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Le Corre S.S.,University of Western Brittany | Berchel M.,University of Western Brittany | Le Gall T.,IBiSA SynNanoVect Platform | Le Gall T.,University of Western Brittany | And 6 more authors.
European Journal of Organic Chemistry | Year: 2014

We report herein the synthesis of a novel family of cationic lipids, characterized by a trimethylammonium headgroup linked through a phosphate function to either two identical or two different lipid chains. The novelty of this study arises from the use of a trialkyl phosphate group to associate the hydrophobic domain to the cationic polar head. The structure of these new cationic lipids, which differs from that of previously reported lipophosphoramidates, is closer to the phospholipids encountered in the plasma membrane, and possesses a phosphocholine polar head. Evaluation of the transfection activity allowed us to compare the efficacy of cationic lipophosphates with that of lipophosphoramidates. These results demonstrate that cationic lipophosphates and lipophosphoramidates having otherwise identical chemical structures exhibit similar transfection efficacies. The second conclusion is that the structure of the lipid domain is a much more important parameter in governing transfection efficacy than the composition of the linker moiety. The best results were obtained with cationic lipophosphates or lipophosphoramidates possessing two different lipid chains, for example one oleyl chain with one phytanyl chain. These nonsymmetric cationic lipids exhibited transfection efficacies that were 10-to 200-fold better than those obtained with Lipofectamine used as a commercial standard. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fraix A.,European University of Brittany | Montier T.,IBiSA SynNanoVect Platform | Montier T.,French Institute of Health and Medical Research | Carmoy N.,French Institute of Health and Medical Research | And 10 more authors.
Organic and Biomolecular Chemistry | Year: 2011

The synthesis of cationic lipo-thiophosphoramidates, a new family of cationic lipids designed for gene delivery, is reported herein. This new class of lipids is less polar than its oxygenated equivalent the lipo- phosphoramidates. Fluorescence anisotropy and FRET were used to determine the fluidity and fusogenicity of the lipo-phosphoramidates 3a-b and lipo-thiophosphoramidates 7a-b. The determination of both the size and the zeta potential of the nano-objects (liposomes and lipoplexes) and the determination of the DNA binding ability of the liposomes have completed the physico-chemical characterizations of the cationic lipids studied. Finally, the cationic lipids 3a-b and 7a-c have been evaluated as synthetic vectors for gene transfection into a variety of mammalian cell lines. The lipo-thiophosphoramidate 7a proved to be an efficient and low toxicity synthetic vector even when used at low lipid to DNA charge ratios. © 2011 The Royal Society of Chemistry.

Fraix A.,European University of Brittany | Le Gall T.,IBiSA SynNanoVect Platform | Le Gall T.,French Institute of Health and Medical Research | Berchel M.,European University of Brittany | And 7 more authors.
Organic and Biomolecular Chemistry | Year: 2013

Lipophosphoramidates have previously been identified as efficient vectors for gene delivery. The incorporation of functional groups that respond to a physiological stimulus is hypothesised to further improve the efficacy of this type of vector and eventually reduce its cytotoxicity. In the present work, we report the effects of the incorporation of two disulfide motifs into the hydrophobic domain, close to the phosphoramidate group. Three cationic vectors possessing such a red/ox sensitive function were synthesised. The capability of one of them (5b) to compact DNA is reported jointly with its ability to release that DNA in the presence of a reducing agent. Finally, compound 5b was tested as a vector for gene delivery into human cells in vitro and its cytotoxicity was also evaluated. This journal is © 2013 The Royal Society of Chemistry.

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