Ornithine and Tryptophan Analogs as Efficient Polycations for Short Interference RNA Delivery to Tumor Cells
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概要
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The delivery of nucleic acids to cancer cells represents a potentially useful strategy. Previously, we developed a multifunctional envelope-type nano device (MEND) for the efficient delivery of plasmid DNA. In addition, we successfully delivered short interference RNA (siRNA) into cytoplasm using a MEND which contains siRNA particles that were produced using stearyl octaarginine (STR-R8). In the present study, to achieve further gene silencing activity compared with STR-R8, various additional polycations were screened. We used protamine and 10 different polypeptides containing random sequence of basic amino acids. The ability of these polycations to form nano particles with siRNA were evaluated by measuring the size and zeta-potential of produced nano particles, and as a consequence, 6 of the polycations were selected for further evaluation. We then prepared MENDs containing the particles. The lipid composition of the MEND consisted of dioleoylphosphatidyl ethanolamine (DOPE)/phosphatidic acid (PA) (7/2). For cellular uptake and endosomal escape, the MEND was modified with PPD (polyethylene glycol (PEG)-peptide-DOPE), STR-R8 and GALA, pH-sensitive fusogenic peptide. The resulting MEND had a diameter of 120—170 nm and a zeta-potential of 15—25 mV. The MEND was transfected into HeLa cells stably expressing luciferase and the silencing activity of the polycations was compared. Most of the polycations failed to knockdown luciferase activity. However, the polypeptide containing ornithine and tryptophan (Orn/Trp) induced a higher knockdown than STR-R8. In addition, Orn/Trp induced a silencing effect at lower doses than STR-R8, as evidenced by dose-response data. In conclusion, the findings suggest that Orn/Trp is a superior polycation to STR-R8 for siRNA delivery.
著者
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Harashima Hideyoshi
Faculty of Pharmaceutical Sciences, Hokkaido University
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Sato Yusuke
Faculty of Pharmaceutical Sciences, Hokkaido University
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Hatakeyama Hiroto
Faculty of Pharmaceutical Sciences, Hokkaido University
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Harashima Hideyoshi
Faculty Of Pharmaceutical Science The University Of Tokushima
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Sato Yusuke
Faculty Of Agriculture Kyushu University
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