Long-circulating DNA lipid nanocapsules as new vector for passive tumor targeting.
Systemic gene delivery systems are needed for therapeutic application to organs that are inaccessible by percutaneous injection. Currently, the main objective is the development of a stable and non-toxic vector that can encapsulate and deliver foreign genetic material to target cells. To this end, DNA, complexed with cationic lipids i.e. DOTAP/DOPE, was encapsulated into lipid nanocapsules (LNCs) leading to the formation of stable nanocarriers (DNA LNCs) with a size inferior to 130 nm. Amphiphilic and flexible poly (ethylene glycol) (PEG) polymer coatings [PEG lipid derivative (DSPE-mPEG(2000)) or F108 poloxamer] at different concentrations were selected to make DNA LNCs stealthy. Some of these coated lipid nanocapsules were able to inhibit complement activation and were not phagocytized in vitro by macrophagic THP-1 cells whereas uncoated DNA LNCs accumulated in the vacuolar compartment of THP-1 cells. These results correlated with a significant increase of in vivo circulation time in mice especially for DSPE-mPEG(2000) 10 mm and an early half-life time (t(1/2) of distribution) 5-fold greater than for non-coated DNA LNCs (7.1 h vs 1.4 h). Finally, a tumor accumulation assessed by in vivo fluorescence imaging system was evidenced for these coated LNCs as a passive targeting without causing any hepatic damage.
Morille
Marie
M
Inserm U646, Université d'Angers, 10 rue André Boquel, F-49100 Angers, France.
Montier
Tristan
T
Legras
Pierre
P
Carmoy
Nathalie
N
Brodin
Priscille
P
Pitard
Bruno
B
Benoît
Jean-Pierre
JP
Passirani
Catherine
C
D000818:Animals; D016923:Cell Death; D002460:Cell Line; D003165:Complement System Proteins / Q000276:immunology; D004247:DNA / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008055:Lipids / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D009369:Neoplasms / Q000628:therapy*; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry; D013499:Surface Properties; D013997:Time Factors; D014018:Tissue Distribution
D008055:Lipids; D053769:Nanocapsules; D010714:Phosphatidylethanolamines; C038089:1,2-distearoylphosphatidylethanolamine; D003165:Complement System Proteins; D004247:DNA