Brush polymers for nucleic acid delivery and self assembly

• Online Access: http://hdl.handle.net/2047/D20248892

Difficult biopharmaceutical characteristics of oligonucleotides, such as poor enzymatic stability, rapid clearance by reticuloendothelial organs, unwanted stimulation of the immune system, and coagulopathies, limit their application as therapeutics. Many of these side effects are initiated via specific or non-specific interactions with proteins. In this thesis, we develop a non-cationic, polyethylene glycol (PEG) brush polymer/DNA conjugate that provides oligonucleotides with nanoscale steric selectivity: hybridization kinetics with complementary DNA remains nearly unaffected, but interactions with proteins are significantly retarded. The relative lengths of the brush side chain and the DNA strand are found to play a critical role in the degree of selectivity. We demonstrate that these unimolecular nanoparticles can enter cells and suppress gene expression without the need of a cationic polymer co-carrier. The PEG brushes also improve the in vivo bio-distribution of oligonucleotide and suppress side effects induced by protein-nucleic acid interactions. Compared to traditional polycationic DNA carriers, our strategy is a radically new approach to addressing several long-lasting challenges in oligonucleotide therapeutics.