Efficient Short Interference RNA Delivery to Tumor Cells Using a Combination of Octaarginine, GALA and Tumor-Specific, Cleavable Polyethylene Glycol System

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  • Sakurai Yu
    Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University CREST, Japan Science and Technology Agency (JST)
  • Hatakeyama Hiroto
    Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University CREST, Japan Science and Technology Agency (JST)
  • Akita Hidetaka
    Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University CREST, Japan Science and Technology Agency (JST)
  • Oishi Motoi
    Tsukuba Research Center for Interdisciplinary Material Science (TIMS), University of Tsukuba CREST, Japan Science and Technology Agency (JST)
  • Nagasaki Yukio
    Tsukuba Research Center for Interdisciplinary Material Science (TIMS), University of Tsukuba CREST, Japan Science and Technology Agency (JST)
  • Futaki Shiro
    Institute for Chemical Research, Kyoto University
  • Harashima Hideyoshi
    Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University CREST, Japan Science and Technology Agency (JST)

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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.

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