno
authors.forename: Maarja
authors.initials: M
authors.lastname: Mäe
authors.forename: Nikita
authors.initials: N
authors.lastname: Oskolkov
authors.forename: Julia
authors.initials: J
authors.lastname: Suhorutšenko
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
authors.forename: Samir E L
authors.initials: SE
authors.lastname: Andaloussi
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D057846:Cell-Penetrating Peptides / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004337:Drug Carriers; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009696:Nucleic Acids / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism*; D014162:Transfection / Q000379:methods*
chemical_list: D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D009696:Nucleic Acids