Design, synthesis, and in vitro gene delivery efficacies of novel cholesterol-based gemini cationic lipids and their serum compatibility: a structure-activity investigation

Abstract

Five cholesterol-based gemini cationic lipids, which differ in the length of the spacer [-(CH₂)_n-] chain between the head groups, have been synthesized. These lipids are useful as nonviral gene delivery agents, and all cholesterol-based gemini lipids (2a-2e) are better transfecting agents than their monomeric lipid counterpart 1. Transfection efficiency of all the gemini lipids except lipid 2a [-(CH₂)₃-] was maintained even when the serum was present during the transfection conditions as compared to the monomeric lipid 1, with which a dramatic decrease in transfection efficiency was observed. With the increase in spacer chain length from propanediyl [-(CH₂)₃-] to pentanediyl [-(CH₂)₅-], transfection efficiency increased both in the absence and presence of serum. However, transfection efficiency decreased with further increase in the length from the pentanediyl [-(CH₂)₅-] to the dodecanediyl [-(CH₂)₁₂-] spacer. Among these gemini lipids 2c showed the highest transfection activity, which was also greater than that of the commercially available formulation.