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Use of dithiodiglycolic acid as a tether for cationic lipids decreases the cytotoxicity and increases transgene expression of plasmid DNA in vitro.

Two major barriers that limit cationic lipids in gene delivery are low transfection efficiency and toxicity. In the present studies, we used dithiodiglycolic acid as a new tether for the polar and hydrophobic domains of a cationic lipid, cholesteryl hemidithiodiglycolyl tris(aminoethyl)amine (CHDTAEA). We compared the transfection activity and toxicity of CHDTAEA with its nondisulfide analogue and cholesteryl N-(dimethylaminoethyl) carbamate (DC-Chol). The liposomes of CHDTAEA had more than 2 orders of magnitude greater transfection activity than DC-Chol in CHO cells and 7 times greater transfection activity in SKnSH cells. CHDTAEA also demonstrated much less toxicity than the other two lipids. Dithiodiglycolic acid may act as an excellent linker in the application of cationic lipid syntheses.