Engineering polymeric biomaterials to treat kidney diseases and leverage boronic acid chemistry for drug delivery

Thesis (Ph.D.)--University of Washington, 2022Polymer drug delivery vehicles are diverse and powerful tools to modulate biodistrubution, cellular uptake, and dosing of therapeutics. As our understanding of the biological barriers improves, the challenges facing the field of precision nanomedicine have become more nuanced requiring specific engineering design. On the other hand, the therapeutic landscape is rapidly evolving to compass a wide range of biologic drugs, in addition to traditional small molecules. As the definition of a therapeutic continues to expand, drug delivery vehicles must be versatile using simple techniques to achieve a broad range of functionality. This work highlights achievements both in improving the understanding of biological barriers, and engineering conjugation techniques to load a variety of therapeutic cargo. First, a brief overview of polymeric nanomaterial drug delivery systems, therapeutic drug cargo, biological barriers, and synthesis techniques are reviewed (Chapter 1). With these design criteria in mind, a panel of anionic polymers was synthesized and screened to optimize passive targeting to kidneys (Chapter 2). We further investigated these anionic polymers by synthesizing novel boronic ester-based polymer-drug conjugates of polyphenolic drugs to specifically treat fibrotic tubular epithelial cells (Chapter 3). While these unimer systems are effective for drug delivery to the tubular epithelial cells of the kidney, we developed a more generalized boronic ester drug delivery approach by encapsulating polyphenolic drugs into micellular nanoparticles and tuning drug release with neighboring tertiary amines (Chapter 4). Finally, we demonstrate the diverse utility of these boronic acid copolymers for enhanced intracellular delivery of peptides, proteins, and nucleic acids (Chapter 5). The work concludes with a summary of major findings and suggestions for future projects (Chapter 6)