Biodegradability in response to the local environment is one of the most effective strategies to achieve controlled gene delivery. Exploiting the differences in reduction potential between the extracellular and intracellular environment, disulfides are frequently incorporated into the backbone of polymeric gene carriers to ensure efficient intracellular release of the payload. However, although to a lesser extent, reduction of disulfides may also occur in the extracellular environment and should be prevented to avoid premature release. To optimize disulfide stability, we prepared bioreducible poly(amido amine)s (PAAs) with varying degrees of steric hindrance adjacent to the disulfide bonds (0, 2 or 4 methyl groups). Degradation of the PAA-based polyplexes consistently required higher reducing strengths as the steric hindrance near the disulfide bonds increased. Specifically, polyplexes from our 2-methyl cysteamine disulfide based PAA polymer (PAA2m) remained stable under extracellular glutathione concentrations (0.001-0.01 mM), while degrading within 1 h under intracellular reducing conditions (1-10 mM glutathione). In contrast, PAA0m polyplexes showed reduced transfection properties compared to PAA2m, likely due to premature degradation, while the severely hindered PAA4m polyplexes displayed significantly decreased cell viability and transfection efficiency as a result of its exceptional stability. These results demonstrate the feasibility of introducing steric hindrance near the disulfide moiety to tune polyplex stability against bioreduction, and show that PAA2m is a promising polymer for gene therapy applications.

Tunable degradability of disulfide-functional poly(amido amine)s as gene carriers

254th National Meeting (2017)

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