Galactosylated DNA lipid nanocapsules for efficient hepatocyte targeting.
The main objective of gene therapy via a systemic pathway is the development of a stable and non-toxic gene vector that can encapsulate and deliver foreign genetic materials into specific cell types with the transfection efficiency of viral vectors. With this objective, DNA complexed with cationic lipids of DOTAP/DOPE was encapsulated into lipid nanocapsules (LNCs) forming nanocarriers (DNA LNCs) with a size suitable for systemic injection (109+/-6 nm). With the goal of increasing systemic delivery, LNCs were stabilised with long chains of poly(ethylene glycol) (PEG), either from a PEG lipid derivative (DSPE-mPEG(2000)) or from an amphiphilic block copolymer (F108). In order to overcome internalisation difficulties encountered with PEG shield, a specific ligand (galactose) was covalently added at the distal end of the PEG chains, in order to provide active targeting of the asialoglycoprotein-receptor present on hepatocytes. This study showed that DNA LNCs were as efficient as positively charged DOTAP/DOPE lipoplexes for transfection. In primary hepatocytes, when non-galactosylated, the two polymers significantly decreased the transfection, probably by creating a barrier around the DNA LNCs. Interestingly, galactosylated F108 coated DNA LNCs led to a 18-fold increase in luciferase expression compared to non-galactosylated ones.
Morille
M
M
Inserm U646, Université d'Angers, 10 rue André Boquel, F-49100 Angers, France.
Passirani
C
C
Letrou-Bonneval
E
E
Benoit
J-P
JP
Pitard
B
B
D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics; D005690:Galactose / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics; D018390:Gene Targeting / Q000379:methods*; D006367:HeLa Cells; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics; D008297:Male; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats
D008055:Lipids; D053769:Nanocapsules; D004247:DNA; D005690:Galactose