title: Cyclen-based lipidic oligomers as potential gene delivery vehicles.
abstract: A series of cyclen-based linear oligomers bearing hydrophobic long chains (lipopolymers Cy-LC, where Cy and LC represent cyclen-based linear backbone and hydrophobic long chain substituents, respectively) were designed and synthesized. The effects of type and degree of substitution (DS) of hydrophobic long chains on the transfection efficiency were systematically studied. The nitrogen atoms with relatively strong basicity on the cyclen ensure their good DNA binding ability, which was confirmed by gel retardation and ethidium bromide exclusion assays. Lipopolyplexes could be formed as nanoparticles with suitable sizes and zeta potentials for gene transfection. In vitro gene delivery experiments revealed that the linoleic acid (LIN) substituted material Cy-LIN has better transfection efficiency than 25 kDa polyethylenimine in the absence or in the presence of serum. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and hemolysis assays showed low cytotoxicity and good biocompatibility of the lipopolyplexes. Fluorescent labeled DNA was used to study the cellular uptake and intracellular distribution of transfected DNA. Flow cytometry results suggested that a long chain is necessary for efficient cellular uptake, and images from confocal laser scanning microscopy showed that after 4h transfection, most of the fluorescent labeled DNA accumulated in the perinuclear region, which was required for efficient gene expression. Moreover, it was also found that the DS of the hydrophobic moiety can adjust the balance between DNA binding ability and dissociation of polyplexes, significantly affecting the transfection efficiency.
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Yi
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Qin-Fang
authors.initials: QF
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, People's Republic of 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, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Laboratory of Genome Stability, Development and Stem Cell Institute, The West China Second Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Laifeng
authors.initials: L
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Qian-Ming
authors.initials: QM
authors.lastname: Chen
authors.affiliation: Laboratory of Genome Stability, Development and Stem Cell Institute, The West China Second Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Liandi
authors.initials: L
authors.lastname: Guo
authors.affiliation: Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China. Electronic address: xqyu@scu.edu.cn.
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Yu
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000080027:Cyclams; D004247:DNA / Q000378:metabolism / Q000648:ultrastructure; D004587:Electrophoresis, Agar Gel; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D005453:Fluorescence; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006461:Hemolysis / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D042541:Intracellular Space / Q000378:metabolism; D019787:Linoleic Acid / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D008156:Luciferases / Q000235:genetics; D010316:Particle Size; D010957:Plasmids / Q000378:metabolism; D011817:Rabbits; D055672:Static Electricity; D014162:Transfection
chemical_list: D001672:Biocompatible Materials; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008055:Lipids; D004247:DNA; C038072:cyclen; D019787:Linoleic Acid; D008156:Luciferases
keywords: Cyclen; Gene delivery; Lipopolymer; Non-viral vector; Structure–activity relationship