In Vivo Studies of Dialkynoyl Analogues of DOTAP Demonstrate Improved Gene Transfer Efficiency of Cationic Liposomes in Mouse Lung
| Autor: | Michael R. Jorgensen, Andrew D. Miller, Andrew John Heron, Ayesha Ahmad, Steven Fletcher, Eric Perouzel |
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| Rok vydání: | 2005 |
| Předmět: |
Cell Survival
In Vitro Techniques Gene delivery Fatty Acids Monounsaturated Mice Structure-Activity Relationship X-Ray Diffraction Genes Reporter In vivo Cell Line Tumor Chlorocebus aethiops Drug Discovery Animals Humans Cationic liposome Lung Mice Inbred BALB C Liposome Molecular Structure Chemistry Genetic transfer Gene Transfer Techniques Endothelial Cells DNA Transfection In vitro Quaternary Ammonium Compounds Cholesterol Biochemistry COS Cells Liposomes Biophysics Molecular Medicine Female Drug carrier HeLa Cells |
| Zdroj: | Journal of Medicinal Chemistry. 49:349-357 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0507227 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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