title: Multilayered polyion complexes with dissolvable silica layer covered by controlling densities of cRGD-conjugated PEG chains for cancer-targeted siRNA delivery.
abstract: Surface functionalization of nanoparticles is a crucial factor for nanoparticle-mediated drug and nucleic acid delivery. Particularly, the density of targeting ligands on nanoparticle significantly affects the affinity of nanoparticles to specific cellular surface (or receptor) through the multivalent binding effect. Herein, multilayered polyion complexes (mPICs) are prepared to possess varying densities of cyclic RGD peptide (cRGD) ligands for cancer-targeted small interfering RNA (siRNA) delivery. A template PIC is first prepared by mixing siRNAs with homo catiomers of N-substituted polyaspartamide bearing tetraethylenepentamine (PAsp(TEP)) in aqueous solution, followed by silica-coating through silicate condensation reaction. Then, silica-coated PICs (sPICs) are further covered with block catiomers of PAsp(TEP) and poly(ethylene glycol) (PEG) equipped with cRGD ligand. Successful preparation of targeted mPICs is confirmed from the changes in size and ζ-potential and the elemental analysis by transmission electron microscopy. Notably, the number of cRGD ligands per mPIC is regulated by altering the silicate concentration upon preparation of sPICs, which is confirmed by fluorescence correlation spectroscopy using fluorescent-labeled block catiomers. Ultimately, the targeted mPICs with a higher number of cRGD ligands demonstrate more efficient cellular uptake in cultured cancer cells, leading to enhanced gene silencing activity.
authors.affiliation: a Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , Tokyo , Japan.
authors.forename: Mitsuru
authors.identifier: 0000-0002-4237-871X
authors.initials: M
authors.lastname: Naito
authors.affiliation: b Department of Materials Engineering , Graduate School of Engineering, The University of Tokyo , Tokyo , Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Azuma
authors.affiliation: c Laboratory for Chemistry and Life Science , Institute of Innovative Research, Tokyo Institute of Technology , Yokohama , Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Takemoto
authors.affiliation: d Department of Bioengineering , Graduate School of Engineering, The University of Tokyo , Tokyo , Japan.
authors.forename: Mao
authors.initials: M
authors.lastname: Hori
authors.affiliation: d Department of Bioengineering , Graduate School of Engineering, The University of Tokyo , Tokyo , Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yoshinaga
authors.affiliation: e Innovation Center of NanoMedicine, Institute of Industry Promotion-KAWASAKI , Kawasaki , Japan.
authors.forename: Shigehito
authors.initials: S
authors.lastname: Osawa
authors.affiliation: b Department of Materials Engineering , Graduate School of Engineering, The University of Tokyo , Tokyo , Japan.
authors.forename: Rimpei
authors.initials: R
authors.lastname: Kamegawa
authors.affiliation: a Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , Tokyo , Japan.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: d Department of Bioengineering , Graduate School of Engineering, The University of Tokyo , Tokyo , Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ishii
authors.affiliation: c Laboratory for Chemistry and Life Science , Institute of Innovative Research, Tokyo Institute of Technology , Yokohama , Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: a Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , Tokyo , Japan.|b Department of Materials Engineering , Graduate School of Engineering, The University of Tokyo , Tokyo , Japan.
authors.forename: Kanjiro
authors.initials: K
authors.lastname: Miyata
authors.affiliation: e Innovation Center of NanoMedicine, Institute of Industry Promotion-KAWASAKI , Kawasaki , Japan.|f Policy Alternatives Research Institute, The University of Tokyo , Tokyo , Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D001483:Base Sequence; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D010456:Peptides, Cyclic / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics; D012822:Silicon Dioxide / Q000737:chemistry*
chemical_list: D008024:Ligands; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; C507169:cyclic arginine-glycine-aspartic acid peptide; D011092:Polyethylene Glycols; D012822:Silicon Dioxide
keywords: PEG; Polyion complex; active targeting; siRNA; silica