Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Stephen Leonard

Committee Co-Chair

James Antonini

Committee Member

Vincent Castranova

Committee Member

Timothy Nurkiewicz

Committee Member

Yon Rojanasakul

Abstract

Nanoparticles, which are defined as a structure with at least one dimension between 1 and 100 nm, have the potential to be used in a variety of consumer products due to their improved functionality compared to similar particles of larger size. Their small size is associated with increased strength, improved catalytic properties, and increased reactivity; however, their size is also associated with increased toxicity in vitro and in vivo. Numerous toxicological studies have been conducted to determine the properties of nanomaterials that increase their toxicity in order to manufacture new nanomaterials with decreased toxicity. Data indicates that size, shape, chemical composition, and valence state of nanomaterials can dramatically alter their toxicity profile. Therefore, the purpose of this dissertation was to determine how altering the shape, size, and chemical composition of various metal oxide nanoparticles would affect their toxicity. Metal oxides are used in variety of consumer products, from spray-sun screens, to food coloring agents; thus, understanding the toxicity of metal oxides and determining which aspects affect their toxicity may provide safe alternatives nanomaterials for continued use in manufacturing. Tungstate nanoparticles toxicity was assessed in an in vitro model using RAW 264.7 cells. The size, shape, and chemical composition of these nanomaterials were altered and the effect on reactive oxygen species and general cytotoxicity was determined using a variety of techniques. Results demonstrate that shape was important in reactive oxygen species production as wires were able to induce significant reactive oxygen species compared to spheres. Shape, size, and chemical composition did not have much effect on the overall toxicity of these nanoparticles in RAW 264.7 cells over a 72 hour time course, implicating that the base material of the nanoparticles was not toxic in these cells. To further assess how chemical composition can affect toxicity, cerium oxide nanoparticles were chemically modified using a process known as doping, to alter their valence state. The size and shape of the cerium oxide nanoparticles remained constant. Overall, results indicated that cerium oxide was not toxic in both RLE-6TN and NR8383 pulmonary rat cells, however, chemically modifying the valence state of the nanomaterial did affect the antioxidant potential. To determine if this trend was measureable in vivo, rats were exposed to various cerium oxide nanoparticles via intratracheal instillation and damage, changes in pulmonary cell differentials, and phagocytic cell activity were assessed. Results implicate that chemically modifying the nanoparticles had an effect on the overall damage induced by the material but did not dramatically affect inflammatory potential or phagocytic cell activity. Overall the data from these studies imply that size, shape, chemical composition, and valence state of nanomaterials can be manipulated to alter their toxicity.

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