title: Effective gene delivery using stimulus-responsive catiomer designed with redox-sensitive disulfide and acid-labile imine linkers.
abstract: A dual stimulus-responsive mPEG-SS-PLL(15)-glutaraldehyde star (mPEG-SS-PLL(15)-star) catiomer is developed and biologically evaluated. The catiomer system combines redox-sensitive removal of an external PEG shell with acid-induced escape from the endosomal compartment. The design rationale for PEG shell removal is to augment intracellular uptake of mPEG-SS-PLL(15)-star/DNA complexes in the presence of tumor-relevant glutathione (GSH) concentration, while the acid-induced dissociation is to accelerate the release of genetic payload following successful internalization into targeted cells. Size alterations of complexes in the presence of 10 mM GSH suggest stimulus-induced shedding of external PEG layers under redox conditions that intracellularly present in the tumor microenvironment. Dynamic laser light scattering experiments under endosomal pH conditions show rapid destabilization of mPEG-SS-PLL(15)-star/DNA complexes that is followed by facilitating efficient release of encapsulated DNA, as demonstrated by agarose gel electrophoresis. Biological efficacy assessment using pEGFP-C1 plasmid DNA encoding green fluorescence protein and pGL-3 plasmid DNA encoding luciferase as reporter genes indicate comparable transfection efficiency of 293T cells of the catiomer with a conventional polyethyleneimine (bPEI-25k)-based gene delivery system. These experimental results show that mPEG-SS-PLL(15)-star represents a promising design for future nonviral gene delivery applications with high DNA binding ability, low cytotoxicity, and high transfection efficiency.
authors.affiliation: The Institute for Advanced Materials and Nano Biomedicine, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Cai
authors.forename: Chunyan
authors.initials: C
authors.lastname: Dong
authors.forename: Haiqing
authors.initials: H
authors.lastname: Dong
authors.forename: Gangmin
authors.initials: G
authors.lastname: Wang
authors.forename: Giovanni M
authors.initials: GM
authors.lastname: Pauletti
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Pan
authors.forename: Huiyun
authors.initials: H
authors.lastname: Wen
authors.forename: Isaac
authors.initials: I
authors.lastname: Mehl
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Li
authors.forename: Donglu
authors.initials: D
authors.lastname: Shi
mesh_terms: D002412:Cations / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004220:Disulfides / Q000737:chemistry* / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005976:Glutaral / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007097:Imines / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D011107:Polylysine / Q000737:chemistry* / Q000235:genetics; D013499:Surface Properties
chemical_list: D002412:Cations; D003432:Cross-Linking Reagents; D004220:Disulfides; D007097:Imines; D011107:Polylysine; D011092:Polyethylene Glycols; D005976:Glutaral