PEI-based vesicle-polymer hybrid gene delivery system with improved biocompatibility.
Wider use of the transfection agent polymer polyethylenimine (PEI) in vivo has been hampered by its toxicity. In order to examine whether material combining properties of polymers and lipid type of carriers would have improved characteristics, four PEI derivatives were synthesised: The methylation of the branched PEI (25 kDa) created a permanently charged quaternary ammonium derivative. Acylation of these backbones using pendant palmitic acid chains created amphiphilic PEI variants which formed nanoparticles or vesicles. Finally hydrophilic groups were added to the polymer backbone by PEGylation. The materials were characterised and their in vitro and in vivo properties were tested. The modifications improved the materials biocompatibility markedly when compared to the starting material but also reduced transfection efficiency. The material bearing ammonium and palmitoyl groups was 10x less toxic while retaining about 30% of the transfection efficiency in vitro. After intravenous administration in a mouse model the materials also gave rise to GFP transgene expression in the liver. The synthetic strategy altered complex physicochemistry and improved biocompatibility while maintaining in vitro gene expression for most formulations. The strategy of combination of complementary properties of cationic lipids and polymers into a hybrid material may also be applicable to other materials.
Brownlie
A
A
Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK.
Uchegbu
I F
IF
Schätzlein
A G
AG
D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D006461:Hemolysis / Q000187:drug effects / Q000502:physiology; D051379:Mice; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry
D011108:Polymers; D011094:Polyethyleneimine