cyclen-based cationic lipids for highly efficient gene delivery towards tumor cellscyclen-based阳离子脂质高效的基因传递到肿瘤细胞.pdfVIP

Cyclen-Based Cationic Lipids for Highly Efficient Gene Delivery towards Tumor Cells Qing-Dong Huang., Guo-Xing Zhong., Yang Zhang, Jiang Ren, Yun Fu, Ji Zhang*, Wen Zhu*, Xiao-Qi Yu* Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract 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 2000TM 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