Novel macrocyclic and acyclic cationic lipids for gene transfer: Synthesis and in vitro evaluation

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 14; pp. 4686 - 4692
• Main Authors: Goldring, William P.D., Jubeli, Emile, Downs, Rachael A., Johnston, Adam J.S., Abdul Khalique, Nada, Raju, Liji, Wafadari, Deena, Pungente, Michael D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.07.2012; Elsevier
• Subjects: animal ovaries; Animals; Biological and medical sciences; Cations - chemistry; Cell Survival - drug effects; Chinese hamsters; CHO Cells; cholesterol; Cricetinae; cytotoxicity; deoxyribonuclease I; DNA transfection; genes; hydrophobicity; in vitro studies; Lipids - chemical synthesis; Lipids - pharmacology; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - pharmacology; Macrocyclic lipids; Medical sciences; Non-viral gene therapy; Pharmacology. Drug treatments; plasmids; Ring-closing metathesis; Structure-Activity Relationship; Transfection; Macrocyclic lipids; DNA transfection; Ring-closing metathesis; Non-viral gene therapy; Evaluation; Organic cation; Metathesis; Drug carrier; In vitro; Macrocycle; Genetic transfer; Quaternary ammonium compound; Transfection; Cyclization; DNA; Chemical synthesis; Gene therapy
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.080

The synthesis and in vitro evaluation of four cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic, and saturated or unsaturated hydrophobic regions, is described. The synthesis employed standard protocols, including ring-closing metathesis for macrocyclic lipid construction. All lipoplexes studied, formulated from plasmid DNA and a liposome composed of a synthesized lipid, 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC), and either 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol as co-lipid, exhibited plasmid DNA binding and protection from DNase I degradation, and concentration dependent cytotoxicity using Chinese hamster ovary-K1 cells. The transfection efficiency of formulations with cholesterol outperformed those with DOPE, and in many cases the EPC/cholesterol control, and formulations with a macrocyclic lipid (+/− 10:1) outperformed their acyclic counterparts (+/− 3:1).