title: Development of flexible nanocarriers for siRNA delivery into tumor tissue.
abstract: Various non-viral delivery systems for small interfering RNAs (siRNA) have been developed. Such delivery systems generally exhibit tightly formed spherical structures. While such carriers have demonstrated good transfection activity in mono-layered cell systems, effects against solid tumors are often less apparent and difficult to demonstrate, likely due to the rigid structures of the carriers, which may prevent penetration to deeper regions within tumor tissue. Herein, we developed a flexible nanocarrier (FNC) system that is able to penetrate to deeper regions within tumor tissue. Specifically, we employed previously found flexible polyplexes comprised of siRNA and poly-l-lysine as wick structures for the preparation of FNCs. FNCs were constructed by coating the wick structures with lipids using a liposomal membrane fusion method. The diameters of the resulting FNCs were ca. 170nm, and the shapes were non-spherical. Lipid coating was confirmed using a nuclease resistance assay. Furthermore, FNCs showed significant RNA interference effects, comparable to Lipofectamine 2000, in a mono-layered cell system. To accelerate tumor penetration, the FNC surface was modified with polyethylene glycol (PEG) and the tight junction opener peptide AT1002. Surface-modified FNCs demonstrated effective penetrability into a cancer spheroid. Thus, we developed a novel and unique tumor-penetrable siRNA FNC system.
authors.affiliation: Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Hyunkyung
authors.initials: H
authors.lastname: Jung
authors.affiliation: Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Shimatani
authors.affiliation: Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Mahadi
authors.initials: M
authors.lastname: Hasan
authors.affiliation: Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Uno
authors.affiliation: Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Hama
authors.affiliation: Department of Pharmaceutical Health Chemistry, Tokushima University Graduate School of Biomedical Sciences, Shomachi 1, Tokushima, 770-8505, Japan. Electronic address: kogure@tokushima-u.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kogure
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D008055:Lipids / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles; D009369:Neoplasms / Q000473:pathology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014162:Transfection / Q000379:methods
chemical_list: D008055:Lipids; C086724:Lipofectamine; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols
keywords: Flexible nanocarrier; Intercellular penetrability; siRNA/PLL polyplexes