title: pH and redox dual-responsive multifunctional gene delivery with enhanced capability of transporting DNA into the nucleus.
abstract: Stimuli-responsive gene delivery vectors based on physiologically triggered structure changing have been recently recognized as a new therapeutic agent for their excellent performance in vivo. Herein, we present an intelligent gene delivery system based on the octa-arginine peptides (R8)-conjugated polyamino acid derivatives noted as PPCRC (PVIm-(PAsp-Cystamine-R8)-Cholesteryl), which processed pH responsive, surface charge-switching, intracellular redox-responsive and enhanced nucleus import of gene together. Due to the imidazole group in the PPCRC backbone, the DNA/PPCRC polyplexes not only exhibited the enhanced buffering capacity in the endosome after endocytosis, but also displayed the reversible surface charge from negative to positive with decreasing the pH value form pH 7.4 to pH 6.5-6.8, which would promote the cell membrane binding and cellular uptake. The disulfide bond for R8peptides conjugation in the polymer side chain could be rapidly cleaved under reductive conditions, facilitating DNA release in the cytoplasm. Subsequently, the DNA would be still associated with the R8peptides, which would promote the intracellular nucleus import of DNA. The luciferase gene expression level of COS-7 cells transfected by DNA/PPCRC polyplexes was almost 2000 folds higher than cells transfected by DNA/PPCC polyplexes (without R8peptides modification) in growth-arrested cell model. Nearly 10 folds enhanced gene transfection efficiency was found on human bone mesenchymal stem cells (hBMSCs) using the same strategy, which revealed that this intelligent vector can be also utilized in transfection of non-dividing cells. Intravenous injection of the DNA/PPCRC polyplexes also achieved the effective transfection in subcutaneous tumor model. Taken together, PPCRC vector has great potential for both dividing and non-dividing cells transfection and in vivo gene delivery application.
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
authors.forename: Yingqin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
authors.forename: Jinbiao
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China. Electronic address: liujie56@mail.sysu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism*; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008156:Luciferases / Q000235:genetics* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D011108:Polymers; D004247:DNA; D008156:Luciferases
keywords: Gene delivery; Octa-arginine peptides; Polyamino acid; Redox-responsive; pH-responsive