Discovery of Polymers for Nucleic Acid Delivery Using Combinatorial and Cheminformatics Methods

The delivery of nucleic acids, including plasmid DNA, to mammalian cells has diverse applications in disease therapies, regenerative medicine, synthetic biology and protein production. Molecular carriers of plasmid DNA have met with limited success compared to viral vectors and some other non-viral vehicles. Despite availability of sophisticated delivery vehicles and investigations into biological factors, a comprehensive approach to the discovery of effective DNA carriers has likely hampered success in this field. Here, we propose a holistic approach in which we integrate exploration of diverse chemical space using library syntheses, cheminformatics-driven molecular engineering, and the discovery and abolition of intracellular resistances, in order to develop a novel discovery paradigm for polymer-nucleic acid delivery. Libraries of polymers and their derivatives were generated using aminoglycoside antibiotics as monomers. Support Vector Regression (SVR)-based Quantitative Structure-Activity Relationship Models (QSAR) modeling approaches were employed in order to elucidate the role of physicochemical properties on transgene expression efficacy of polymers. Given their role in cellular processes, we investigated the role of proteins of the kinome and epigenome in determining the efficacy of polymer-mediated transgene expression. Effective polymers were employed for the ablation of tumors using plasmid delivery, transgene expression in stem cells, gene silencing, and adenoviral transduction of resistant tumors.