Novel synthetic LPDs consisting of different cholesterol derivatives for gene transfer into hepatocytes

In the present study, LPDs composing of a series of novel synthetic cholesterylated derivatives bearing a cluster of galactose residues and different spacer lengths were prepared for performing target gene delivery to hepatocytes and their physiochemical properties as well as gene transfer efficiency were investigated. In agreement with the "clustering effect" known to occur with more complex oligomeric structures, the addition of galactose residues under optimized spatial arrangement condition invariably increased the transfect efficiency into hepatoma cells, which can be owed to the sufficient binding of galactose ligands to the ASGPR on hepatocytes. However, the gene transfer ability to hepatocytes was not always improved with extended spacer arms, suggesting a spatial binding sites arrangement of the receptor. Moreover, our research has established galactosylated LPDs, specifically, LPDIIb, LPDIIIc, and LPDIVe as potential vectors to deliver special genes into hepatocytes with low toxicity, combining the condensing effect of protamine and the targeting capability of cholesterylated thiogalactosides.