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Folate-Equipped Nanolipoplexes Mediated Efficient Gene Transfer into Human Epithelial Cells
INSERM U1078, IFR 148 ScInBIoS, Université de Bretagne Occidentale, 46 rue Félix Le Dantec, CS 51819, 29218 Brest Cedex 2, France
Ecole Nationale Supérieure de Chimie de Rennes, CNRS, UMR 6226, Avenue du Général Leclerc, CS 50837, 35708 Rennes Cedex 7, France
Service d'ORL et de chirurgie cervico-faciale, CHU de BREST hôpital Morvan, 2 avenue du maréchal Foch 29609 Brest, France
IBiSA "SynNanoVect" platform, IFR 148 ScInBIoS, Faculté de Médecine, Université de Bretagne Occidentale, 22 avenue Camille Desmoulins, CS 93837–29238 Brest cedex, France
DUMG–Faculté de médecine, Université de Bretagne Occidentale, 22 avenue Camille Desmoulins, CS 93837–29238 Brest cedex, France
CHRU de Brest, hôpital Morvan, 2 avenue du maréchal Foch 29609 Brest, France
* Author to whom correspondence should be addressed.
Received: 10 December 2012; in revised form: 31 December 2012 / Accepted: 6 January 2013 / Published: 14 January 2013
Abstract: Since recombinant viral vectors have been associated with serious side effects, such as immunogenicity and oncogenicity, synthetic delivery systems represent a realistic alternative for achieving efficacy in gene therapy. A major challenge for non-viral nanocarriers is the optimization of transgene expression in the targeted cells. This goal can be achieved by fine-tuning the chemical carriers and the adding specific motifs to promote cellular penetration. Our study focuses on the development of novel folate-based complexes that contain varying quantities of folate motifs. After controlling for their physical properties, neutral folate-modified lipid formulations were compared in vitro to lipoplexes leading to comparable expression levels. In addition, no cytotoxicity was detected, unlike what was observed in the cationic controls. Mechanistically, the delivery of the transgene appeared to be, in part, due to endocytosis mediated by folate receptor targeting. This mechanism was further validated by the observation that adding free folate into the medium decreased luciferase expression by 50%. In vivo transfection with the folate-modified MM18 lipid, containing the highest amount of FA-PEG570-diether co-lipid (w:w; 90:10), at a neutral charge ratio, gave luciferase transgene expression. These studies indicate that modification of lipids with folate residues could enhance non-toxic, cell-specific gene delivery.
Keywords: cystic fibrosis; cationic lipids; neutral lipid nanocomplexes; folic acid; folate receptors; epithelial cells
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Mornet, E.; Carmoy, N.; Lainé, C.; Lemiègre, L.; Le Gall, T.; Laurent, I.; Marianowski, R.; Férec, C.; Lehn, P.; Benvegnu, T.; Montier, T. Folate-Equipped Nanolipoplexes Mediated Efficient Gene Transfer into Human Epithelial Cells. Int. J. Mol. Sci. 2013, 14, 1477-1501.
Mornet E, Carmoy N, Lainé C, Lemiègre L, Le Gall T, Laurent I, Marianowski R, Férec C, Lehn P, Benvegnu T, Montier T. Folate-Equipped Nanolipoplexes Mediated Efficient Gene Transfer into Human Epithelial Cells. International Journal of Molecular Sciences. 2013; 14(1):1477-1501.
Mornet, Emmanuel; Carmoy, Nathalie; Lainé, Céline; Lemiègre, Loïc; Le Gall, Tony; Laurent, Isabelle; Marianowski, Remi; Férec, Claude; Lehn, Pierre; Benvegnu, Thierry; Montier, Tristan. 2013. "Folate-Equipped Nanolipoplexes Mediated Efficient Gene Transfer into Human Epithelial Cells." Int. J. Mol. Sci. 14, no. 1: 1477-1501.