Efficient gene transfection to liver cells via the cellular regulation of a multifunctional polylactitol-based gene transporter.

In recent years, the introduction of non-viral gene transfer systems for the treatment of inherited and acquired liver diseases has attracted a lot of attention. To facilitate liver-directed gene delivery, a liver cell targeting strategy and a intracellular control of gene trafficking for the design of an ideal non-viral gene delivery system are crucial and a great challenge. In order to meet these needs, a new multifunctional gene carrier, the polylactitol-based gene transporter (PLT), was prepared by crosslinking low molecular weight polyethylenimine (LMW PEI) with lactitol diacrylate (LDA) composed of d-galactose and d-sorbitol. These provide synergistic effects that increase cellular uptake, result in liver cell targeting and a rapid release of the gene from the endosome, because the hyperosmotic property of the polysorbitol part selectively stimulates caveolae-mediated endocytosis, the polygalactose part provides liver cell targeting ability and the PEI part assists in the rapid endosomal escape of the gene due to its proton sponge effect. With these unique multifunctions, PLT/DNA nanocomplexes showed low cytotoxicity, high transfection efficiency, liver cell targeting in vitro and in vivo, and a selective transition of the cellular uptake pathway into the caveolae-mediated endocytosis avoiding lysosomal degradation. PLT was confirmed as a safe and efficient vector, highlighting a potential candidate for targeted gene therapy in hepatic diseases.