Liposome encapsulated polyethylenimine/ODN polyplexes for brain targeting

Despite high in vitro transfection efficiency, the use of the cationic polymer polyethylenimine (PEI) for systemic application is limited due to its rapid blood clearance and accumulation by RES sites upon intravenous administration of PEI/DNA polyplexes. Therefore, it is important to improve the properties of the PEI/DNA complex with respect to extending the systemic circulation time and suppression of RES uptake. In this study, we applied PEGylated liposome technology for systemic delivery of PEI polyplex of oligodeoxynucleotides (ODN), based on encapsulation of the PEI/ODN polyplexes into PEGylated liposomes. The PEI/ODN polyplex was prepared with a low-branched PEI with MW 2.7 kDa and 20-mer double stranded ODN and was then entrapped into PEGylated liposomes with 95% loading efficiency, leading to a virus-like structure with ∼ 130 nm diameter. The PEG-stabilized liposome (PSL) entrapping PEI/ODN polyplexes remained stable in the presence of serum. Upon intravenous administration, the DNA in the PSL was cleared from systemic circulation at a significantly slower rate as compared to the naked PEI/ODN complex. Furthermore, targeting of the PSL with antibody specific to transferrin receptor redirected biodistribution of the entrapped ODN, leading to significant accumulation in the targeted organ, i.e. brain. Encapsulation of the PEI/ODN polyplexes within a long-circulating liposome provided a promising ODN delivery system for in vivo application.