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Paradoxical Roles of Nanoparticles in Cancer Therapeutics and Carcinogenesis Emily Despeaux Nanoparticles (NPs) are becoming increasingly common in consumer goods and are under investigation for a variety of industrial and biomedical applications. However, challenges in determining NP toxicity may prevent them from reaching their full potential. NPs cannot be treated as single class for toxicity evaluations. Even among particles made from the same material, particle-specific physical properties, including size, shape, surface charge, agglomeration state, and surface modifications have a strong effect on the toxicity. Even so, the obstacles to conclusively and reproducibly evaluating toxicity span all NP classes. NP literature is riddled with confusing and often contradictory reports regarding the biocompatibility of both engineered NPs, designed with biocompatibility as a priority, and NPs from occupational or environmental exposures. Incomplete NP characterization and sample inhomogeneity represent major confounding factors in disparate results from seemingly comparable study setups. Additionally, NPs can interfere with many conventional toxicity screening methods. Inappropriate doses, exposure routes, and toxicity endpoints further diminish the utility of many published studies. Given the burgeoning interest in NP-based therapeutic agents, consistent, reliable standards are needed to ensure the biocompatibility of new formulations. To those ends, the synthesis, characterization, and in vitro toxicity of a multi-functional NP therapeutic were investigated (Chapter 2). Specifically, superparamagnetic iron oxide nanoparticles (SPIONs) were coated with amphiphilic polymer and functionalized with antisense oligonucleotides targeting survivin, an anti-apoptotic protein that is highly overexpressed in cancer. SPION physical properties, including particle size and composition, were characterized at each step of synthesis. Our results showed that the SPION platform is biocompatible and capable of delivering functional antisense oligonucleotides to regulate survivin expression; however, significant refinement of the DNA-to-SPION coupling step is needed. Applied clinically, antisense survivin coupled SPIONs can reduce the required dose of, adverse effects from, and resistance to, current cancer chemotherapy regimens. In contrast to engineered NPs for biomedical applications, where real-world exposures would involve careful control of both exposure timeand dose, occupational NP exposures are variable, chronic, and difficult to model in laboratory settings. Chapter 3 focuses on identifying the mechanisms behind carbon nanotube (CNT)-induced malignant transformation of bronchial epithelial cells using a chronic in vitro exposure model. We specifically investigated the role of mesothelin (MSLN), a cell-surface protein that is highly overexpressed in many cancers, in the aggressive phenotype noted following chronic, low-dose CNT exposure. MSLN knockdown resulted in significantly decreased invasion, migration, colonies on soft agar, and tumor sphere formation. In vivo, MSLN knockdown cells formed smaller primary tumors and less metastases. The mechanism by which MSLN contributes to these more aggressive behaviors was investigated using Ingenuity Pathway Analysis, which predicted that increased MSLN could induce cyclin E, a cell cycle regulator known to be associated with human cancer. We found that MSLN knockdown cells had decreased cyclin E, and their proliferation rate was reverted to nearly that of untransformed cells. Cell cycle analysis results were consistent with the decreased rate of proliferation. Together, our results indicate a novel role of MSLN in the malignant transformation of bronchial epithelial cells following CNT exposure, suggesting its utility as a potential biomarker and drug target for CNT-induced malignancies. As demonstrated by the two studies presented here, NPs have the potential to function as both cancer therapeutics and carcinogens. Careful evaluation of toxicity, ensuring that appropriate doses, assays, exposure routes, and endpoints are used, is imperative. Elucidating the physical properties and functionalization that contribute to toxicity, and the mechanisms of that toxicity, will allow NP benefits to be fully exploited while minimizing the risk of widespread, detrimental public health effects