The ability of engineered cerium oxide nanoparticles to confer radioprotection was examined. Rat astrocytes were treated with cerium oxide nanoparticles to a final concentration of 10 nanomolar, irradiated with a single 10 Gy dose of ionizing radiation and cell death was evaluated by propidium iodine uptake at 24 and 48 hours after radiation insult. Treatment of rat astrocytes with nanoceria resulted in an approximate 3-fold decrease in radiation induced death. These results suggest that the nanoceria are conferring protection from radiation induced cell death. Further experiments with human cells were conducted. Human normal and tumor cells (MCF-7 and CRL8798) were treated with the same dosage of cerium oxide nanoparticles, irradiated and evaluated for cell survival. Treatment of normal cells (MCF-7) conferred nearly 99% protection from radiation-induced cell death while the same concentration of nanoceria showed almost no protection in tumor cells (CRL8798). TUNEL analysis results of similarly treated cells demonstrated that nanoceria reduced radiation-induced cell death by 3-fold in normal breast cells but not in MCF-7 tumor cell lines when cultured under the same conditions. We concluded that cerium oxide nanoparticles confer radioprotection in a normal human breast line (CRL 8798) but not in a human breast tumor line (MCF-7). It is hoped that the outcome of this study will guide future endeavors toward a better elucidation of the molecular pathways involved in the protection of cells with nanoceria against radiation-induced cell death, as well as the minimization of the bystander effect in radiation therapy.

Cerium oxide nanoparticles (CeO2 NPs)(nanoceria) have been shown to possess a substantial oxygen storage capacity via the interchangeable surface reduction and oxidation of cerium atoms, cycling between the Ce4+ and Ce3+ redox states. Reduction of Ce4+ to Ce3+ causes oxygen vacancies or defects on the surface of the crystalline lattice structure of the particles, generating a cage for redox reactions to occur. The study of the chemical and biological properties of CeO2 NPs has expanded recently, and the methods used to synthesize these materials are also quite diverse. This has led to a plethora of studies describing various preparations of CeO2 NPs for potential use in both industry and for biomedical research. Our own work has centered on studies that measure the ability of water-based CeO2 NPs materials to reduce reactive oxygen and nitrogen species in biological systems, and correlating changes in surface chemistry and charge to the catalytic nature of the particles. The application in experimental and biomedical research of CeO2 NPs began with the discovery that water-based cerium oxide nanoparticles could act as superoxide dismutase mimetics followed by their ability to reduce hydrogen dioxide similar to catalase. While their ROS scavenging ability was well established, their ability to interact with specific RNS species, specifically nitric oxide (·NO) or peroxynitrite (ONOO- ) was not known. The studies described in this dissertation focus on the study of RNS and cerium oxide nanoparticles. Our in vitro work revealed that CeO2 NPs that have higher levels of reduced cerium sites (3+) at the surface (which are effective SOD mimetics) are also capable of accelerating the iv decay of peroxynitrite in vitro. In contrast, CeO2 NPs that have fewer reduced cerium sites at the particle surface (which also exhibit better catalase mimetic activity) have ·NO scavenging capabilities as well as some reactivity with peroxynitrite. Our studies and many others have shown cerium oxide nanoparticles can reduce ROS and RNS in cell culture or animal models. The accumulation of ROS and RNS is a common feature of many diseases including Alzheimer’s disease (AD). Testing our CeO2 NPS in cortical neurons, we used addition of Aβ peptide as an AD model system. CeO2 NPs delayed Aβ-induced mitochondrial fragmentation and neuronal cell death. When mitochondrial ROS levels are increased, mitochondrial fission is activated by DRP1 S616 phosphorylation. Specifically, our studies showed the reduction of phosphorylated DRP1 S616 in the presence of CeO2 NPs. Results from our studies have begun to unravel the molecule mechanism behind the catalytic nature of how CeO2 NPs reduce ROS/RNS in biological systems and represents an important step forward to test the potential neuroprotective effects of CeO2 NPs in model systems of AD. A plethora of studies describing various preparations of CeO2 NPs for potential use in both industry and for biomedical research have been described in the past five years. It has become apparent that the outcomes of CeO2 NPs exposure can vary as much as the synthesis methods and cell types tested. In an effort to understand the disparity in reports describing the toxicity or protective effects of exposure to CeO2 NPs, we compared CeO2 NPs synthesized by three different methods; H2O2 (CNP1), NH4OH (CNP2) or hexamethylenetetramine (HMT-CNP1). Exposure to HMT-CNP1 led to reduced metabolic activity (MTT) at a 10-fold lower concentration than CNP1 or CNP2 and surprisingly, exposure to HMT-CNP1 led to substantial v decreases in the ATP levels. Mechanistic studies revealed that HMT-CNP1 and CNP2 exhibited robust ATPase (phosphatase) activity, whereas CNP1 lacked ATPase activity. HMT-CNP1 were taken up into HUVECs far more efficiently than the other preparations of CeO2 NPs. Taken together, these results suggest the combination of increased uptake and ATPase activity of HMT-CNP1 may underlie the mechanism of the toxicity of this preparation of CeO2 NPs, and may suggest ATPase activity should be considered when synthesizing CeO2 NPs for use in biomedical applications. Overall the studies have uncovered two new catalytic activities for water-based CeO2 NPs (·NO scavenging and accelerated decay of peroxynitrite), demonstrated their ability to reduce RNS in an AD cell culture model as well as identifying a catalytic activity (phosphatase) that may underlie the observed toxicity of CeO2 NPs reported in other studies.

Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and the inhibition of the pancreatic tumor growth without harming the normal tissues or host mice. Mechanistically, CONPs were not able to significantly impact RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, JNK activation, which is known to be a key driver of RT-induced apoptosis, was significantly upregulated by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activation was associated with marked increases in Caspase 3/7 activation, indicative of apoptosis. We have shown CONPs increase ROS production in cancer cells; ROS has been shown to drive the oxidation of thioredoxin (TRX) 1 which results in the activation of Apoptosis Signaling iv Kinase (ASK) 1. The dramatic increase in ASK1 activation following the co-treatment of pancreatic cancer cells with CONPs followed by RT in vitro suggests that increased the c-Jun terminal kinase (JNK) activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue, or the JNK activation was blocked by an inhibitor,. Additionally, angiogenesis in pancreatic tumors treated with CONPs and RT was significantly reduced compared to other treatment options. Taken together, these data demonstrate an important role and mechanisms for CONPs in specifically killing cancer cells and provide novel insight into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.

Malignant melanoma cancer is the sixth common cancer diagnosed in the United States. Surgery, chemotherapy and radiation are some of the successful techniques in killing tumor cells. However, in these techniques, it is not easy to distinguish tumor cells from the healthy once which inadvertently get exposed to chemical agent/radiation. Therefore it is required to develop an anticancer agent which selectively kills the cancer cells, while still protecting the normal tissues. In our preliminary work, we have shown that Dextran (1000Da) coated Cerium oxide nanoparticles (Dex-CNPs) selectively kills the cancer cells (50% killing at a concentration of 150μM) without inducing toxicity to the normal cells. However, the mechanism involved on how CNPs/Dex-CNPs attain the selectivity and efficiently kill the tumor cells is still unknown. In this study we have synthesized Dextran coated ceria nano particles (Dex- CNPs) with different surface oxidation state ratio (Ce4+/Ce3+). This will provide an in depth understanding of the key chemical and physical properties of the system that can improve its efficacy. The varied surface oxidation of the particles is achieved by exposing Dex-CNPs to light which initiates a color change from dark to pale yellow indicating the reduction of Ce4+ to Ce3+. Interestingly we have found that the DexCNPs exposed to light have reduced cytotoxicity towards squamous cell carcinoma cell line (CCL30) compared to the protected once. Characterization of the same revealed that Dex- CNPs exposed to light have decreased Ce4+ /Ce3+ surface oxidation ratio compared to the other. This provides more insight in useful synthesis of Dex-CNPs in terms of storage and handling. In summary, higher Ce4+ /Ce3+ surface oxidation ratio is more efficient in hindering tumor growth by effectively hindering the tumor-stoma interaction.

The application of Cerium oxide nanoparticles (CNPs) for therapeutic purposes requires a stable dispersion of nanoparticles in biological environment. The objective of this study is to tailor the properties of polyelectrolyte coated CNPs as a function of molecular weight to achieve a stable and catalytic active dispersion. This was achieved by coating CNPs with polyacrylic acid (PAA) which increased the dispersion stability of CNPs and enhanced the catalytic ability. The stability of PAA coating was analysed using the change in the Gibbs free energy computed by Langmuir adsorption model. The adsorption isotherms were determined using soft particle electrokinetics which overcomes the challenges presented by other techniques. The Gibbs free energy was highest for PAA coated CNPs by 250 kg/mole indicating the most stable coating. The free energy for PAA 100 kg/mole coated CNPs is 85% lower than the PAA250 coated CNPs. This significant difference is caused by the strong adsorption of PAA100 on CNPs. Catalytic activity of PAA-CNPs is accessed by the catalase enzymatic activity of nanoparticles. The catalase activity was higher for PAA coated CNPs as compared to bare CNPs which indicated preferential adsorption of hydrogen peroxide induced by coating. Apart from PAA coating the catalase activity is also affected by the structure of the coating layer.

Cerium is the most abundant of the rare earth metals, found on average at a level of 66 parts per million in the earth's crust. The unique redox properties of cerium and cerium oxide nanoparticles have led to its use in a wide variety of industrial and commercial uses such as oxygen sensors, fertilizers and as a catalyst to remove toxic gases in automobile exhaust. The use of cerium has also garnered interest in the nanotechnology field. Nanoceria has been generated in its oxide form as nanoparticles and nanorods. Recently, nanoceria has been shown to protect against oxidative stress in both animal and cell culture models. Although not fully understood, this observed protective effect of nanoceria is believed to be the result of recently identified SOD mimetic activity. Currently there is little understanding as to how nanoceria is capable of scavenging radicals or what properties makes nanoceria an effective SOD mimetic. Our data shows strong evidence that the oxidation state of nanoceria is directly related to its reported SOD mimetic activity. As such, future studies of nanoceria should be mindful of the oxidation state of nanoceria preparations as only nanoceria with a high concentration of cerium (III) have shown effective SOD mimetic activity. In addition to the characterization of nanoceria and its SOD mimetic activity, we have evidence that free cerium is capable of generating radicals and damaging DNA in vitro in the presence of hydrogen peroxide. These data strongly suggests that the rare earth inner-transition metal cerium is capable of generating hydroxyl radicals via a Fenton-like reaction. Based on these results the use of free cerium salts should be monitored to limit environmental exposure to cerium. Altogether our data would suggest that cerium by virtue of its unique redox chemistry is quite capable of accepting and donating electrons from its surroundings. In its free form cerium is able to redox cycle easily and can generate radicals. However, paradoxically nanoceria may not easily redox cycle due to the bound lattice structure of the particle. The unique nature of nanoceria and cerium leads to a unique circumstance where nanoceria is a radical scavenger while free cerium generates radicals. As such, further investigation is needed to insure that leeching or cerium from nanoceria does not abrogate any potential benefit nanoceria may provide.

The rise of antimicrobial resistance demands the development of more rapid screening methods for the detection of antimicrobial resistance in clinical samples to both give the patient the proper treatment and expedite the treatment of patients. Cerium oxide nanoparticles may serve a useful role in diagnostics due to their ability to exist in a mixed valence state and act as either oxidizing agents or reducing agents. Considering that cerium oxide nanoparticles have been shown to shift in absorbance upon oxidation, a useful method of antimicrobial resistance detection could be based on the oxidation of cerium oxide nanoparticles. Herein, an assay is described whereby cerium oxide nanoparticle oxidation is a function of glucose metabolism of bacterial samples in the presence of an antimicrobial agent. Cerium oxide nanoparticles were shown to have an absorbance in the range of 395nm upon oxidation by hydrogen peroxide whereas mixed valence cerium oxide nanoparticles lacked an absorbance around 395nm. In the presence the hydrogen peroxide-producing glucose oxidase and either increasing concentrations of glucose or bacterial medium supplemented with increasing concentrations of glucose, cerium oxide nanoparticles were shown to increase in absorbance at 395nm. This oxidation assay was capable of measuring differences in the absorbance of E. coli and S. aureus samples grown in the presence of inhibitory and non-inhibitory concentrations of ampicillin in as little as six hours. Therefore, this cerium oxide nanoparticle oxidation assay may be very useful for use in clinical laboratories for the detection of antimicrobial resistance due to the relatively low cost, no requirement for specialized equipment and, most importantly, the reduced incubation time of the assay to as little as six hours compared to current gold standard antimicrobial resistance detection methods that require 24 hours.; This assay may thus also help partially circumvent the issue of knowledge of antimicrobial resistance in infected patients before prescribing improper regimens.

Cerium and zirconium oxides are important materials in industrial catalysis. Particularly, the great advances attained in the past 30 years in controlling levels of gaseous pollutants released from internal combustion engines can be attributed to the development of catalysts employing these materials. Unfortunately, oxides of sulfur are known threats to the longevity of many catalytic systems by irreversibly interacting with catalytic materials over some time period. In this work, polycrystalline cerium-zirconium mixed-metal-oxide (MMO) solid solutions of various molar ratios were synthesized. High resolution x-ray photoelectron spectroscopy (XPS) was used to characterize the model system. The spectral data was examined for revelation of the surface species that form on these metal oxides after insitu exposures to sulfur dioxide at various temperatures. The model catalysts were exposed to sulfur dioxide using a custom modified in-situ reaction cell. A reliable sample platen heater was designed and built to allow the exposure of the model system at temperatures up to 673 K. The results of this study demonstrate the formation of sulfate and sulfite adsorbed sulfur species. Temperature and compositional dependencies were displayed, with higher temperatures and ceria molar ratios displaying a larger propensity for forming surface sulfur species. In addition to analysis of sulfur photoemission, the photoemission regions of oxygen, zirconium, and cerium were examined for the materials used in this study before and after the aforementioned treatments with sulfur dioxide. The presence of surface hydroxyl groups was observed and metal oxidation state changes were probed to further enhance the understanding of sulfur dioxide adsorption on the synthesized materials. Palladium loaded mixed-metal oxides were synthesized using a unique solid-state methodology to probe the effect of palladium addition on sulfur dioxide adsorption. Microscopic characterization of the wafers made using palladium-loaded MMO materials provide justification for using this material preparation method in surface science studies. The addition of palladium to this model system is shown to have a strong effect on the magnitude of adsorption for sulfur dioxide on some material/exposure condition combinations. Ceria/zirconia sulfite and sulfate species are identified on the palladium-loaded MMO materials with adsorption sites located on the exposed oxide sites.

<p>Thorium complexes primarily exist in the thermodynamically stable (IV) oxidation state with only a few low-valent thorium(III) and thorium(II) complexes having been isolated. As a result, redox chemistry with thorium at the metal center is synthetically challenging without carefully selected ligand systems. This redox-restricted nature of thorium(IV) makes redox-active ligands (RALs) an attractive option to facilitate multi-electron redox chemistry with thorium. In this work, first, a series of thorium(IV) complexes featuring the redox-active iminoquinone ligand and its derivatives, including the iminosemiquinone and amidophenolate species, were synthesized and characterized. Rare thorium oxygen multiple bonds were then accessed by exploiting the RALs on the thorium center and using dioxygen in dry air. Other oxidation chemistry was attempted with the thorium amidophenolate complexes as well. Second, armed with the knowledge of synthesizing multiple bonds with thorium(IV) complexes, similar chemistry was explored with cerium as it is in the same group as thorium. A series of cerium(III) and cerium(IV) complexes featuring the redox-active iminoquinone ligand and its derivatives were synthesized. Oxidation chemistry was explored with the cerium amidophenolate complexes and a rare cerium oxo was isolated. Finally, with interest in expanding and addressing a gap in the literature related to the synthesis, characterization, and utility of thorium alkyls, several tetrabenzylthorium complexes were synthesized, characterized, and some reactivity was explored. A highlight of this work involved the isolation of the first crystal structure of ligand and solvent free tetrabenzylthorium since its first synthesis in 1974. Full spectroscopic and structural characterization of the complexes was performed via ¹H NMR spectroscopy, X-ray crystallography, EPR spectroscopy, electronic absorption spectroscopy, and SQUID magnetometry, which all confirmed the identity and electronic structure of these complexes. </p>

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