title: Elucidation of the physicochemical properties and potency of siRNA-loaded small-sized lipid nanoparticles for siRNA delivery.
abstract: Because nanoparticles with diameters less than 50nm penetrate stromal-rich tumor tissues more efficiently, the synthesis of small-sized nanoparticles encapsulating short interfering RNA (siRNA) is important in terms of realizing novel siRNA medicine for the treatment of various cancers. Lipid nanoparticles (LNPs) are the leading systems for the delivery of siRNA in vivo. Limit size LNPs were successfully synthesized using a microfluidic mixing technique. However, the physicochemical properties and potential for in vivo siRNA delivery of the limit-size LNPs have not been examined in detail. In the present study, we prepared LNPs with different diameters from 32 to 67nm using a microfluidic mixing devise and examined the physicochemical properties of the particles and the potential for their use in delivering siRNA in vitro and in vivo to liver. Reducing the size of the LNPs causes poor-packing and an increased surface area, which result in their instability in serum. Moreover, it was revealed that the ability of endosomal escape (cytosolic siRNA release) of the smaller LNPs is subject to inhibition by serum compared to that of larger counterparts. Taken together, an increase in packing and avoiding the adsorption of serum components are key strategies for the development of next-generation highly potent and small-sized LNPs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Note
authors.affiliation: Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita 13 Nishi 8, Kita-ku, Sapporo 060-8628, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Maeki
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan; ImPACT Research Center for Advanced Nanobiodevices, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan.
authors.forename: Noritada
authors.initials: N
authors.lastname: Kaji
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan; ImPACT Research Center for Advanced Nanobiodevices, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita 13 Nishi 8, Kita-ku, Sapporo 060-8628, Japan; ImPACT Research Center for Advanced Nanobiodevices, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Tokeshi
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000378:metabolism; D005167:Factor VII / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006367:HeLa Cells; D006461:Hemolysis; D006801:Humans; D056656:Lab-On-A-Chip Devices; D008055:Lipids / Q000008:administration & dosage* / Q000737:chemistry; D049409:Luciferases, Firefly; D049410:Luciferases, Renilla; D008813:Mice, Inbred ICR; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D013499:Surface Properties
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; D005167:Factor VII; D049410:Luciferases, Renilla; D049409:Luciferases, Firefly
keywords: Endosomal escape; Microfluidic device; Protein adsorption; Small-sized lipid nanoparticles; Stability; siRNA delivery