Thiabicyclononane-Based Hyperbranched Polycations for Low-Dose Oligonucleotide Delivery

Hyperbranched bicyclo[3.3.1]nonane (BCN) polycations were synthesized by the reaction of the bivalent electrophile thiabicyclo[3.3.1]nonane dinitrate with a series of simple tris(pyridine) nucleophiles, including one alkyne-containing nucleophile to allow for postpolymerization functionalization. The hyperbranched polymers were found to be efficient binders of nucleic acid and exhibited higher efficiencies for oligo DNA and siRNA transfection than their linear counterparts, enabling knockdown at low siRNA concentrations to a superior extent than standard hyperbranched polyethylenimine and lipofectamine transfection agents. The use of an amide-containing linkage in the tris(pyridine) building block was found to be highly advantageous, but built-in fragmentability of the polycation structure, a unique potential feature of this new family of materials, did not give significantly better performance.