title: Octaarginine- and pH sensitive fusogenic peptide-modified nanoparticles for liver gene delivery.
abstract: We previously reported that octaarginine peptide modified liposomes (R8-liposomes) largely accumulated in the liver after intravenous administration and that this is dependent on the R8-density. We report herein on the development of a Multifunctional Envelope-type Nano Device modified with R8 and GALA, as a pH-sensitive fusogenic peptide (R8-GALA-MEND) for liver gene delivery. An R8-MEND encapsulating pDNA prepared using two different cores (negatively or positively charged pDNA/polyethylene imine condensed particles) failed to produce a high gene expression in the liver. Modification with GALA dramatically increased gene expression particularly in the liver only in the case of a negative core R8-MEND. Quantification of the number of gene copies delivered to liver cells and nuclei revealed that the amount of pDNA was significantly higher in the case of positive core R8-MENDs, regardless of the absence or presence of GALA. However, gene expression efficiencies per nucleus-delivered pDNA were much higher in the case of the negative core R8-MEND, especially the R8-GALA-MEND suggesting that the substantial improvement in gene expression can be explained by an improved gene expression efficiency per pDNA in the presence of GALA. A comparative study between the developed R8-GALA-MEND and a similar system containing DOTAP, a commonly used cationic lipid, instead of R8 showed that gene expression of the R8-GALA-MEND was 29 times higher than that of the DOTAP-GALA-MEND and is more selective for the liver. Collectively, these results suggest that the combination of a negatively charged core system and GALA modification of the R8-MEND is useful system for efficiently delivering genes to the liver.
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Ikramy A
authors.initials: IA
authors.lastname: Khalil
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Mizuno
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D004247:DNA / Q000008:administration & dosage*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D010957:Plasmids / Q000008:administration & dosage
chemical_list: D008055:Lipids; D009842:Oligopeptides; D010455:Peptides; C448619:octaarginine; C066951:GALA peptide; D004247:DNA