Cationic Lipid-Mediated Gene Delivery to Murine Lung:  Correlation of Lipid Hydration with in Vivo Transfection Activity

• Published in: Journal of medicinal chemistry Vol. 40; no. 25; pp. 4069 - 4078
• Main Authors: Bennett, Michael J, Aberle, Alfred M, Balasubramaniam, Rajiv P, Malone, Jill G, Malone, Robert W, Nantz, Michael H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.12.1997; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Biotechnology; Chemistry, Medicinal; Fundamental and applied biological sciences. Psychology; Gene therapy; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Life Sciences & Biomedicine; Lipids - administration & dosage; Lung - metabolism; Mice; Pharmacology & Pharmacy; Plasmids; Science & Technology; Transfection; Transgenes; LIPOSOME COMPLEXES; THERAPY; CFTR CDNA; FORMULATIONS; PLASMID DNA; MEMBRANES; PHOSPHOLIPIDS; CYSTIC-FIBROSIS; PHASE-I; GAUCHER DISEASE; Organic cation; Hydration; Enzyme; Luciferase; Lung; Rodentia; Monounsaturated fatty acid; Liposome; Drug carrier; Physicochemical properties activity relationship; Complex lipid; Cis stereoisomer; Genetic transfer; Quaternary ammonium compound; Vertebrata; Mammalia; Transfection; Mouse; Animal; DNA; Oxidoreductases; Gene therapy; Acylate; Intratracheal administration
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970155q

A panel of lipidic tetraalkylammonium chlorides has been prepared and screened in studies of both lipid hydration and in vivo mouse transfection. The effect of cationic lipid structure on liposome surface hydration was determined using differential scanning calorimetry. Increases in headgroup steric bulk and the inclusion of cis-unsaturation in the hydrophobic domain led to greater lipid hydration, indicative of a decrease in lipid polar domain associations. Cationic lipids containing hydrogen-bonding functionality in the polar domain exhibited a corresponding decrease in observed lipid hydration, indicative of an increase in lipid polar domain associations. To explore a potential correlation of the hydration data with transfection activity, we examined the in vivo transfection activity of the lipid panel by direct intratracheal instillation of cationic liposome−DNA complexes into BALB/c mice. The more active transfection agents were the lipids that featured headgroup structures promoting close polar domain association in combination with fatty acyl cis-unsaturation. The hydration data suggest that the more effective transfection lipids for mouse lung delivery are those possessing the greatest imbalance between the cross-sectional areas occupied by the polar and hydrophobic domains.