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Background  Gene therapy has tremendous potential for both inherited and acquired diseases. However, delivery problems limited their clinical application, and new gene delivery vehicles with low cytotoxicity and high transfection efficiency are greatly required.    Methods  In this report, we designed and synthesized three amphiphilic molecules ( L1 – L3 ) with the structures involving 1, 4, 7, 10-tetraazacyclododecane (cyclen), imidazolium and a hydrophobic dodecyl chain. Their interactions with plasmid DNA were studied via electrophoretic gel retardation assays, fluorescent quenching experiments, dynamic light scattering and transmission electron microscopy. The in vitro gene transfection assay and cytotoxicity assay were conducted in four cell lines.    Results  Results indicated that  L1  and  L3 -formed liposomes could effectively bind to DNA to form well-shaped nanoparticles. Combining with neutral lipid DOPE,  L3  was found with high efficiency in gene transfer in three tumor cell lines including A549, HepG2 and H460. The optimized gene transfection efficacy of  L3  was nearly 5.5 times more efficient than that of the popular commercially available gene delivery agent Lipofectamine 2000™ in human lung carcinoma cells A549. In addition, since  L1  and  L3  had nearly no gene transfection performance in normal cells HEK293, these cationic lipids showed tumor cell-targeting property to a certain extent. No significant cytotoxicity was found for the lipoplexes formed by  L1 – L3 , and their cytotoxicities were similar to or slightly lower than the lipoplexes prepared from Lipofectamine 2000™.    Conclusion  Novel cyclen-based cationic lipids for effective in vitro gene transfection were founded, and these studies here may extend the application areas of macrocyclic polyamines, especially for cyclen.

Cyclen-Based Cationic Lipids for Highly Efficient Gene Delivery towards Tumor Cells