Synthesis of a novel series of cationic lipids that can act as efficient gene delivery vehicles through systematic heterocyclic substitution of cholesterol derivatives

The synthesis of a series of novel cationic lipids through the systematic s ubstitution of cholesterol derivatives that could greatly enhance the deliv ery and expression of plasmid DNA in vitro and in vivo is described. Two of the newly synthesized lipids, designated as NCC4 and NCC10, were chosen to be studied in detail and gave much higher levels of gene expression than t hat which could be obtained with some of the conventional cationic polymers and cationic liposomes. In vivo studies with both NCC4 and NCC10 also show ed better ability in delivering the reporter gene to the target cells throu gh intrasplenic injection. In addition, by varying the DNA/lipid charge rat ios, NCC4 and NCC10 can withstand serum inactivation in vitro. However, thi s does not correlate with the corresponding increase in the level of gene e xpression following systemic gene delivery with NCC4 and NCC10 in vivo.