Hierarchically Assembled Theranostic Nanopolyplexes Enable Robust Tumor Gene Therapy and Magnetic Resonance Imaging In Vivo

Abstract

Theranostic nanosystems encompassing imaging reagents and therapeutic genes are promising for concurrent tumor diagnosis and gene therapy. In this work, we developed bioresponsive gadolinium (Gd)-based nanopolyplexes (denoted as Gdplexes) for in vivo tumor theranostic applications. Gdplexes were generated by a hierarchical assembly method involving the neutralization of DNA with a Gd-chelated bioreducible cationic polyurethane (termed as GdCPUA), which was followed by condensation of DNA with a cationic dextran conjugate (DP800). By adjusting GdCPUA/DP800 ratios, the resultant Gdplexes had GdCPUA/DNA complex as an inner core and a dextran outer shell; thus, Gdplexes exhibit an improved colloidal stability under physiological conditions and perform active gene release in an intracellular reductive environment. In vitro tests against cancer cells revealed that optimized Gdplexes afforded comparable transfection efficiency to that of the 25 kDa branched polyethylenimine used as a positive control. Additionally, the Gdplexes could robustly transfer small hairpin RNA plasmids to silence vascular endothelial growth factor expression in SKOV-3 cells. In vivo, the Gdplexes loaded with plasmid were practical for systemic gene delivery via intravenous administration, yielding marked growth repression of an SKOV-3 tumor xenograft in a BALB/c nude mouse model. The tumor could be visualized by T1-weighted magnetic resonance (MR) imaging. Such efficient gene therapy had no adverse effects on hepatorenal functions and weight gain in the mouse. This work highlights Gdplexes as biosafe and robust nanocarriers for tumor theranostic applications in vivo.