pH-sensitive, tail-modified, ester-linked ionizable cationic lipids for gene delivery

Ionizable cationic lipids have great potential for gene delivery, yet the effect of the molecular structure of such lipids on gene delivery efficiency is an ongoing research challenge. To better understand corresponding structure-function activity relationships, we synthesized four ester-linked, pH-responsive, ionizable cationic lipids. The screened DEDM4 lipid, containing 2-ethylenedimethylamine in the headgroup and a branched-chain tail, exhibited a high delivery efficacy of plasmid DNA and siRNA in A549 cells, which was comparable with that of the commercial reagent lipofectamine 3000 (lipo3000). Moreover, because of its pKa value of 6.35 and pH-sensitivity under acidic conditions, DEDM4 could carry sufficient positive charge in the acidic environment of endosomes and interact with the endosome lumen, leading to destruction of the endomembrane and subsequent release of siRNA into the cytoplasm with endosomal escape. Furthermore, we used DEDM4 to deliver IGF-1R siRNA to induce cancer cell apoptosis, thereby leading to great tumor inhibition. More importantly, it also showed very low toxicity in vivo. These structure-activity data for DEDM4 demonstrate potential clinical applications of DEDM4-mediated gene delivery for cancer.