title: Cyclen-based double-tailed lipids for DNA delivery: Synthesis and the effect of linking group structures.
abstract: The gene transfection efficiency (TE) of cationic lipids is largely influenced by the lipid structure. Six novel 1, 4, 7, 10-tetraazacyclododecane (cyclen)-based cationic lipids L1-L6, which contain double oleyl as hydrophobic tails, were designed and synthesized. The difference between these lipids is their diverse backbone. Liposomes prepared by the lipids and DOPE showed good DNA affinity, and full DNA condensation could be achieved at N/P of 4 to form lipoplexes with proper size and zeta-potentials for gene transfection. Structure-activity relationship of these lipids as non-viral gene delivery vectors was investigated. It was found that minor backbone structural variations, including linking group and the structural symmetry would affect the TE. The diethylenetriamine derived lipid L4 containing amide linking bonds gave the best TE, which was several times higher than commercially available transfection reagent lipofectamine 2000. Besides, these lipids exhibited low cytotoxicity, suggesting their good biocompatibility. Results reveal that such type of cationic lipids might be promising non-viral gene vectors, and also afford us clues for the design of novel vectors with higher TE and biocompatibility.
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, PR China.
authors.forename: Yi-Mei
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, PR China.
authors.forename: De-Chun
authors.initials: DC
authors.lastname: Chang
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, PR China. Electronic address: ji_zhang@163.com.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, PR China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, PR China. Electronic address: xqyu@scu.edu.cn.
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Yu
mesh_terms: D000080027:Cyclams; D004247:DNA / Q000737:chemistry*; D018014:Gene Transfer Techniques / Q000706:statistics & numerical data*; D006571:Heterocyclic Compounds / Q000378:metabolism*; D006801:Humans; D055666:Lipopeptides / Q000235:genetics*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D000080027:Cyclams; D006571:Heterocyclic Compounds; D055666:Lipopeptides; D004247:DNA; C038072:cyclen
keywords: Cationic lipids; Cyclen; Gene delivery; Non-viral vector; Structure–activity relationship