Journal
JOURNAL OF GENE MEDICINE
Volume 7, Issue 8, Pages 1023-1034Publisher
WILEY
DOI: 10.1002/jgm.746
Keywords
gene therapy; non-viral vectors; lipoplex; liposome
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Background As gene therapy using viral vectors involves clinical risks, limited DNA-carrying capacity, and manufacturing problems, non-viral vectors, including cationic lipids, have been investigated. Unfortunately, these agents have significantly lower transfectional ability and, due to the complexity of the transfectional pathway, no general schemes exist for correlating cationic lipid chemistry with transfectional efficacy. Methods Quantitative structure-activity relationship (QSAR) analyses were and unsuccessful experimental carried out on sets of routinely used,, cationic lipid vectors taken from the literature. This approach described the amphipathic character, basicity, headgroup size, lipophilicity and shape of cationic lipids using numerical parameters. Compounds were plotted onto various parameter diagrams, and correlations were sought between numerical parameters and transfectional efficiency. Results Transfectionally effective cationic lipids fell into restricted zones in various parameter spaces, indicating that amphipathic character, lipid shape and lipophilicity were generally significant factors, whilst basicity and headgroup size were only important for certain compounds. The data supported the general significance of membrane mixing followed by induction of membrane curvature, and the more limited role of osmotic shock, as mechanisms of membrane disruption. QSAR descriptions of effective lipids permitted detailed chemical guidelines for optimizing cationic lipid structure to be given. Limitations of the approach and models are discussed. Conclusions QSAR modeling indicated that induction of membrane curvature and osmotic shock are important mechanisms for membrane disruption by cationic lipids. The models also allowed specification of chemically detailed guidelines for selection or design of optimal cationic lipids. Copyright (c) 2005 John Wiley & Sons, Ltd.
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