Cationic lipophosphoramidates containing a hydroxylated polar headgroup for improving gene delivery.
The structure of the cationic moiety of amphiphiles is a key factor which directly influences their transfection efficacy. Accordingly, in the present work, we have synthesized three new lipophosphoramide-based amphiphilic compounds incorporating a methoxy 5, hydroxyl 6, or dihydroxyl 7 functional group in their cationic part. Gene delivery efficacies of these novel vectors were compared to our benchmark compound, the arsenolipophosphoramidate KLN47, and to its trimethylammonium (TMA) analogue 4. We next studied the characteristics (size, ζ potential) of the nanometric assemblies formed (liposomes and lipid/DNA complexes), and the DNA binding ability of the cationic liposomes was characterized at the physicochemical level. In vitro, all of the cationic lipids evaluated were efficient not only to condense plasmids but also to transfect two types of human airway epithelial cells. Interestingly, in vivo administration to mice (via simple tail vein injection) showed that compound 6 was the most efficient in transfecting the lungs when compared to that of the other cationic lipids studied, including compound KLN47. All of these results suggest that a hydroxyethyldimethylammonium (HE-DMA) polar head could be a valuable alternative to a trimethylarsonium (TMAs) polar head and that they also invite further evaluation of the in vivo potential of compound 6 using more clinically relevant delivery procedures.
†CEMCA, CNRS UMR 6521, SFR ScInBioS, Université Européenne de Bretagne, Université de Brest, Brest, France.|⊥Plateforme IBiSASynNanoVect, SFR ScInBioS, Université de Bretagne Occidentale, Université Européenne de Bretagne, 29238 Brest, Cedex 3, France.
Mathieu
M
Berchel
‡Unité INSERM 1078, SFR ScInBioS, Université de Bretagne Occidentale, Université Européenne de Bretagne, Faculté de Médecine et des Sciences de la Santé, 22 avenue Camille Desmoulins, 29218 Brest, France.|⊥Plateforme IBiSASynNanoVect, SFR ScInBioS, Université de Bretagne Occidentale, Université Européenne de Bretagne, 29238 Brest, Cedex 3, France.
Tony
T
Le Gall
†CEMCA, CNRS UMR 6521, SFR ScInBioS, Université Européenne de Bretagne, Université de Brest, Brest, France.
Jean-Pierre
JP
Haelters
‡Unité INSERM 1078, SFR ScInBioS, Université de Bretagne Occidentale, Université Européenne de Bretagne, Faculté de Médecine et des Sciences de la Santé, 22 avenue Camille Desmoulins, 29218 Brest, France.
Pierre
P
Lehn
‡Unité INSERM 1078, SFR ScInBioS, Université de Bretagne Occidentale, Université Européenne de Bretagne, Faculté de Médecine et des Sciences de la Santé, 22 avenue Camille Desmoulins, 29218 Brest, France.|§CHRU de Brest, Service de Génétique Moléculaire et d'Histocompatibilité, 5 avenue du maréchal Foch, 29609 Brest Cedex, France.|∥DUMG, Faculté de Médecine et des Sciences de la Santé, 22 avenue Camille Desmoulins, 29238 Brest, France.|⊥Plateforme IBiSASynNanoVect, SFR ScInBioS, Université de Bretagne Occidentale, Université Européenne de Bretagne, 29238 Brest, Cedex 3, France.
Tristan
T
Montier
†CEMCA, CNRS UMR 6521, SFR ScInBioS, Université Européenne de Bretagne, Université de Brest, Brest, France.|⊥Plateforme IBiSASynNanoVect, SFR ScInBioS, Université de Bretagne Occidentale, Université Européenne de Bretagne, 29238 Brest, Cedex 3, France.
Paul-Alain
PA
Jaffrès
D002412:Cations / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D018014:Gene Transfer Techniques; D006900:Hydroxylation; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry
D002412:Cations; D004337:Drug Carriers; D008055:Lipids; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; C009571:phenyltrimethylammonium
DNA; amphiphiles; cationic lipids; gene delivery; liposomes