Graduate Thesis Or Dissertation
 

Nanotoxicology to Nanotherapeutics : Prioritizing Hazard and Anticancer Efficacy of Nanomaterials using the Embryonic Zebrafish Model

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  • The numerous different types of nanomaterials and paucity of reliable in vivo information on toxicity has resulted in enduring uncertainties associated with health and safety risks, thereby slowing progress in nanotherapeutic assessment and development. This dissertation explores how the embryonic zebrafish model can be applied to prioritize commonly used nanomaterial (multi-walled carbon nanotubes-MWNTs and metal oxide nanoparticles-MO NPs) hazard and anticancer efficacy bridging the gap between high throughput in vitro assays and low throughput, mammalian assays to advance glioblastoma drug development and safety. First, the zebrafish model was utilized to evaluate comprehensively characterized MWNTs systematically modified to introduce oxygen functional groups on the surface. Advanced multivariate statistical methods identified MWNT physicochemical properties that best estimated the probability of observing an adverse outcome. The properties considered included surface charge, percent surface oxygen, dispersed aggregate size and morphology and electrochemical activity. Total surface oxygen and the highly related parameter surface charge, quantified as the point of zero charge (PZC), were determined as the best predictor of embryonic zebrafish mortality at 24 hpf. Second, the embryonic zebrafish model was used to evaluate the toxicity of seven widely used semiconductor MO NPs made from zinc oxide (ZnO), titanium dioxide, cerium dioxide and tin dioxide prepared in pure water and in synthetic salt water to identify the physicochemical properties associated with toxicity. Significant agglomeration, elemental composition and dissolution potential were identified as major drivers of toxicity. Only ZnO caused significant adverse effects and only when prepared in pure water (point estimate median lethal concentration = 3.5-9.1 mg/L) despite charge and size similarities with one cerium dioxide and titanium dioxide NP. This toxicity was life stage dependent. The 24 h toxicity increased greatly (~22.7 fold) when zebrafish exposures started at the larval life stage compared to the 24 h toxicity following embryonic exposure. Measurement of ZnO dissolution revealed high levels of zinc ion (40-89% of total sample) were generated. Exposure to zinc ion equivalents revealed dissolved Zn²⁺ may be a major contributor to ZnO toxicity. Third, an orthotopic zebrafish xenograft screening assay was created to discover and prioritize the testing of potential nanotherapeutics targeting glioblastoma proliferation, migration and invasion. Evaluation of the potential anti-cancer efficacy of zinc oxide nanoparticles (ZnO NP) and the model phosphatidylinositide 3-kinase (PI 3-kinase) inhibitor LY294002, revealed divergent responses in the assay. ZnO NPs significantly enhanced glioblastoma proliferation by up to 23% and migration/invasion by 22 to 49% at the periphery of the cell mass (161+ μm) compared to vehicle control. Exposures of 3.125-6.25 μM LY294002 significantly decreased glioblastoma proliferation by up to ~34% and 6.25 μM LY294002 significantly inhibited migration/invasion by 30 and 48% within the glioblastoma cell mass (0-80 μm and 81-160 μm respectively). Overall, this dissertation demonstrates how novel methodologies employing the zebrafish model can be used to quickly and efficiently identify nanomaterial hazard and advance applications in nanomedicine, thereby efficiently bridging toxicity and therapeutic efficacy assessments.
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