title: Efficient RNA delivery by integrin-targeted glutathione responsive polyethyleneimine capped gold nanorods.
abstract: RNA interference (RNAi) mediated gene silencing holds significant promises in gene therapy. A major obstacle to efficient RNAi is the systemic delivery of the therapeutic RNAs into the cytoplasmon without being trapped in intracellular endo-/lyso-somes. Herein we report the development of a PEGylated, RGD peptide modified, and disulfide cross-linked short polyethylenimines (DSPEIs) functionalized gold nanorod (RDG) for targeted small hairpin (sh)RNA delivery. The RDG effectively condensed shRNAs into stable nanoparticles, allowing for highly specific targeting of model human brain cancer cells (U-87 MG-GFP) via the αvβ3 integrins-mediated endocytosis. The combined effects of endosomal escape (via the proton-sponge effect of the PEIs) and efficient cleavage of the disulfide-cross-linked DSPEIs by the high intracellular glutathione content triggered rapid cytoplasma shRNAs release resulting in excellent RNAi efficiency and low cytotoxicity. Furthermore, the high stability and prolonged blood circulation afforded by PEGylation allowed for highly effective, targeted tumor accumulation and internalization of the carriers, resulting in outstanding intra-tumor gene silencing efficiency in U-87 MG-GFP tumor bearing BALB/c mice. Combining the capabilities of both passive and active targeting, intracellular glutathione-triggered "off-on" release and endosomal escape, the RDG nanocarrier developed herein appears to be a highly promising non-viral vector for efficient RNAi.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China; Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshan Beiyi Road, Shanghai 200437, PR China.
authors.forename: Feihu
authors.initials: F
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.affiliation: School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. Electronic address: d.zhou@leeds.ac.uk.
authors.forename: Dejian
authors.initials: D
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China; School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. Electronic address: srguo@sjtu.edu.cn.
authors.forename: Shengrong
authors.initials: S
authors.lastname: Guo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods; D005978:Glutathione / Q000378:metabolism*; D006046:Gold / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy / Q000379:methods; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D043942:Nanotubes / Q000737:chemistry* / Q000648:ultrastructure; D009842:Oligopeptides / Q000493:pharmacokinetics; D011094:Polyethyleneimine / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome
chemical_list: D039302:Integrin alphaVbeta3; D053769:Nanocapsules; D009842:Oligopeptides; D034741:RNA, Small Interfering; D006046:Gold; C047981:arginyl-glycyl-aspartic acid; D011094:Polyethyleneimine; D005978:Glutathione
keywords: Disulfide-linked polyethylenimine; Glutathione; Gold nanorods; RGD peptide; RNA delivery