Zn(II)-cyclen complex-based liposomes for gene delivery: the advantage of Zn coordination

The unique properties of 1, 4, 7, 10-tetraazacyclododecane (cyclen) make it not only a proper polyamine headgroup in cationic lipids for gene delivery, but also a good host molecule for metal coordination. In this study, a series of cyclen-based lipids and their Zn(II)-complexes were synthesized to study the effect of Zn-coordination on the gene transfection. Both the Zn-free and Zn-contained lipids could form nano-sized particles with proper positive potential to condense and protect DNA from degradation by DNase. More importantly, Zn coordination could significantly reduce the cytotoxicity of the liposomes. Meanwhile, the gene transfection efficiency of the cyclen-based lipids could also be distinctly improved by the Zn-coordination. Mechanism studies reveal that the Zn-free and Zn-contained liposomes showed similar cellular uptake properties. However, confocal microscopy exhibit that Zn-contained liposomes may induce more efficient endosomal escape than Zn-free counterpart, which could be attributed to their much higher pH buffering capacity. This study presents an efficient strategy to enhance the gene transfection efficiency and biocompatibility of cyclen-based cationic lipids.