Specific and efficient gene delivery mediated by an asialofetuin-associated nanosystem

Abstract

Gene therapy is considered a promising approach for the treatment of hepatocellular carcinoma (HCC). In this regard, the main goal of this work was to develop a specific and efficient gene delivery nanosystem to HCC based on 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine:cholesterol cationic liposomes and asialofetuin (ASF), a specific ligand to the asialoglycoprotein receptor (ASGP-R) that is overexpressed in HCC. Our results show that association of ASF to lipoplexes promotes a substantial increase in their biological activity in HCC cells, not only in vitro, but also in an animal model. The transfection activity obtained with this novel nanosystem (ASF-lipoplexes) was much higher than that observed with a highly efficient commercial formulation. On the other hand, the presence of high concentrations of galactose substantially reduced the cell uptake and biological activity of the ASF-lipoplexes. These results, together with those obtained in the presence of inhibitors of endocytosis, show that the potentiation induced by the association of ASF to lipoplexes is due to its specific interaction with the ASGP-R. The physicochemical properties of the generated nanosystem also reinforce this observation. Overall, our results demonstrate for the first time that the novel ASF-lipoplexes present a noticeable ability to specifically and efficiently deliver genetic material into HCC cells.