Optimization of Gold Nanoparticle Radiosensitizers for Cancer Therapy

Radiation therapy (RT) plays a pivotal role in cancer treatment, and radiosensitizing agents are widely used to improve the outcome of RT. There is keen interest in the development of new tumor-specific radiosensitizing strategies given that most of the commonly used radiosensitizers are inherently toxic. In recent years, the radosensitizing effects of gold nanoparticles (AuNPs) have been explored extensively. To further optimize radiosensitization by AuNPs, this thesis aims to (1) synthesize and characterize AuNPs with varied physicochemical properties including size, surface coating, and targeting moieties (2) investigate the cellular response (i.e., cell uptake and toxicity) to AuNPs (3) assess the in vitro radiosensitizing effects of AuNPs and identify the key parameters which determine the extent of radiosensitization by AuNPs and (4) evaluate and compare the individual and combined radiation enhancement effects of AuNPs and cisplatin both in vitro and in vivo. Overall, the current work demonstrated that the cell response to AuNPs is highly dependent on a number of factors including the physicochemical properties and concentration of the AuNPs, incubation time with AuNPs, as well as the cell line employed. Importantly, cellular localization of AuNPs and oxygen conditions were shown to be crucial in determining the radiosensitizing effect of AuNPs. The highest level of radiosensitization was observed when AuNPs are internalized, and in cells that are under oxia. In comparison to cisplatin at three doses of IC25, AuNPs administered intratumorally demonstrated an equivalent radiation enhancement effect without showing intrinsic toxicity or increasing the toxicity of IR, as such AuNPs can be considered as a true radiosensitizer. The combination of AuNPs and cisplatin resulted in an additive and significant radiation enhancement effect with fractionated RT, and is thus a promising strategy to be further considered. Future research is warranted on the design of formulations that resulted in improved tumor bioavailability of AuNPs and co-delivery of AuNPs and cisplatin to tumor sites, for the achievement of tumor-specific radiosensitzation, minimal toxicity, and therefore a greater therapeutic window for AuNP aided RT.Ph.D