Synthesis and Evaluation of Cyclic Cationic Polymers for Nucleic Acid Delivery

The architecture of polycation gene carriers has been shown to affect both their transfection efficiency and cytotoxicity. This work reports the synthesis of cyclic polycations and their use for gene transfer to mammalian cells. Cyclic poly((2-dimethylamino) ethylmethacrylate) (pDMAEMA) homopolymers of various molecular weights were synthesized by “intrachain”click cyclization of α-alkyne-ω-azide heterodifunctional linear precursors prepared by atom transfer radical polymerization (ATRP). Polymers were characterized by size exclusion chromatography and FT-IR analyses to confirm efficient cyclization and products with low polydispersity. Cyclic polymers formed more compact particles with plasmid DNA compared to linear analogues. Cellular uptake, membrane disruption, and nucleic acid delivery efficiency were determined for all polymers. In general, cyclic polymers complexed and delivered nucleic acids with efficiencies similar to their linear counterparts. Notably, cyclic polymers were less cytotoxic than linear polymers due to reduced membrane disruption and are therefore promising alternative structures for biological applications.