Correlation of the cytotoxic effects of cationic lipids with their headgroups.

As effective non-viral vectors of gene therapy, cationic lipids still have the problem of toxicity, which has become one of the main bottlenecks for their applications. The toxicity of cationic lipids is strongly connected to the headgroup structures. In this article, we studied the cytotoxicity of two cationic lipids with a quaternary ammonium headgroup (CDA14) and a tri-peptide headgroup (CDO14), respectively, and with the same linker bond and hydrophobic domain. The IC50 values of CDA14 and CDO14 against NCI-H460 cells were 109.4 μg mL-1 and 340.5 μg mL-1, respectively. To determine the effects of headgroup structures of cationic lipids on cytotoxicity, apoptosis related pathways were investigated. As the lipids with a quaternary ammonium headgroup could induce more apoptotic cells than the ones with a peptide headgroup, the enzymatic activity of caspase-9 and caspase-3 increased obviously, whereas the mitochondrial membrane potential (MMP) decreased. At the same time, the reactive oxygen species (ROS) levels also increased and the cell cycle was arrested at the S phase. The results showed that the toxicity of the cationic lipid had a close relationship with its headgroup structures, and the cytotoxic mechanism was mainly via the caspase activation dependent signaling pathway and mitochondrial dysfunction. Through this study, we hope to provide the scientific basis for exploiting safer and more efficient cationic lipids for gene delivery.