In Vivo Studies of Dialkynoyl Analogues of DOTAP Demonstrate Improved Gene Transfer Efficiency of Cationic Liposomes in Mouse Lung

• Published in: Journal of medicinal chemistry Vol. 49; no. 1; pp. 349 - 357
• Main Authors: Fletcher, Steven, Ahmad, Ayesha, Perouzel, Eric, Heron, Andrew, Miller, Andrew D, Jorgensen, Michael R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.01.2006; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Biotechnology; Cell Line, Tumor; Cell Survival - drug effects; Cercopithecus aethiops; Chemistry, Medicinal; Cholesterol - pharmacology; COS Cells; DNA - drug effects; DNA - genetics; DNA - pharmacology; Endothelial Cells - chemistry; Endothelial Cells - drug effects; Fatty Acids, Monounsaturated - chemical synthesis; Fatty Acids, Monounsaturated - chemistry; Fatty Acids, Monounsaturated - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Gene therapy; Gene Transfer Techniques; Genes, Reporter; Health. Pharmaceutical industry; HeLa Cells; Humans; In Vitro Techniques; Industrial applications and implications. Economical aspects; Life Sciences & Biomedicine; Liposomes; Lung - cytology; Lung - drug effects; Lung - metabolism; Mice; Mice, Inbred BALB C; Molecular Structure; Pharmacology & Pharmacy; Quaternary Ammonium Compounds - chemical synthesis; Quaternary Ammonium Compounds - chemistry; Quaternary Ammonium Compounds - pharmacology; Science & Technology; Structure-Activity Relationship; X-Ray Diffraction; SYSTEM; DNA COMPLEXES; THERAPY; OCTADECYNOIC ACIDS; PLASMID-DNA; CANCER; DELIVERY; LIPIDS; Lung disease; Endothelial cell; Acetylenic compound; Respiratory disease; Aliphatic compound; Lung; Rodentia; Liposome; Drug carrier; Malignant tumor; In vitro; Genetic transfer; Quaternary ammonium compound; In vivo; Vertebrata; Mammalia; Treatment; Structure activity relation; Mouse; Animal; DNA; Gene therapy; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0507227

A novel set of dialkynoyl analogues of the cationic, gene delivery lipid DOTAP (1) was synthesized. Structure−activity studies demonstrate that replacement of the cis-double bonds of DOTAP with triple bonds in varying positions alters both the physical properties of the resultant cationic liposome−DNA complexes and their biological functionalities, both in vitro and in vivo. Particularly, in vivo studies demonstrate that pDNA transfection of mouse lung endothelial cells with lead analogue DS(14-yne)TAP (4):cholesterol lipoplexes exhibits double the transfection level with less associated toxicity relative to the well-established DOTAP:cholesterol system. In fact, 4:cholesterol delivers up to 3 times the dose of pDNA in mice than can be tolerated by DOTAP, leading to nearly 3 times greater marker-gene expression. X-ray diffraction studies suggest that lipoplexes containing analogue 4 display increased stability at physiological temperatures. Our results thus suggest that analogue 4 is a potentially strong candidate for the gene therapy of lung tumors.