Synthesis, characterization, and evaluation of sulfonium lipids as potential nonviral gene vectors

Abstract IntroductionNon-viral gene vectors have attracted much attention in the last few decades, because of its potential activity and less side effects. Headgroup chemistry is a key aspect in lipid design. MethodsIn this study, a group of sulfonium lipids were designed and constructed by combining tetrahydrothiophene or tetrahydrothiopyran with an ethoxy linker and carbon aliphatic chains. 12 sulfonium lipids were synthesized and characterized by 1H NMR, 13C NMR, and Mass. The compounds were evaluated in terms of their ability as potential gene vectors. Condensates of sulfonium lipids (SL) and DNA were examined by gel electrophoresis and particle size and zeta potential were measured. Sulfonium compounds were tested on HepG2 cells for cytotoxicity. SL/DNA condensates were studied incellular uptake and distribution using fluorescent microscopy.ResultsThe results showed that sulfonium cation can effectively interact with phosphorous in DNA. Compounds containing a longer lipid chains can effectively retard DNA at S/P ratio higher than 10/1 and can condense DNA into a nanosize particles with particle size in the range 150 nm ~ 300 nm, zeta potential in the range of +20~+40. Sulfonium compounds were calculated IC50s on HepG2 cells in the range of 3.52 ng/mL to 1.64 μg/mL. The intra-cellular uptake experiments revealed that SL/DNA nano particle was taken into the cell at low efficiency.ConclusionSulfonium headgroup can interact with phosphate of DNA. The structural environment of sulfonium ion influences the DNA bonding effect. The designed cyclic sulfonium ion was buried in the middle of structure, and thus was hindered interaction with DNA. This type of molecule is worthy of further modification to increase DNA capacity and to reduce cell cytotoxicity.