Reducible cationic PAA-g-PEI polymeric micelle/DNA complexes for enhanced gene delivery

Abstract

The design of unique vectors to overcome the cytotoxicity and increase the efficiency of gene transfection has enormous challenges. Polyethylenimine (PEI) is one of the most effective polymer-based gene carriers. However, the transfection efficiency and toxicity of PEI correlate strongly to its molecular weight (MW). In this study, novel reduction-sensitive amphiphilic poly[phenethylamido- N,N-bis(acryloyl) cystine]- g-polyethylenimine (PAA- g-PEI) copolymers were synthesized by grafting low-MW PEIs onto reducible poly[phenethylamido-N,N-bis(acryloyl) cystine] (PAA). These copolymers self-assembled in aqueous solution into micelles with sizes <70 nm, as determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The PAA- g-PEI2000 micelles effectively condense with the plasmid DNA to form complex nanoparticles with diameters of ~100 nm at an N/P ratio of 4/1. The PAA- g-PEI2000 micelle/DNA complexes protected the DNA from degrading by nuclease and released DNA under reductive conditions by the cleavage of the disulfide bonds and the subsequent disassembly of the micelles. As determined by gene transfection experiments, the transfection efficiency of the PAA- g-PEI2000 micelle/DNA complexes was significantly greater than that of the PEI25K/DNA complexes, while the cytotoxicity of the copolymers was much lower than that for PEI25K.