Efficient short interference RNA delivery to tumor cells using a combination of octaarginine, GALA and tumor-specific, cleavable polyethylene glycol system.
We recently developed a multifunctional envelope-type nano device (MEND) for efficient nucleic acid delivery. Here, we report on the development of an octaarigine (R8)-modified MEND encapsulating small interfering RNA (siRNA) with a tumor-specific, cleavable, polyethylene glycol (PEG)-lipid (PPD). We first determined the optimal concentration of R8 and pH-sensitive fusogenic peptide (GALA) on the lipid envelope of MEND (R8/GALA-MEND). Then, we examined the combination of optimized R8/GALA-MEND with a PEG-lipid. When a conventional PEG-lipid was used, the R8/GALA-MEND failed to knockdown expression of the target gene. On the other hand, PPD-modified R8/GALA-MEND exhibited efficient silencing activity to the level of the PEG-unmodified R8/GALA-MEND. In addition, we compared a R8/GALA-MEND with a MEND composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) that is a conventional cationic lipid used as a lipoplex component. The knockdown ability of the R8/GALA-MEND was much higher than that of the DOTAP-based MEND at the dose that is commonly employed in in vitro siRNA transfection. These results demonstrate that the R8/GALA-MEND is a promising delivery system for the transfer of siRNA to tumor cells.
Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yu
Y
Sakurai
Hiroto
H
Hatakeyama
Hidetaka
H
Akita
Motoi
M
Oishi
Yukio
Y
Nagasaki
Shiro
S
Futaki
Hideyoshi
H
Harashima
D016503:Drug Delivery Systems / Q000379:methods*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D020868:Gene Silencing / Q000187:drug effects; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D053758:Nanoparticles / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014162:Transfection
D005229:Fatty Acids, Monounsaturated; D009842:Oligopeptides; D010455:Peptides; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; C448619:octaarginine; C066951:GALA peptide; D011092:Polyethylene Glycols; D008156:Luciferases; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane