Size reduction of galactosylated PEI/DNA complexes improves lectin-mediated gene transfer into hepatocytes

Hepatocytes are interesting targets for gene therapy applications. Several hepatocyte-directed gene delivery vectors have been described. For example, simple galactosyl residues coupled to polyethylenimine (PEI) gave an effic ient vector which selectively transfected hepatocytes via the asialoglycopr otein receptor-mediated endocytosis [Zanta, M. A., et al. (1997) Bioconjuga te Chem. 8, 839-844]. However, the large size of these galactosylated PEI/D NA complexes prevented their use in vivo. We have investigated the role of the saccharide length on the size of glycosylated-PEI/DNA particles. When 5 % of the PEI nitrogens were grafted with a Linear tetragalactose structure (lGal4), small and stable particles were formed upon complexation with plas mid DNA. These particles were essentially toroids having a size of 50-80 nm and a zeta-potential close to neutrality, Moreover, these slightly charged PEI-lGal4/DNA complexes were as selective as the previously described gala ctosylated-PEI vector to transfect hepatocytes, but in addition, they were more efficient. It is expected that the properties of the PEI-lGal4/DNA com plexes may increase their diffusion into the liver and their efficiency to transfect hepatocytes.