Bioreducible polyplexes are promising vectors for delivery of nucleic acids due to low toxicity and favorable transfection activity. The often improved transfection is usually explained by enhanced intracellular reductive disassembly of the polyplexes. This study evaluated the effect of enhanced reductive disassembly on transfection activity of plasmid DNA and antisense oligonucleotide (AON) polyplexes based on a series of bioreducible poly(amido amine)s (PAA). We found that the presence of disulfide bonds in PAA had no effect on nucleic acid binding, hydrodynamic size and zeta potential of polyplexes. Increasing the disulfide content in PAA increased susceptibility to reduction-triggered DNA and AON release from the polyplexes. Increasing the disulfide content in PAA increased DNA transfection but had no effect on AON transfection. Plasma membrane protein thiols played a key role in the observed enhancement of DNA transfection. The presence of disulfide bonds in PAA had no significant effect on the rate of intracellular DNA clearance, suggesting that enhanced intracellular disassembly of the bioreducible polyplexes is not a major contributing factor to the improved transfection activity.
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