Disulfide-Containing Brushed Polyethylenimine Derivative Synthesized by Click Chemistry for Nonviral Gene Delivery

Polyaspartamide-based disulfide-containing brushed polyethylenimine derivatives P(Asp-Az)(X)-SS-PEIs were synthesized via click chemistry and evaluated as nonviral gene delivery carrier. First, azide-functional poly(aspartic acid) derivatives with various azide-group densities and monoalkyne-terminated PEI with disulfide linkages were synthesized. Then, click reaction between the azide-functional poly(aspartic acid) derivative as main chain and the monoalkyne-terminated PEI as branched chain resulted in high-molecular-weight disulfide-containing brushed PEI derivative. The structure of obtained polymers was confirmed by H-1 NMR and FTIR It was shown that the disulfide-containing P(Asp-Az)(X)-SS-PEIs were able to bind plasmid DNA and condense DNA into small positive nanoparticles. The reduction-sensitivity of the P(Asp-Az)(X)-SS-PEI/DNA polyplexes was confirmed by gel retardation dynamic light scattering (DLS) in the presence of DTT. In vitro experiments revealed that the reducible P(Asp-Az)(X)-SS-PEI not only had much lower cytotoxicity, but also posed high transfection activity (both in the presence and absence of serum) as compared to the control nondegradable 25 kDa PEI. This study indicates that a reducibly degradable brushed polymer P(Asp-Az)(X)-SS-PEI composed of low-molecular-weight (LMW) PEI via a disulfide-containing linkage can be a promising gene delivery carrier.