Rational Biomaterials Design and Synthesis for Gene Delivery

Polymeric vectors have shown enormous promise for gene delivery, as a safer alternative to viral vectors. However, the transfection efficiencies of polymeric vectors are comparatively lower. The polymeric vectors have largely been cationic because of their ability to complex with DNA. However, cationic polymers can suffer from cytotoxicity issues, and/or aggregation with serum proteins that can decrease the transfection efficiency. There is a need for the development of new biomaterials that serve as efficient gene delivery vectors with minimal cytotoxicity. We have developed pentablock copolymers with cationic and neutral blocks, and the ratio of the various blocks can be adjusted by controlled radical polymerization methods. The polymeric blocks can be selected to allow the vector to promote endosomal escape to improve transfection efficiencies. In addition, the rational design of gene delivery vectors also allows for polymer chemistry to be used to target specific cell types. For instance, small intracellular differences in pH between normal and cancer cells are being exploited in our work to design vectors that can selectively transfect cancer cells as opposed to normal cells. This provides a paradigm shift from regular targeting methods that rely on ligand attachment, and relies instead on the polymer chemistry instead to achieve targeting.