Abstract
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.
Highlights
Gene therapy presents a novel strategy for the treatment of various significant human diseases with gene defects such as cancer [1]
4-arm poly(ethylene glycol) (PEG)-b-poly(disulfide histamine) copolymer was prepared via a two-step procedure (Figure 1)
(SSPHIS) oligomer was prepared by Michael addition reaction of cystamine bisacrylamide (CBA) and an excess amount of histamine (HIS)
Summary
Gene therapy presents a novel strategy for the treatment of various significant human diseases with gene defects such as cancer [1]. Polyplexes of bioreducible cationic polymers are capable of redox-responsive unpacking by the disulfide cleavage and efficient gene unloading inside the cells, thereby promoting transfection efficacy. This intracellular degradation process causes lower cytotoxicity for bioreducible cationic polymers compared to their non-degradable counterparts [11]. (a) gene binding of 4-arm PEG-SSPHIS copolymer to form the polyplexes with almost neutral surface; (b) increased surface charge upon the polyplexes in acidic tumor microenvironment via protonation of imidazole groups; (c) enhanced cellular uptake of the polyplexes to tumor cells; (d) intracellular gene release after disulfide cleavage
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