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.

Reactive oxygen and nitrogen species play a critical role in many degenerative diseases and in aging. Nanomaterials, especially modified fullerenes and cerium oxide nanoparticles, have been shown to effectively protect mammalian cells against damage caused by increased reactive oxygen or nitrogen species, likely through their direct reaction with superoxide radical, since each of these materials has been shown to act as effective superoxide dismutase mimetics in vitro. This critical review discusses the chemistry of these nanomaterials and the context in which their radical scavenging activities have been studied in biological model systems. Current studies are focused on determining the uptake, metabolism, distribution, toxicity and fate of these nanomaterials in cell and animal model systems. Ultimately if shown to be safe, these nanomaterials have the potential to be used to reduce the damaging effects of radicals in biological systems (101 references).

Cerium oxide nanoparticles (CNPs) have been demonstrated to protect biological tissues against radiation induced damage and scavenging of superoxide anions, prevent laser induced retinal damage, reduce spinal injury, possess pH dependent antioxidant properties, prevent cardiovascular myopathy, and as a tool for immunoassays and other inflammatory diseases.1a-j It is speculated that nanoceria is a regenerative radical scavenger with the ability to regenerate the active Ce 3+ oxidation state for radical scavenging which separates it from other nanomaterials based antioxidant systems such as hydroxylated and water-soluble C-60 and SWCNTs.1k, l Thus far there are no reports on controlling the regeneration of the Ce 3+ oxidation state which is the most important parameter in the application of CNPs as a reliable, regenerative radical scavenger. There is an imminent need to increase the residence time of CNPs in the body and to control the regeneration of the Ce 3+ oxidation state. PEG has been reported to increase the residence time of NPs and proteins inside cells and provide biocom-patibility.2 PEGylated counterparts of the Superoxide Dismutase (SOD) enzymes have shown improved performance over non-PEGylated enzymes. 2 Herein, we report our efforts to synthesize CNPs directly in PEG (600 MW) solution and determine the effect of increasing [PEG] (PEG vol % as 5, 10, 20, 40, 60, and 80) on the SOD mimetic properties exhibited by nanoceria. We also report how the active Ce 3+ oxidation state can be regenerated and demonstrate the role of PEG on the redox chemistry of CNPs catalyzed by H 2 O 2 . Several complexes of PEGs with lanthanides have been reported and characterized.3 To evaluate the effect of [PEG] on the complexation of cerium, UV-vis spectra of the precursor salt of cerium (cerium nitrate hexahydrate) in different solutions of PEG were obtained (SI-1). All PEG solutions show higher absorption relative to the water based solution of cerium nitrate, but the observed nonspecific trend could not be ascribed to a systematic decrease in the solvent polarity or dielectric constant. This observation indicates the complexation of cerium ions with PEG. In contrast to this Uekawa et al.4a, b reported a red shift upon addition of cerium nitrate in PEG and ascribed the red shift to the complexation of PEG with cerium ions. The CNPs were synthesized as described in the experimental details (SI-2). A high resolution transmission electron micrograph (Figure 1a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptdemonstrates that PEG is present as an amorphous layer on CNPs confirmed by an amorphous background around the crystalline CNPs. To confirm further, CNPs synthesized in PEG were dialyzed using a 3500 MWCO cellulose membrane and the FTIR spectrum was collected from the dried powder. Figure 1b confirms the presence of PEG on the nanoceria particles from FTIR of 20% PEG CNPs. Biocompatibility and SOD Mimetic Activity of CNPs in PEGCell viability analysis was performed for CNPs in PEG solution u...

Cerium oxide nanoparticles (CeNPs) have shown promise as catalytic antioxidants in cell culture and animal models as both superoxide dismutase and catalase mimetics. The reactivity of the cerium (Ce) atoms at the surface of its oxide particle is critical to such therapeutic properties, yet little is known about the potential for a protein or small molecule corona to form on these materials in vivo. Moreover Ce atoms in these active sites have the potential to interact with small molecule anions, peptides, or sugars when administered in culture or animal models. Several nanomaterials have been shown to alter or aggregate under these conditions, rendering them less useful for biomedical applications. In this work we have studied the change in catalytic properties of CeNPs when exposed to various biologically relevant conditions in vitro. We have found that CeNPs are resistant to broad changes in pH and also not altered by incubation in cell culture medium. However to our surprise phosphate anions significantly altered the characteristics of these nanomaterials and shifted the catalytic behavior due to the binding of phosphate anions to cerium. Given the abundance of phosphate in biological systems in an inorganic form, it is likely that the action of CeNPs as a catalyst may be strongly influenced by the local concentration of phosphate in the cells and/or tissues in which it has been introduced.

Cerium oxide nanoparticles have oxygen defects in their lattice structure that enables them to act as a regenerative free radical scavenger in a physiological environment. We performed a comprehensive in vivo analysis of the biological distribution and antioxidant capabilities of nanoceria administered to mice perorally (PO), intravenously (IV), or intraperitoneally (IP) by dosing animals weekly for 2 or 5 weeks with 0.5 mg kg(-1) nanoceria. Next, we examined if nanoceria administration would decrease ROS production in mice treated with carbon tetrachloride (CCl(4)). Our results showed that the most extensive and cumulative nano-deposition was via IV and IP administered while PO administration showed mice excreted greater than 95% of their nanoceria within 24 h. Organ deposition for IV and IP mice was greatest in the spleen followed by the liver, lungs, and kidneys. Elimination for all administration routes was through feces. Nanoceria administration showed no overt toxicity, however, WBC counts were elevated with IV and IP administration. Our in vivo studies show that nanoceria administration to mice with induced liver toxicity (by CCl(4)) showed similar findings to mice treated with N-acetyl cystine (NAC), a common therapeutic to reduce oxidative stress. Taken together, our studies show that nanoceria remains deposited in tissues and may decrease ROS, thereby suggesting that cerium oxide nanoparticles may be a useful antioxidant treatment for oxidative stress.

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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 nanoparticle (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 Ce3+/Ce4+ ratio, surface charge, size, and shape were also explored. High surface area and increased Ce3+/Ce4+ 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.

There has been significant progress in the biological synthesis of nanomaterials. However, the molecular mechanism of synthesis of such bio-nanomaterials remains largely unknown. Here, we report the extracellular synthesis of crystalline silver nanoparticles (AgNPs) by using Morganella sp., and show molecular evidence of silver resistance by elucidating the synthesis mechanism. The AgNPs were 20+/-5 nm in diameter and were highly stable at room temperature. The kinetics of AgNPs formation was investigated. Detectable particles were formed after an hour of reaction, and their production remained exponential up to 18 h, and saturated at 24 h. Morganella sp. was found to be highly resistant to silver cations and was able to grow in the presence of more than 0.5 mM AgNO(3). Three gene homologues viz. silE, silP and silS were identified in silver-resistant Morganella sp. The homologue of silE from Morganella sp. showed 99 % nucleotide sequence similarity with the previously reported gene, silE, which encodes a periplasmic silver-binding protein. The homologues of silP and silS were also highly similar to previously reported sequences. Similar activity was totally absent in closely related Escherichia coli; this suggests that a unique mechanism of extracellular AgNPs synthesis is associated with silver-resistant Morganella sp. The molecular mechanism of silver resistance and its gene products might have a key role to play in the overall synthesis process of AgNPs by Morganella sp. An understanding of such biochemical mechanisms at the molecular level might help in developing an ecologically friendly and cost-effective protocol for microbial AgNPs synthesis.