The Development and Evaluation of Next-Generation Metallic Nanomedicines for Oncology

Nanoparticles (NPs) are ultrasmall objects with profound applications in research, industry, and medicine. Next-generation nanomedicines, such as gold, hafnium, iron, and copper nanoparticles, are particularly interesting due to their excellent physical, chemical, and quantum properties that can be exploited for cancer diagnosis and therapy. However, despite their demonstrated preclinical effectiveness, the potential of these inorganic nanomedicines, both in oncology and the broader medical field, is hampered by mechanistic uncertainty and a lack of detailed regulatory guidance. Together, these factors have resulted in many failed clinical trials and unexpected and sometimes severe side effects for approved formulations. The therapeutic efficacy and toxicity of nanomedicines are controlled by an extremely complex interplay of nanoparticle physicochemical properties and individual patient biology, where many confounding factors exist. This makes designing and evaluating nanomedicines a challenging task. To progress metal-based nanomedicines to the clinic and for them to be considered safe, even in the life-or-death circumstances of cancer, a deep understanding of nano-bio interactions is necessary across different stakeholders. This includes physicians, academia, industry, and government. By understanding and utilizing these in vivo behaviors, powerful nanomedicines and novel treatments can be applied to oncology. This thesis begins with a summary of the fundamental concepts relating to nanotechnology and the origins, properties, and treatment of cancer. Chapter 2 expands this discussion for a comprehensive analysis of cancer nanomedicines and their structure-activity relationships (SARs) in the body, which are central to both treatment efficacy and safety. Fundamentally, SARs describe the interactions between NP properties and the biological systems that ultimately produce their effects. To assist in the communication of this information, identified SARs were integrated into a simple, adaptable, and guiding framework composed of a parameter space, a pathway model, and various evaluation metrics. By resolving the complexity of nanomedicine into three parts, representing the interactions of NPs with 1) whole organs, 2) individual cells, and 3) fundamental biochemical pathways, this framework provides a clear illustration of how to fine-tune nanomedicines via pathway analysis. This framework and SARs were then used to guide the design, application, and evalua