Influence of reduction-sensitive diselenide bonds and disulfide bonds on oligoethylenimine conjugates for gene delivery

Bioreducible polymers have appeared as ideal gene delivery vectors due to the high stability in extracellular fluids and rapid DNA unpacking in an intracellular reducing environment, as well as decreased cytotoxicity. Disulfide bonds have long been regarded as the only golden standard for this design. Recently, diselenide bonds have emerged as a new reduction-sensitive linkage. However, its reduction sensitivity has not been systematically reported. The primary aim of this study is to compare its reduction sensitivity with the golden standard disulfide bonds. Bioreduction-triggered polymer degradation revealed that diselenide bonds are more stable than disulfide bonds with a lower redox potential (i.e. 10 μM GSH). The changes in DNA binding ability, particle size, zeta potential, and morphology all demonstrated that diselenide bonds have similar reduction sensitivity as disulfide bonds, but it could be only cleaved at a tumor-relevant glutathione concentration (i.e. 10 mM GSH). Förster resonance energy transfer (FRET) spectra suggested that diselenide bond conjugated OEI800 (OEI-SeSe_x) complexes could not only maintain high stability under 10 μM GSH conditions, but could also timely release DNA under 10 mM GSH conditions. Cell viability assay results showed that OEI-SeSe_x has a similar cell viability profile as disulfide bond conjugated OEI800 (OEI-SS_x), which is much less toxic than PEI25k. Biological efficacy assessment indicated comparable or even outweigh transfection efficiency of OEI-SeSe_x with OEI-SS_x and PEI25k. These results suggested that the unique properties of diselenide bonds have enabled a versatile design of multifunctional bioreducible polymers for in vivo gene delivery.