Engineering Nanomaterials to Overcome Barriers in Cancer Therapy

Thesis (Ph.D.)--University of Washington, 2016-12Cytotoxic chemotherapy is used for the frontline treatment of most types of cancer but is associated with significant toxicity due to the lack of cell specificity of these drugs. Newer treatment strategies, such as polymeric drug delivery vehicles that preferentially accumulate in tumors via the EPR effect and oncolytic adenoviruses that replicate conditionally in tumor cells, can reduce the adverse side effects associated with systemic anti-cancer treatments. However, there remain numerous barriers to the successful clinical translation of these therapeutics. Part I focuses on the diffusional barriers to drug delivery to solid tumors. In Chapter 1, we investigate tight junction-opening proteins as a means to enhance nanoparticle penetration into tumors. Part II describes the development of polymer nanostructures for anti-cancer drug delivery. Chapter 2 summarizes the major design parameters for drug delivery to tumors and introduces controlled living polymerization as a synthetic tool. Chapters 3 and 4 describe the synthesis of polymeric drug carriers with a novel sunflower-like architecture. Part III focuses on methods to improve the safety of adenoviruses for cancer gene therapy. Chapter 5 provides an overview of adenovirus pharmacology and current modification strategies, while Chapter 6 describes a new approach to developing materials that can shield adenoviruses against immune recognition. Finally, Chapter 7 summarizes the major findings of this work and concludes with recommendations for future directions