Intracellular redox-responsive nanocarrier for plasmid delivery: in vitro characterization and in vivo studies in mice

Although some modifications of polyethyleneimine (PEI) properties have been explored to balance the transfection efficiency and cytotoxicity, its successful plasmid delivery in vitro and in vivo to realize its true therapeutic potentials remains a major challenge, mainly due to intracellular trafficking barriers. Herein, we present a delivery nanocarrier Pluronic-PEI-SS by conjugating reducible disulfide-linked PEI (PEI-SS) to biocompatible Pluronic for enhanced DNA delivery and transfection efficiency in vitro and in vivo. Pluronic-PEI-SS strongly condensed plasmid DNA to low positively charged nanocomplexes, exhibited good stability against deoxyribonuclease I digestion, and tended to be easily degraded in the presence of reducing agent 1,4-dithiothreitol. The in vitro transfection of the complex Pluronic-PEI-SS/DNA into HeLa and 293T cells resulted in lower cytotoxicity as well as significantly higher cellular uptake, nucleus transfection, and gene expression than Pluronic-PEI (25 kDa), PEI-SS, and PEI 25 kDa given alone. Furthermore, the in vivo transfection study demonstrated that Pluronic-PEI-SS/DNA complexes induced a higher enrichment than the commercial PEI/DNA complex in the tumor, indicating their potential application as biocompatible vector in gene delivery.