title: Efficient, dual-stimuli responsive cytosolic gene delivery using a RGD modified disulfide-linked polyethylenimine functionalized gold nanorod.
abstract: Controlled-release systems capable of responding to external stimuli and/or unique internal environments have received great interests in site-specific gene and/or drug delivery. In this work, a functionalized gene nanocarrier for dual-stimuli triggered cytosolic gene delivery is developed and showing high gene delivery efficacy with low cytotoxicity. The nanocarrier is prepared by conjugating gold nanorod (GNR) with multiple disulfide cross-linked short PEIs to harness the advantageous properties of GNR based near infrared (NIR) laser induced photothermal heating and intracellular stimuli-triggered degradability of disulfide cross-linked short PEIs (DSPEI). The DSPEI is further grafted with a poly(ethylene glycol) (PEG) section to afford high carrier stability in cell cultures and a terminal RGD peptide for specific targeting of cancer cells. The nanocarrier is found to effectively condense plasmid DNA to form a highly stable GNR-DSPEI-PEG-RGD/DNA complex with tumor cell-targeting ability that can be efficiently uptaken by cancer cells. Moreover, the loaded genes can be effectively released from the complex triggered by the high intracellular glutathione content and/or by photothermal effect of NIR irradiation at 808 nm. Interestingly, the GNRs-based complex can easily escape from intracellular endo-/lyso-somal compartments and release the gene load into the cytosol upon exposure to NIR irradiation, resulting in significantly improved gene transfection efficiency. Our new gene carrier exhibits high gene transfection efficiency, comparable to or even better than that of high MW PEIs, but with a much lower cytotoxicity. Additionally, neither the GNR-based carrier nor the laser treatment shows any significant evidence of cytotoxicity. This work demonstrates a promising strategy for intracellular stimuli triggered, photothermal controllable gene delivery system, which can be further applied to many other nanomedicine fields.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, 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: 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: 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: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Chemistry, 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, 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: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism*; D004247:DNA / Q000008:administration & dosage; D004220:Disulfides / Q000737:chemistry*; D004337:Drug Carriers; D018014:Gene Transfer Techniques; D006046:Gold; D006801:Humans; D043942:Nanotubes; D009842:Oligopeptides / Q000008:administration & dosage*; D011094:Polyethyleneimine / Q000737:chemistry*
chemical_list: D004220:Disulfides; D004337:Drug Carriers; D009842:Oligopeptides; D006046:Gold; C047981:arginyl-glycyl-aspartic acid; D011094:Polyethyleneimine; D004247:DNA
keywords: Controlled gene delivery; Disulfide-linked polyethylenimine; Glutathione; Gold nanorod; Near-infrared laser; Photochemical effect