A pH and redox dual responsive 4-arm poly(ethylene glycol)-block-poly(disulfide histamine) copolymer for non-viral gene transfection in vitro and in vivo.
A novel 4-arm poly(ethylene glycol)-b-poly(disulfide histamine) copolymer was synthesized by Michael addition reaction of poly(ethylene glycol) (PEG) vinyl sulfone and amine-capped poly(disulfide histamine) oligomer, being denoted as 4-arm PEG-SSPHIS. This copolymer was able to condense DNA into nanoscale polyplexes (<200 nm in average diameter) with almost neutral surface charge (+(5-10) mV). Besides, these polyplexes were colloidal stable within 4 h in HEPES buffer saline at pH 7.4 (physiological environment), but rapidly dissociated to liberate DNA in the presence of 10 mM glutathione (intracellular reducing environment). The polyplexes also revealed pH-responsive surface charges which markedly increased with reducing pH values from 7.4-6.3 (tumor microenvironment). In vitro transfection experiments showed that polyplexes of 4-arm PEG-SSPHIS were capable of exerting enhanced transfection efficacy in MCF-7 and HepG2 cancer cells under acidic conditions (pH 6.3-7.0). Moreover, intravenous administration of the polyplexes to nude mice bearing HepG2-tumor yielded high transgene expression largely in tumor rather other normal organs. Importantly, this copolymer and its polyplexes had low cytotoxicity against the cells in vitro and caused no death of the mice. The results of this study indicate that 4-arm PEG-SSPHIS has high potential as a dual responsive gene delivery vector for cancer gene therapy.
Department of Periodontoloy, Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology, Tongji University, Shanghai 200072, China. xxstiger@tongji.edu.cn.
Kangkang
K
An
Institute of Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, Shanghai 200092, China. tjzhaopeng@gmail.com.
Peng
P
Zhao
Institute of Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, Shanghai 200092, China. c.lin@tongji.edu.cn.
Chao
C
Lin
Department of Periodontoloy, Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology, Tongji University, Shanghai 200072, China. hwliu@tongji.edu.cn.
Hongwei
H
Liu
D000818:Animals; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D005822:Genetic Vectors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014162:Transfection; D014183:Transplantation, Heterologous
D011108:Polymers; D011092:Polyethylene Glycols