Improving in Vivo Hepatic Transfection Activity by Controlling Intracellular Trafficking: The Function of GALA and Maltotriose

The successful control of intracellular trafficking (i.e., endosomal escape and nuclear delivery) is prerequisite for the development of a gene delivery system. In the present study, we developed an in vivo hepatic gene delivery system using a plasmid DNA (pDNA)-encapsulating lipid envelope-type nan...

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Published inMolecular pharmaceutics Vol. 8; no. 4; pp. 1436 - 1442
Main Authors Akita, Hidetaka, Masuda, Tomoya, Nishio, Takashi, Niikura, Kenichi, Ijiro, Kuniharu, Harashima, Hideyoshi
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 01.08.2011
Subjects
Animals
Gene Transfer Techniques
Liver - metabolism
Male
Mice
Nanostructures - chemistry
Peptides - chemistry
Plasmids - chemistry
Transfection - methods
Trisaccharides - chemistry
gene delivery
plasmid DNA
nuclear delivery
liver
sugar
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Summary:The successful control of intracellular trafficking (i.e., endosomal escape and nuclear delivery) is prerequisite for the development of a gene delivery system. In the present study, we developed an in vivo hepatic gene delivery system using a plasmid DNA (pDNA)-encapsulating lipid envelope-type nanoparticle, to which we refer as a multifunctional envelope-type nanodevice (MEND). The critical structural elements of the MEND are a DNA/protamine condensed core coated with lipid bilayers including serum-resistant cationic lipids. Intravenous administration of bare MEND represents minimal transfection activity. For the surface modification of functional devices, hydrophobic moieties were chemically attached, which are shed in the spontaneous orientation outward from the MEND surface by anchoring to the lipid bilayers. Modification of the pH-dependent fusogenic peptide GALA as an endosome escape induced transfection activity by 1 and 2 orders of magnitude. In an attempt to induce the nuclear delivery of pDNA, maltotriose, a recently characterized nuclear localization signal, was additionally modified. As a result, transfection activity further enhanced by 1 order of magnitude, and it reached to the higher level obtained for a conventional lipoplex and an in vivo jetPEI-Gal, with less hepatic toxicity. The data show that the combination of GALA and maltotriose results in a highly potent functional device that shows an enhanced endosomal escape and nuclear delivery in vivo.
ISSN:1543-8384
1543-8392
DOI:10.1021/mp200189s