Catherine Dubertret

Synthesis of glycosylated polyethylenimine with reduced toxicity and high transfecting efficiency.

A safe and efficient synthesis of glycosylated polyethylenimine using titanium (IV) isopropoxide and sodium borohydride has been carried out as a substitute for the highly toxic sodium cyanoborohydride method currently used. Poryplexes formed between DNA and the various glycosylated polyethylenimines appeared to be much less cytotoxic than polyethylenimine (PEI)/DNA polyplexes.

Novel nonviral vectors for gene delivery: Synthesis and applications

We have synthesized novel cationic lipids for gene delivery bearing an ester bond between the lipid moiety and the polyamine head. We have found that an intramolecular rearrangement occurs during purification of one of the products. The rearrangement led to a cyclic lipopolyamine which was active for DNA gene transfer. The formation of cyclization products depends on the spacer found between the lipid and the polyamine. The introduction of arginine in the linker position prevents the formation of cyclic products. Linear as well as cyclic analogues showed high-efficiency gene transfer when tested in vitro for luciferase gene expression as compared to dioctadecylamidoglycyl spermine or lipofectamine and also in vivo in the Lewis lung carcinoma model. The introduction of arginine in the linker position promoted increased transfection activity, demonstrating that a diversity of linkers, such as short peptides or glycosides, can be introduced into cationic lipids for targeted gene transfer.