Position of Disulfide Bond Determines the Properties of Novel Stimuli‐Responsive Cationic Lipids

Effective release of nucleic acids from the lipoplexes to the cytoplasm is one of the challenges of gene delivery systems. Stimuli‐responsive groups such as disulfide linkages offer an attractive solution. We designed two novel polycationic amphiphiles with disulfide links (2S3 and 2S4) and compared their transfection efficiency with their nonredox‐sensitive analogue 2X3. The stability and redox sensitivity of lipoplexes formed by cationic liposomes 2X3, 2S3, and 2S4 with plasmid DNA were studied using different destabilizing agents, such as glutathione, 1,4‐dithiothreitol, and heparin using electrophoresis and fluorescent titration assays. Further, we performed size and ζ‐potential analysis of cationic liposomes and lipoplexes, and also compared their transfection efficiencies in the presence of the destabilizing agents. Depending on their structure, disulfide lipoplexes exhibited different sensitivity towards the destabilizing agents. Moreover, high redox‐sensitivity correlated well with higher transfection activity into HEK293 cells.