Janet M. Dowding

Nanoceria exhibit redox state-dependent catalase mimetic activity

In this study we have found that cerium oxide nanoparticles exhibit catalase mimetic activity. Surprisingly, the catalase mimetic activity correlates with a reduced level of cerium in the +3 state, in contrast to the relationship between surface charge and superoxide scavenging properties.

Cerium oxide nanoparticles: applications and prospects in nanomedicine.

Promising results have been obtained using cerium (Ce) oxide nanoparticles (CNPs) as antioxidants in biological systems. CNPs have unique regenerative properties owing to their low reduction potential and the coexistence of both Ce(3+)/Ce(4+) on their surfaces. Defects in the crystal lattice due to the presence of Ce(3+) play an important role in tuning the redox activity of CNPs. The surface Ce(3+):Ce(4+) ratio is influenced by the microenvironment. Therefore, the microenvironment and synthesis method adopted also plays an important role in determining the biological activity and toxicity of CNPs. The presence of a mixed valance state plays an important role in scavenging reactive oxygen and nitrogen species. CNPs are found to be effective against pathologies associated with chronic oxidative stress and inflammation. CNPs are well tolerated in both in vitro and in vivo biological models, which makes CNPs well suited for applications in nanobiology and regenerative medicine.

The induction of angiogenesis by cerium oxide nanoparticles through the modulation of oxygen in intracellular environments

Angiogenesis is the formation of new blood vessels from existing blood vessels and is critical for many physiological and pathophysiological processes. In this study we have shown the unique property of cerium oxide nanoparticles (CNPs) to induce angiogenesis, observed using both in vitro and in vivo model systems. In particular, CNPs trigger angiogenesis by modulating the intracellular oxygen environment and stabilizing hypoxia inducing factor 1α endogenously. Furthermore, correlations between angiogenesis induction and CNPs physicochemical properties including: surface Ce(3+)/Ce(4+) ratio, surface charge, size, and shape were also explored. High surface area and increased Ce(3+)/Ce(4+) ratio make CNPs more catalytically active towards regulating intracellular oxygen, which in turn led to more robust induction of angiogenesis. Atomistic simulation was also used, in partnership with in vitro and in vivo experimentation, to reveal that the surface reactivity of CNPs and facile oxygen transport promotes pro-angiogenesis.

Cellular interaction and toxicity depend on physicochemical properties and surface modification of redox-active nanomaterials.

The study of the chemical and biological properties of CeO2 nanoparticles (CNPs) has expanded recently due to its therapeutic potential, and the methods used to synthesize these materials are diverse. Moreover, conflicting reports exist regarding the toxicity of CNPs. To help resolve these discrepancies, we must first determine whether CNPs made by different methods are similar or different in their physicochemical and catalytic properties. In this paper, we have synthesized several forms of CNPs using identical precursors through a wet chemical process but using different oxidizer/reducer; H2O2 (CNP1), NH4OH (CNP2), or hexamethylenetetramine (HMT-CNP1). Physicochemical properties of these CNPs were extensively studied and found to be different depending on the preparation methods. Unlike CNP1 and CNP2, HMT-CNP1 was readily taken into endothelial cells and the aggregation can be visualized using light microscopy. Exposure to HMT-CNP1 also reduced cell viability at a 10-fold lower concentration than CNP1 or CNP2. Surprisingly, exposure to HMT-CNP1 led to substantial decreases in ATP levels. Mechanistic studies revealed that HMT-CNP1 exhibited substantial ATPase (phosphatase) activity. Though CNP2 also exhibits ATPase activity, CNP1 lacked ATPase activity. The difference in catalytic (ATPase) activity of different CNPs preparation may be due to differences in their morphology and oxygen extraction energy. These results suggest that the combination of increased uptake and ATPase activity of HMT-CNP1 may underlie the biomechanism of the toxicity of this preparation of CNPs and may suggest that ATPase activity should be considered when synthesizing CNPs for use in biomedical applications.

Multicolored redox active upconverter cerium oxide nanoparticle for bio-imaging and therapeutics

Cytocompatible, co-doped cerium oxide nanoparticles exhibited strong upconversion properties that were found to kill lung cancer cells by inducing apoptosis thereby demonstrating the potential to be used as clinical contrast agents for imaging and as therapeutic agents for treatment of cancer.

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death.

Evidence indicates that nitrosative stress and mitochondrial dysfunction participate in the pathogenesis of Alzheimer’s disease (AD). Amyloid beta (Aβ) and peroxynitrite induce mitochondrial fragmentation and neuronal cell death by abnormal activation of dynamin-related protein 1 (DRP1), a large GTPase that regulates mitochondrial fission. The exact mechanisms of mitochondrial fragmentation and DRP1 overactivation in AD remain unknown; however, DRP1 serine 616 (S616) phosphorylation is likely involved. Although it is clear that nitrosative stress caused by peroxynitrite has a role in AD, effective antioxidant therapies are lacking. Cerium oxide nanoparticles, or nanoceria, switch between their Ce3+ and Ce4+ states and are able to scavenge superoxide anions, hydrogen peroxide and peroxynitrite. Therefore, nanoceria might protect against neurodegeneration. Here we report that nanoceria are internalized by neurons and accumulate at the mitochondrial outer membrane and plasma membrane. Furthermore, nanoceria reduce levels of reactive nitrogen species and protein tyrosine nitration in neurons exposed to peroxynitrite. Importantly, nanoceria reduce endogenous peroxynitrite and Aβ-induced mitochondrial fragmentation, DRP1 S616 hyperphosphorylation and neuronal cell death.

Cerium Oxide Nanoparticles Accelerate the Decay of Peroxynitrite (ONOO

Cerium oxide nanoparticles (CeO2 NPs) 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. It has been well established in many studies that depending on their reactivity and surface chemistry, CeO2 NPs can effectively convert both reactive oxygen species (superoxide, O2•−, and hydrogen peroxide) into more inert species and scavenge reactive nitrogen species (RNS)(nitric oxide, •NO), both in vitro and in vivo. Since much of damage attributed to •NO and O2•− is actually the result of oxidation or nitration by peroxynitrite or its breakdown products and due to the multiple species that these nanoparticles target in vivo, it was logical to test their interaction with the highly reactive molecule peroxynitrite (ONOO−). Here, we report that CeO2 NPs significantly accelerated the decay of ONOO− by three independent methods. Additionally, our data suggest the ability of CeO2 NPs to interact with ONOO− is independent of the Ce3+/Ce4+ ratio on the surface of the CeO2 NPs. The accelerated decay was not observed when reactions were carried out in an inert gas (argon), suggesting strongly that the decay of peroxynitrite is being accelerated due to a reaction of CeNPs with the carbonate radical anion. These results suggest that one of the protective effects of CeO2 NPs during RNS is likely due to reduction in peroxynitrite or its reactive breakdown products.

Characterizing the phosphatase mimetic activity of cerium oxide nanoparticles and distinguishing its active site from that for catalase mimetic activity using anionic inhibitors

Cerium oxide nanoparticles (CeNPs) are potent reactive oxygen and nitrogen species scavengers and demonstrate beneficial antioxidant properties in both cell culture and animal studies. However, their environmental fate, particularly in animals, is still under investigation. Studies have shown that CeNPs at very high doses can be retained briefly in organs such as the liver and in the bone marrow. The interaction of these nanoparticles with their local environment plays a major role in their distribution and long-term stability. We have previously shown that CeNPs with a low 3+/4+ cerium oxidative state ratio exhibit both catalase and phosphatase mimetic activities. Here, we aimed at further characterizing the active site(s) involved in these catalytic activities using potentially inhibitory anions. Results indicated that tungstate and molybdate inhibited the phosphatase activity without altering the oxidative state of cerium atoms but were ineffective against catalase activity. This suggests that distinct chemistry and active sites are involved in these two catalytic activities. Additionally, it was observed that CeNPs in aqueous environments were more active, strongly suggesting that water plays an important role in the phosphatase activity. Given the abundance of phosphate and other metal anions in both tissues and the environment, studying the nature of catalytic activities of CeNPs and the surface chemistry involved will help us form a stronger understanding of their environmental fate and thus qualify their biomedical applications.