Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 12, Issue 13, Pages 14825-14838Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.9b22394
Keywords
cancer gene delivery; nonviral vectors; polymeric vector; gene release; glutathione-responsive polymer; charge-reversal polymer
Funding
- National Natural Science Foundation [U1501243, 21875211, 51833008, 51603181]
- National Key Research and Development Program of China [2016YFA0200301]
- Fundamental Research Funds for the Central Universities of China [2019FZA4020]
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Cationic polymers condense nucleic acids into nanosized complexes (polyplexes) that are widely explored for nonviral gene delivery, but their strong electrostatic binding with DNA causes inefficient intracellular gene release and translation and thereby unsatisfactory gene transfection efficiencies. Facilitated intracellular dissociation of polyplexes by making the polymer undergo positive-to-negative/neutral charge reversal can effectively solve these problems, but they must be sufficiently stable during the delivery. Herein, we report the first glutathione (GSH)-specific intracellular labile polyplexes for cancer-targeted gene delivery. The polymers are made from p-(2,4-dinitrophenyloxybenzyl)-ammonium cationic moieties, whose p-2,4-dinitrophenyl ether is cleaved specifically by GSH, rather than other biological thiols, triggering the conversion of the ammonium cation into the carboxylate anion and thus the fast intracellular DNA release of the polyplexes. Furthermore, the polyplexes coated with PEG-functionalized lipids are stable in biological fluids to gain long blood circulation for tumor accumulation. Thus, the efficient tumor accumulation and cell transfection of the polyplexes loaded with the tumor suicide gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) give rise to potent antitumor activity similar to that of the first-line chemotherapy drug paclitaxel but with much less adverse effects.
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