The advancement in gene therapy relies upon the discovery of safe and efficient delivery agents and methods. In this study, we report the design and synthesis of a cationic bolaamphiphile as a non-viral gene delivery agent. The bolaamphiphile is composed of 1,12-diaminododecane as the central hydrophobic unit linked to the hydrophilic pentaethylenehexamine via thioether-based glycidyl units. This bolaamphiphile condensed DNA efficiently into nanoparticles of sizes around 150-200 nm with positive zeta potential of 30-35 mV. In vitro luciferase expression levels and percentage of GFP expressing cells induced by the bolaamphiphile/DNA complexes were higher than those mediated by the often used "golden" standard of non-viral systems, polyethyleneimine (PEI, branched, 25 kDa) at its optimal N/P ratio in HEK293, HepG2, NIH3T3, HeLa and 4T1 cells. In vitro cytotoxicity testing revealed that the DNA complexes fabricated from this cationic bolaamphiphile displayed marginal toxicity towards all the cell lines tested. In addition, in vivo transfection studies carried out in a 4T1 mouse breast cancer model showed that the cationic bolaamphiphile delivered DNA more efficiently than PEI. This cationic bolaamphiphile may make a promising gene delivery vector for future gene therapy.
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