Improving the Synthesis of Degradable Cationic Nanogels for Nucleic Acid Delivery

ABSTRACT Cationic, core‐crosslinked, fully hydrophilic nanogels are well suited for nucleic acid delivery. Here, we report on an improved synthesis strategy to generate these biodegradable nanoparticles by elegant protecting group chemistry. Polycarbonate‐based nanocarriers degrade into non‐toxic components at physiological conditions that are removed by standard metabolic processes, thus increasing biocompatibility. However, polycarbonate backbones are susceptible to premature degradation at comparatively harsh synthesis conditions. It was previously necessary to carefully tune reaction parameters when working with the aliphatic polycarbonates and integrating the biogenic amine spermine as a crosslinker. Now, the secondary amines of the crosslinker are converted into hydrophobic Boc‐protected carbamates in a simple one‐pot reaction with high yield. This non‐charged and more hydrophobic linker molecule greatly reduces nanogel core hydrophilicity during synthesis and, thereby, avoids premature aliphatic polycarbonate backbone hydrolysis. The Boc protecting groups are then easily removed by slightly modifying the already established acidic aqueous purification process, affording high quantities of nanogel for loading with various interesting therapeutic polyanionic cargo.