Biological, biomedical and pharmaceutical applications of cerium oxide

Biological, biomedical and pharmaceutical applications of cerium oxide

8

Alexander B. Shcherbakova, Nadezhda M. Zholobaka, Vladimir K. Ivanovb,c a Zabolotny Institute of Microbiology and Virology of the National Academy of Sciences, Kyiv, Ukraine, bKurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia, cNational Research Tomsk State University, Tomsk, Russia

8.1 Introduction It has become a conventional fact that cerium oxide nanoparticles (nanoceria) possess anomalous biological activity [1–4]. Nevertheless, an unambiguous explanation of the mechanisms of this activity is still absent. Many aspects related to both physical and chemical properties and the biological behavior of nanoceria remain unclear. To explain the specific biological action of nanoceria, most authors extrapolate existing data on its catalytic activity in industrially relevant processes (the cracking of heavy oils, conversion of exhaust gases, water splitting, and oxidation of organic substances) to biological phenomena, eventually calling nanoceria a biological catalyst. Such nanomaterials are attributed to a special class of compounds called “nanozymes” (nanoparticles capable of performing the function of enzymes) [5–7]. Such extrapolation has several major drawbacks. The first one is that “the mechanisms by which a ceramic catalyst, whose normal chemical action is usually associated with the high temperatures (>450°C), beneficially operate at physiological temperatures (37°C) are presently unclear” [8]. Another serious counterargument is the fact that nanoceria in biological systems typically acts as an antioxidant, while in technical processes, it predominantly catalyzes processes of oxidation [9]. In processes where the substrate is reduced, cerium oxide does not act as a reducing agent but catalyzes the oxidation of an external reductant to reduce substrate [10], (e.g., this is the case for the reduction of SO2 by carbon monoxide or NOx with ammonia). In order to eliminate these contradictions, researchers typically rely on the hypothesis of high oxygen nonstoichiometry of cerium oxide nanoparticles in biological environments. However, even partially reduced nonstoichiometric CeO2−x exhibits oxidant properties in technical processes due to the generation of ROS (reactive oxygen species, viz., superoxide radical) on its surface [11], oxygen vacancies of ceria were found to promote the decomposition of water molecules into active OH∙ radicals [10,12], whereas in living systems, nanoceria generally acts as a ROS neutralizer and a free radicals’ scavenger.

Cerium Oxide (CeO2): Synthesis, Properties and Applications. https://doi.org/10.1016/B978-0-12-815661-2.00008-6 Copyright © 2020 Elsevier Inc. All rights reserved.

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Cerium Oxide (CeO2): Synthesis, Properties and Applications

So, is nanoceria really a catalyst capable of acting under the soft biological conditions, or is its activity based on other factors? Could the biological effects of nanoceria be associated with cerium ions only (or primarily), wherein the main role of nanoparticles is drug delivery of Ce4+ ions via the least toxic pathway?

8.2 Physical properties of nanoceria: A knowledge gap Most authors consider the nonstoichiometry of cerium oxide nanoparticles (the presence of a large amount of trivalent Ce ions on the surface) to be the main reason for their ability to inactivate ROS. In turn, nonstoichiometry of ceria nanoparticles and, consequently, the content of trivalent cerium in the bulk or on the surface of nanoceria are believed to increase with the decreasing size of nanoparticles [13,14]. Several physical properties of cerium oxide nanoparticles are considered in the argument for this approach. The decrease in the size of ceria nanoparticles is accompanied by lattice expansion. Tsunekawa et al. [15,16] and other researchers [17,18] have suggested that the observed growth in the unit cell size is caused by the partial removal of oxygen atoms from the surface layer of particles with the formation of oxygen vacancies, which is accompanied by a decrease in the effective degree of Ce oxidation (the Ce4+ and Ce3+ ionic radii are 0.97 and 1.14 Å, respectively). However, size-dependent lattice expansion of nanoparticles is also observed for many ionic compounds; Diehm et al. have shown that the surface stress due to negative Madelung pressure is the main reason for lattice expansion, while the point defects of various charge states of cerium can be excluded as a general explanation [19]. Another mechanistic approach to the oxygen storage ability of ceria was proposed by Sun et al. [20], taking into account the Ce/O ratio on the surface of the crystalline ceria; this parameter characterizes the oxygen affinity of nanoceria and drastically increases with the decrease in particle size. Both bulk ceria and large nanoparticles (D > 14 nm) of CeO2 have a Ce/O ratio of 0.50. With decreasing nanoparticle size to D = 0.55 nm, the Ce/O ratio increases to 0.75; the major effect on oxygen affinity of ceria is observed when D is smaller than 4.34 nm. This lack of oxygen could lead to cerium reduction at the edges of the lattice [20]. However, all biological media are aqueous solutions, where the surface of ceria nanocrystals is hydrated [21], so the cerium ion has no vacant sites in its nearest environment. Furthermore, assumptions that the adsorption of water can lead to an increase in the Ce3+ content on the nanoceria surface are untenable [10]. Moreover, when Ce3+ ions were artificially created in a cerium oxide nanoparticle layer by ­Ar-ions’ irradiation in a vacuum, they were rapidly oxidized in water within a day [22]. Due to fast nanoparticle oxidation, under the same experimental conditions of Ar+ bombardment or X-ray irradiation, the reduction level of Ce4+–Ce3+ has been shown to be even lower for nanoceria than for microcrystalline CeO2 [23]. Many authors [24–28] consider the coloration/discoloration of ceria sols during the interaction with hydrogen peroxide to be the main visual evidence of nonstoichiometry of cerium oxide nanoparticles and their regenerability. However, the scheme “colorless ceria sol + H2O2 → brown ceria sol → colorless ceria sol” does not mean the process of oxidation—regeneration of cerous ions in the nonstoichiometric ceria

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nanoparticles, Ce3+ + H2O2 → Ce4+ → Ce3+, but associates with the formation and decomposition of dark-colored ceric peroxides: Ce4+ + H2O2 → Ce4+(OOH) → Ce4+ (see later in Section 8.4.1.2). To quantify the valence states of cerium ions on the surface of ceria particles, X-ray photoelectron spectroscopy (XPS) and X-ray absorption near-edge spectroscopy (XANES) are the most widely used techniques [2,29–32]. These methods have repeatedly demonstrated the presence of a large amount of trivalent cerium on the surface of nanoceria. Nevertheless, many researchers have convincingly shown that the high-vacuum XPS studies of ceria overestimated the Ce3+ concentration in nanoceria, due to the surface reduction of CeO2 in the XPS vacuum chamber upon the action of X-ray irradiation [32–36]. In turn, XANES spectroscopy data showed only a low Ce3+ content in nanoceria when Ce(III) compounds were used as precursors and no Ce3+ traces when Ce(IV) compounds were used as precursors [37]. The same data were obtained by chemical analysis [38]. In addition the effect of the partial reduction of Ce under the action of synchrotron radiation has been observed too [36]. The authors [36,37,39,40] have suggested that results obtained previously, showing a significant Ce3+ content in nanocrystalline cerium oxide, can be explained by synthesis errors that leave Ce(III) traces on the particle surface and by the photoreduction of Ce under the action of high-power synchrotron and electron beams. Moreover, ceria nanoparticles of any size do not contain Ce3+ ions under standard conditions [36,37,39] without an external reductant. Sokolov et al. asked the reasonable question: “It still remains unanswered which factor, if not significant oxygen nonstoichiometry, causes the high chemical and biological activity of nanocrystalline CeO2” [36]. By changing the precursors and synthetic circumstances (solvent, pH, the presence of oxidizers or stabilizers, oxygen partial pressure, etc.), ceria nanoparticles of different stoichiometry can be obtained, wherein any particles will be quickly and irreversibly oxidized under appropriate conditions of aerobic environment (e.g., in a biological medium at neutral pH values). The oxidation degree of thus obtained particles and their surface state will not depend on their size and synthetic prehistory. In turn, their solubility could be one plausible explanation for the different biological activity of ceria nanoparticles of different sizes. In ceria-containing aqueous colloids, the role of free cerium ions is usually neglected, since it is considered a priori that their concentration is vanishingly small. Cerium oxide and ceric hydroxide are typically referred to as insoluble compounds [41]. Nevertheless, it should be noted that the solubility of a substance is exponentially increased at the nanoscale. These phenomena occur due to both the large specific surface area of the dispersed phase and the high curvature of the nanoparticles’ interface. In biological (aqueous) media, ceria is readily hydrated to form a Ce(IV) hydroxide layer on the surface. The Ce(OH)4 solubility constant is Ksp = 2 × 10−42 [42]; in normal saline (0.9% w/v NaCl), the concentration of Ce+4 ions has been calculated as 2.2 × 10−10 M. According to the Ostwald-Freundlich equation, the enhanced ­solubility 2 γµ

α

of a nanoparticle could be expressed as follows [43]: CS = C∞ e RT ρ r or CS = C∞ e r , where CS is the solubility of a particle of a given radius, M; C∞ solubility of a ­particle of infinite radius (bulk material), M; γ interfacial tension between particle and ­solution,

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J/m2; μ molar mass of the material, g/mol; R gas constant, J/(mol*K); T absolute temperature, К; ρ density of the material, g/m3; r radius of the particle, m; and α capillary length, m. The interfacial tension between hydrated ceria particle and aqueous solution could be calculated based on experimental data [44,45]. According to this equation, while coarse-grained cerium oxide is nearly insoluble, the solubility of fine nanoceria is at the mM level. The calculated plot for CeO2 particles’ solubility is shown in Fig.  8.1. Experimental data on solubility are usually higher than those obtained from this equation; for example, the solubility of 5-nm CeO2 particles is 10−7.8 M at pH = 7.18 (see Fig. 8.1) [46]. Thus, in the nanoceria colloid at biomedically applied low concentrations, a considerable part of cerium is present in the dissolved form. The effect of pH on the solubility of Ce(IV) oxide/hydroxides is noticeable in a very acidic medium only (pH < 3); however, at pH < 6, the ceric species readily undergo reduction, and the solubility of nanoceria is enhanced due to Ce(III) ions formation (see Fig.  8.2 [46]), so nanoparticles having a large Ce3+ fraction should be more soluble. The presence of reductants (antioxidants) promotes the dissolution of nanoceria, which is accompanied by the reduction of Ce4+ too [47]. The dissolution process inevitably leads to the growth of the particles in the ceria colloid (Ostwald ripening), while in the biological systems, cerium ions are quickly absorbed and digested by the cells, hindering this recrystallization. Moreover, in biological systems, the process of dissolution–crystallization of bigger ceria nanoparticles can even result in the formation of smaller ones [48,49]. Similar processes (dissolution, uptake, and reprecipitation of nanoceria) can take place in plants [50]. Ceric ions could be transferred into the cell by transport proteins of the transferrin family (see later in Section 8.6).

Fig. 8.1  Solubility of bulk and nanosized cerium oxide.

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Fig. 8.2  Experimental data for CeO2 solubility in 0.01 M NaClO4, along with theoretical modeling. The green line corresponds to reductive dissolution [46]. Reprinted with permission from T. V. Plakhova, A.Y. Romanchuk, S.N. Yakunin, T. Dumas, S. Demir, S. Wang, … and A.V. Egorov. Solubility of nanocrystalline cerium dioxide: experimental data and thermodynamic modeling. J. Phys. Chem. C 120(39) (2016), 22615–22626. Copyright 2016 American Chemical Society.

8.3 Biological activity of cerium species: Points of view Cerium compounds have been widely used in medicine, long before nanoceria. This is primarily true for inorganic salts having good solubility (nitrate and chloride), while the list of cerium-containing drugs also includes barely soluble salts (cerous oxalate) and organic compounds (cerous sulfanilate) [51]. For example, cerium (III) oxalate has been used as an antiemetic drug (medicine for nausea treatment). It is interesting to note that attempts to replace it with the salts of other lanthanides have not been successful in a wide range of concentrations [52]. Recently, the biological activity of other cerium compounds has been demonstrated, including insoluble nanoparticles, (e.g., cerous fluoride [53]). Despite this the role and the behavior of cerium and lanthanides in biological processes are still a matter of debate. There exists an opinion that all the lanthanide compounds (including nanoceria) are toxic for living beings, and the favorable effect of their administration is just the result of hormesis [54,55]. Also in the case of plants, Agathokleous et al. argued that the positive effect of lanthanides is a particular case of hormesis [56]. Wong [57] considered the short-term hypoxia caused by cerium oxide nanoparticles in the cell and the mild oxidative stress that upregulates the endogenous adaptive stress responses in the cell, to be the reason for hormesis. Hormesis is the bimodal response of biological systems to an external unfavorable stressor (e.g., the toxic chemical compounds) in which low doses cause stimulation (mainly due to the activation of the defense mechanisms of organisms) and higher doses exert an inhibition (depressing effect) [58]; see Fig. 8.3. Indeed the influence of

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Fig. 8.3  Hormetic bimodal response.

lanthanide concentration on certain biological processes is bimodal. Favorable concentrations of cerium species are low enough: the optimal therapeutic dose of nanoceria is often at the level of micro- or even nanomoles, and higher concentrations have a pronounced toxic effect (see later in Section 8.5). Analogous relationships are also shown for cerium salts. For example, Shen et al. [59] studied the influence of Ce3+ on ROS content in hepatocytes and V79 cells using microfluorometry: cerium was found to reduce the concentration of ROS at low doses and to increase it at high doses. Liu et al. [60] studied the effect of lanthanide ions on the respiratory burst of peritoneal macrophages (O2∙– and OH∙ radicals were detected using the EPR-trap method). It was shown that Ce3+ at concentrations below 10−5 M inhibits and at higher concentrations increases the respiratory burst. It has been suggested that lanthanide ions can prevent the formation of ROS at low concentrations, while at high concentrations, the results are the opposite [61]. Numerous examples of the protective effect of cerium compounds (including CeO2 nanoparticles) against other unfavorable factors (or toxic substances) upon simultaneous administration or post factum contradict the definition of hormesis [58]. For example, toxic cadmium ions damage the DNA from the liver of loaches in a dose-­ dependent manner, forming low-molecular fragments. At low concentrations, cerium ions protect DNA from the destructive action of Cd ions (the DNA ladder did not appear). At higher concentrations, cerium ions amplify the destructive effect of cadmium ions, in a synergetic manner [62]. Cerium species in low concentrations display beneficial protective activity against ROS in all schemes of administration: both prophylactic (before toxic agent) and therapeutic (after toxic agent) ones. It should be noted that the effect of the action of vitamins and essential trace elements can also be judged as hormesis, since they formally have similar dose-­dependent effects [63]: “Vitamins and minerals are hormetic essential nutrients that are necessary to maintain human health. Small daily levels of these substances are both required and beneficial, while excessive dietary levels can lead to hypervitaminosis, tissue mineralization or electrolyte imbalance. All trace elements are toxic at high levels, and

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some (e.g., arsenic, nickel, and chromium) have been implicated in carcinogenesis.” Cerium is not considered as essential or biologically significant element, although it has been noted that cerium compounds can stimulate metabolism [64]. Some researchers suppose lanthanides to be potentially beneficial elements [65,66]. A number of authors have suggested that rare-earth elements (REE) are essential trace elements, but these properties have not been sufficiently investigated. Thus, Panichev et al. [67–69] consider the natural need for REEs as the main reason for geophagy in animals and humans. According to common opinion the biological activity of lanthanides (primarily lighter elements—cerium and lanthanum) is due to the similarity of Ln3+ and Ca2+ ionic radii, wherein a higher charge density of lanthanides provides them with an increased affinity for calcium sites. As a result, lanthanides are able to replace calcium in various biological processes. In some cases, lanthanide ions are also able to replace ions of other metals (e.g., Fe2+, Mg2+, Mn2+, and Zn2+) [70]. Ln3+ ions are able to [70,71]: ●

●

●

●

●

●

block calcium channel receptors; reduce the voltage of calcium channels; replace calcium in enzymes; replace calcium in Ca-binding proteins; competitively replace Fe2+, Mg2+, Mn2+, and Zn2+ in metalloproteins; inhibit Ca-mediated processes associated with immune functions.

In turn, biological response depends on the behavior of the resulting compounds: it is generally assumed that such substitution decreases, or even completely neutralizes, the specific properties of biologically active molecules, which results in the inhibition of biological functions and in toxic effects. Unexpectedly, ceria nanoparticles generally act as redox-active nanozymes. The physical and chemical parameters of the particles (oxygen nonstoichiometry, the presence of surface defects, etc.) are considered to be the main factors influencing the activity and toxicity of nanoceria. According to a generally accepted opinion, nanoceria protects cell from the oxidative stress caused by ROS, acting as oxidoreductases. Nanoceria reduces inflammatory response, (it regulates cytokine levels, kinases, and nuclear factor activity), including mediation of the phosphorylation processes, by performing functions of the phosphatase. The ability of nanoceria to catalyze these processes is shown in biological systems both in vitro and in vivo and in the case of direct interaction with the substrate, outside biological systems. Thus it is expedient to analyze the database on the biochemical properties of cerium ions and compare them with those for nanoceria. What are the principal differences, and do they exist at all?

8.4 Cerium in the catalytic processes The catalytic properties of cerium compounds were known for a very long time before the study of the properties of CeO2 nanoparticles. For example, cerium (IV) ions catalyze the oxidation of organic compounds in acidic media [72]. The BelousovZhabotinsky reaction (oxidation of citric acid and inorganic model of the biochemical

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Cerium Oxide (CeO2): Synthesis, Properties and Applications

Krebs cycle) is also well studied [73]; cerium can replace manganese in the oscillating reaction of Briggs-Rauscher [74], etc.

8.4.1 Cerium ions versus nanoceria as an oxidoreductases mimetic “Perhaps most intriguing is the question of the mechanism by which nanoceria appears to beneficially modulate excess reactive oxygen species (ROS). It is generally agreed that ceria must perform two functions: one, to act to oxidize superoxide (a so-called superoxide dismutase (SOD) mimetic), and secondly, to act as a hydrogen peroxide catalase to destroy peroxide. This mechanism or mechanisms needs to be elucidated” [8].

8.4.1.1 Oxidase-like activity Many industrial catalytic applications of cerium oxide involve oxidation of the substrate (HR to R on the scheme) with air-oxygen, that is, the ceria catalyst acts as an analogue of oxidase. In the aqueous solution, nanoceria is also primarily capable of performing the function of oxidase [75–82]; in the acidic medium the reduction of Ce4+ ions and dissolution of the nanoparticles (partial or complete) take place [83,84]: 2CeO2 + 2HR → Ce2O3 + 2R + H2O, Ce2O3 + 6H+ → 2Ce3+ + 3H2O after which Ce3+ ions are oxidized by dissolved oxygen and nanoceria is regenerated [7]: 4Ce3+ + O2 +  12OH− → 4CeO2 + 6H2O (Scheme 1). In the other words the transportation of oxygen and the oxidation of the substrate are associated with the individual cerium ions, not with entire CeO2 nanoparticles. Any other soluble/insoluble salts or complex cerium compounds could replace nanoceria in this reaction; for example, some metal-organic frameworks containing cerium (Ce-MOFs) can act as a highly effective oxidase mimetic [85,86]. Some phenomena involving nanoceria are incorrectly considered to be the manifestations of its oxidase-mimetic properties. Hayat et al. proposed the oxidase-like activity of nanoceria as a main mechanism of colorimetric assays for the detection of dopamine and catechol [78], but it was known long ago that ceric ion and catechol form black complex compound before oxidation [87]. Sharpe et al. claimed that such oxidase-based nanoceria colorimetric assay could be used as a general sensing

Scheme 1  Ionic mechanism of the nanoceria oxidase-like activity.

Biological, biomedical and pharmaceutical applications of cerium oxide 287

­platform for rapid detection of food antioxidants [88–90], but nonoxidant coloration can appear with many organic species (e.g., alcohols, hydroxylated carboxylic acids, and reducing or nonreducing carbohydrates [91]). Due to the high oxophilicity, ceric ions interact with the hydroxyl groups of organic molecules, resulting the dark-colored alkoxy cerium (IV) compounds. Thus ceric ammonium nitrate (CAN) has long been used for the colorimetric determination of alcohols (CAN test) in qualitative organic analysis [92–94]. CAN test gives pink to red color for aliphatic alcohols and brown to black color for phenols and phenolic compounds: [Ce(NO3)6]2− + ROH ⟶ [R–O– Ce(NO3)5]2− + HNO3 [95]. A similar color reaction takes place in the case of nanoceria, that is why many of ceria sols stabilized with polysaccharides or hydroxy acids are colored from yellow to dark brown; one can see that the effect occurs not due to the catalytic behavior of nanoparticles but due to the specific properties of ceric ions.

8.4.1.2 Catalase-like activity It is a well-known fact that nanoceria is able to decompose hydrogen peroxide [96]. In this case, nanoceria acts as an inorganic analogue of catalase (catalase mimetic). During the enzymatic processes involving catalase, the following redox reactions take place, including oxidation and reduction of iron in the active center of the enzyme [97]: H 2 O2 + Fe ( III )  E → H 2 O + O = Fe ( IV )  E (·+ ) H 2 O2 + O = Fe ( IV )  E (·+ ) → H 2 O + Fe ( III )  E + O2 A similar scheme is widely used for the description of nanoceria action: H 2 O2 + Ce ( III )  CeO2 → H 2 O + O = Ce ( IV )  CeO2 H 2 O2 + O = Ce ( IV )  CeO2 → H 2 O + Ce ( III )  CeO2 + O2 A number of researchers (e.g., Celardo et al. [98]) have proposed a regenerative mechanism in which H2O2 reacts with Ce+4 to produce Ce+3 while releasing the proton and oxygen. This mechanism is hardly valid, since hydrogen peroxide does not reduce tetravalent cerium at biologically relevant pH values—neither the free hydrated ceric ion nor the Ce+4 ion in the nanoceria crystal lattice, since this reaction proceeds at low pH (<4) only [99], while at pH ≤4, the catalase activity of nanoceria is inhibited [100]. The equilibrium concentration of cerium species in hydrogen peroxide solutions can be calculated from the following equation [101]: log

[CeO2 ] = 3pH + 1.961 + 1 log Ce 3+ 

2

[H 2 O2 ]

The calculated pH dependence of the trivalent cerium concentration over solid ceria in solutions having different content of hydrogen peroxide is shown in Fig. 8.4. One can see that at physiological pH values (near pH = 7.0), there are practically no Ce3+ ions (fewer than 10−19 M, wherein their concentration decreases with increasing ­hydrogen

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Fig. 8.4  The calculated pH-dependence of Ce3+ concentration in aqueos solutions with different content of hydrogen peroxide over solid ceria.

peroxide content). Similarly, Ce3+/Ce4+ ion pairs cannot catalytically decompose hydrogen peroxide in a cyclic redox process (unlike the Fe2+/Fe3+ pair [102]). Wang et al. [103] showed that all lanthanides inhibit the oxidation of liposomes by hydrogen peroxide, but “although the most efficient one is Ce3+, the inhibition cannot be explained on the basis of the redox chemistry of cerium.” Cafun et al. [39] monitored the oxidation state of cerium in CeO2 during ­catalase-like activity. The presence of Ce3+ ions was not detected, even in very small CeO2 nanoparticles, but a change in the CeO interatomic distance was observed. To explain the mechanism of hydrogen peroxide decomposition by CeO2, the authors supposed the ceria particle to be an “electronic sponge,” while this model does not explain the similar catalytic activity of cerium ions. Compounds of tetravalent cerium, in neutral and alkaline media, are able to bind with and to inactivate H2O2 without changing the oxidation state of cerium; this process takes place due to the formation of a peroxide (hydroperoxide or perhydroxide, probably η2 type) complex of tetravalent cerium, which decomposes to form oxygen and water [2,7]: CeO2 + 2H 2 O ↔ Ce ( OH )4 Ce ( OH )4 + H 2 O2 ↔ Ce ( OOH )( OH )3 + H 2 O Ce ( OOH )( OH )3 → Ce ( OH )4 + 1 O2 2

∑ : H 2 O2 → H 2 O + 1 2 O2

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Fig. 8.5  The absorption spectra of H2O2 (1), aqueous nano-ceria sol synthesized from (NH4)2Ce(NO3)6 according to Ref. [104] before (2) and after (2a) introduction of H2O2, aqueous (NH4)2Ce(NO3)6 solution before (3) and after (3a) injection of H2O2. On the sidebar—the appearance of corresponding systems (unpublished data).

The phenomenon of dark-colored cerium peroxide formation is essentially the same for both nanoceria and ceric ions (see Fig. 8.5). It is known long ago that cerium hydroxide in the aqueous solution reacts quantitatively with hydrogen peroxide to form a precipitate of ceric hydroperoxide [105]. Cerium compounds as a capturing agent for hydrogen peroxide trapping were used in histochemistry for a long time [106]. The ability of Ce4+ ions of selective and firm binding with Н2О2 was clearly demonstrated using an example of a cerium–calcein complex: hydrogen peroxide replaces the molecule of this luminescent dye from both the coordination sphere of cerium ion and the surface of ceria nanoparticles in aqueous solutions [107]; hydrogen peroxide can displace oleate capping ligands in nonaqueous ceria sols too [108]. For all REEs, a high affinity to oxygen and ROS (oxophylicity or oxyphilicity [109,110]) is typical, according to the hard and soft acids and bases concept too. Among the REEs (hard Lewis acids), Ce4+ has the greatest oxyphilicity, due to the highest charge density. Cerium complexes (e.g., Ce(IV)-EDTA) also readily decompose hydrogen peroxide, the pseudo-first-order reaction rate increasing with the increase in pH [111]. Cerous species can scavenge hydrogen peroxide too; in the neutral and alkaline media, they are easily oxidized by H2O2 consistently forming ceric compounds, intermedial ceric peroxides, and ceric compounds again. There is some evidence that an unstable cerous peroxide is formed as an intermediate in the reaction between cerium(III) hydroxide and H2O2 [112] However, it should be noted that the oxidation of Ce3+ by H2O2 can lead to hydroxyl radicals’ formation according to the Fenton

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Cerium Oxide (CeO2): Synthesis, Properties and Applications

pathway [107,113,114], and so, for the inactivation of peroxides in biological systems at pH >7, tetravalent cerium species are preferable.

8.4.1.3 Peroxidase-like activity Nanoparticles of cerium oxide are capable of performing the functions of a peroxidase enzyme [76]. Popov et al. [7] demonstrated that catalase-like and peroxidase-like activities of nanoceria are two sides of the same coin, being dependent on the pH value: in neutral and alkaline solutions, nanoceria decomposes hydrogen peroxide by a catalase-like mechanism, while a peroxidase-mimic mechanism prevails in an acidic environment. Similarly, for free ions of tetravalent cerium, oxidation reactions of organic compounds (including the Belousov-Zhabotinsky reaction) proceed in an acidic medium. For example, in hydrochloric acid solutions, Се4+ ions catalytically accelerate the oxidation of the Ponso S dye with hydrogen peroxide, that is, they demonstrate peroxidase-like properties [115]. Се4+ complexes with cyclodextrin dimer and the EDTA derivative significantly accelerate the oxidation of luminol by hydrogen peroxide [116,117]. The activity of the composite containing a cerium coordination polymer and platinum nanoparticles exceeds that of native peroxidase in the oxidation of TMB (3,3′,5,5′-tetramethylbenzidine) [118]. Nanoparticles of cerium coordination compound ATP-Ce-TRIS have been shown to be a good analogue of peroxidase in the analytical reactions of hydrogen peroxide determination [119].

8.4.1.4 SOD-like activity Nanoceria destroys the superoxide radical catalytically [120]. SOD-like activity is one of the most important properties in the biologically relevant behavior of ceria nanoparticles [121]. The mechanism of superoxide radical inactivation by cerium ions had been described long before detailed studies of nanoceria. It is essentially the same for both nanoceria and cerium ions: Ce3+ reduces O2∙− to H2O2 and is oxidized to Ce4+; in turn, Ce4+ oxidizes O2∙− to O2 and is reduced to Ce3+ [122,123]. It has been shown [123] that Ce3+ and Ce4+ diluted aqueous solutions can inactivate large amounts of superoxide radical formed upon irradiation of the flavin: “as a result, a small amount of cerium ion can clear a large amount of O2∙−.” Kostova et al. [124,125] demonstrated that Ce(III) complexes of coumarin derivatives are good SOD mimetics; unlike with similar Nd(III) complexes, the effect is observed even at low concentrations. Ce(IV) complexes with water-soluble polysaccharides of algae [126] or ceria/polyoxometalates [127] have SOD-like activity too: “Herein, we rationally designed an artificial nanozyme, ceria/polyoxometalates hybrid (nanoceria@POMs) with both proteolytic and SOD activities that can degrade ­amyloid-β peptides (Aβ).” Adrenaline (epinephrine) autooxidation in an alkaline media occurs via the superoxide anion-radical pathway, nano-ceria inhibits this process due to its SOD-like activity in the dose-dependent manner [128]; the inhibition rate of the process depends on the particle size and aggregative stability of sols, oxidation strongly increases when the threshold of coagulation has been achieved [129]. Ionic lanthanides (La, Ce, Nd) can dose-dependent inhibit the superoxide formation in this process too [130,131],

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cerium salt has the highest SOD-mimetic activity (78.4% at 10−4 M) [130]. According to Batinić-Haberle et al., the redox-potential of "ideal" dismutation catalyst (including SOD) is located between reduction and oxidation of superoxide-anion, specifically, in the range of 0.2–0.4 V [132,133]. Popov et al. have shown [7] that any cerium system fulfills this requirement wherein the balance of concentrations [Ce3+] ≈ [Се(ОН)4] takes place. However, in this case the nonredox mechanism obviously takes place, because other lanthanides (La, Nd) demonstrate SOD-mimetic activities too.

8.4.1.5 Hydroxyl radical and other ROS scavenging Nanoceria is capable of inactivating hydroxyl radical, both in biological systems [24] and in vitro, directly in the Fenton reaction (Fe2+/Fe3+ with H2O2) [134]. Martin et al. [135] showed that under the conditions of the Fenton reaction, many REEs (Ce, La, Nd, Sm, Gd, and Dy) exhibit antioxidant activity to some extent; the radical scavenging abilities of lanthanides increase upon complexation with 5-aminoorotic acid or coumarin-3-carboxylate. Previously, Cheng et al. [136] also showed, using EPR, that lanthanide ions have the ability to inactivate free radicals in a Fe2+/Fe3+ system with tert-butyl hydroperoxide. All lanthanides inhibited lipid peroxidation by H2O2, but when the oxidation promoter was tert-butyl hydroperoxide, light lanthanides demonstrated antioxidant properties, while heavy lanthanides exhibited prooxidant properties [103]. Lanthanides (LaCl3, CeCl3) are able to scavenge the hydroxyl radical produced by chrysotile [137]. Yu et al. [138] investigated lanthanide complexes of pyruvic acid semicarbazone (PASH), Ln(PAS)3∙nH2O (where Ln = La-Nd, Sm-Dy, Er, Yb, n = 1–3) in the reactions of inactivation of OH∙ and O2∙− radicals. It was shown that all lanthanide complexes can participate in these processes, but the cerium complex has the highest activity, which is probably due to the ability of the cerium ion to change the degree of oxidation [138]. Additional examples are known where cerium compounds inactivate other free radicals and ROS. Thus Ce3+/Ce4+ redox pair protects Nafion polymeric membranes from destruction by hydroxyl radicals: Gubler et al. [139] studied the mechanism of ROS formation (including the Fenton reaction) in perfluoroalkyl sulfonic fuel cells and the process of ROS deactivation by cerium ions. Xuewu et al. [140], with an ESR method using the DMPO trap, showed that Ce(III) ions inactivate hydroxyl radical formed upon UV irradiation of TiO2 nanoparticles. The cerium-curcumin complex demonstrated pronounced antioxidant properties [141]. Ce(IV) complexes with water-­ insoluble bioflavonoids in water-DMSO systems at biological pH values also exhibited radical scavenging activity [142]. The biological action of the pesticide paraquat (1,1′-dimethyl-4,4′-bipyridinium) is associated with oxidative stress: “Paraquat a well-known O2∙− producing redox cycler” [143]. Nanoceria is able to reduce the toxicity of paraquat to Drosophila fruit flies [144] and human fibroblasts [145], and cerium chloride can decrease its toxicity to pea plants [146]. Cerium (III) complex with aminoorotic acid reduces the level of free radicals in the blood plasma of Wistar rats [125]. Cerium oxide nanoparticles are known to scavenge reactive nitrogen species, including nitric oxide radical (∙NO) [147], peroxynitrite (ONOO−) [148], and stable nitroxyl radicals [149]. At the same time, it was found that due to the high oxophilicity,

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ionic cerium (cerous chloride) can selectively and efficiently accelerate the deoxygenation of amine N-oxides [150]. It is interesting to compare two reports describing the advantages of both nanoceria and water-soluble ionic cerium species over organic antioxidants in terms of catalytic activity and oxyphilicity, respectively: “Traditional antioxidants (ascorbic acid, tocopherol, methionine etc.) are capable of partaking in only one redox cycle after which they inactivate. Obviously, nanoceria in the given case has an advantage over the existing antioxidants, and in a series of cases it even exceeds them in its activity” [151,152]. “The involvement of lanthanide in ROS removal is quite different from the inhibition of ROS by organic compounds like tocopherol, ascorbate, etc. Most of the organic antioxidants scavenge free radicals by single electron exchange with radicals and thus transform themselves into radicals hence acting as “prooxidants.” Ln3+ easily interacts with either free radicals or peroxides, but is not transformed as radicals” [103,110,153]. It should be noted that most organic antioxidants are actually reducing agents, since they are hydrogen donors; conversely, oxyphilic elements perform the function of antioxidants since they act as a direct oxygen acceptor. “The lanthanide inhibiting ROS strongly involves their oxyphilicity; because of the availability of oxygen binding sites on these free radicals, they are excellent targets for Ln(III) coordination. This causes lanthanide to play the role of ROS scavenger, therefore presenting good potential for lanthanides as future drugs” [110]. Considering the density of charge, the oxyphilicity of Ce4+ ions should be the highest among other lanthanides.

8.4.2 Cerium ions versus nanoceria as a phosphatase mimetic Nanoceria is able to perform the functions of the phosphatase enzyme [154]. It is well known that free lanthanide ions are also good catalysts in the hydrolysis of phosphoether bonds [155]. Brown et al. noted that REEs possess “strong affinity for both oxygen and phosphate” [156]; as in the case of oxidoreductase-like activity, the phosphatase-like activity of cerium ions was demonstrated long before detailed nanoceria studies [102,157]. Moreover, catalytic hydrolysis of orthophosphoric monoesters by lanthanum and cerium hydroxides, discovered by Bamann et al. in the 1950s [158], has been proposed as a model for alkaline phosphatase (ALP) action.

8.4.2.1 Cleavage of organophosphorus compounds All lanthanide ions are able to cleave phosphoric acid esters to some extent, but cerium ions have the highest activity; the activity of tetravalent cerium species is higher than that of trivalent ones [159]. Complex compounds of cerium (III) demonstrate high and reproducible phosphatase-like activity in the decomposition of bis(4-nitrophenyl) phosphate (BNPP) [160]. In the presence of this complex, the rate of catalytic degradation is approximately 109 times higher than the rate of spontaneous decomposition of BNPP under the same conditions. Moreover, phosphatase-like activity of some ceric compounds is higher than that of nanoceria; thus β-cyclodextrin complexes of Ce4+ have exhibited binding with BNPP more effectively than other ceric species, for example, [Ce4(OH)15]+, by two orders of magnitude [161]. Like CeO2, other

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cerium compounds are very promising in the processes of dephosphorylation. For instance, nanoceria can be effectively used in order to inactivate organophosphates, including pesticides (e.g., paraoxon, parathion, and malathion [162–164]) and warfare nerve agents (e.g., sarin and soman [165–167]). High activity in the inactivation of organophosphates is also inherent in metal–organic frameworks (coordination polymers) containing Ce(IV) [168]. A film-forming complex of cerium (IV) with chitosan and zinc preserves Chinese jujube fruits (Zizyphus jujuba Mill. cv. Dongzao) during storage and destroys residual organophosphorus pesticides: the degradation rates of chlorpyrifos and parathion have been shown to increase to 97.31% and 92.70% for complex treatment and 30.18% and 17.02% higher than for control fruits, respectively [169]. Like nanoceria, cerium salts are able to protect living beings from the toxic effects of organophosphorus pesticides—for example, cerium (III) chloride protects silkworm larvae from phoxim [170–173].

8.4.2.2 Cleavage of phosphorus-containing biologically significant molecules Like nanoceria, cerium compounds easily cleave biologically significant phosphorus-­ containing molecules, with tetravalent cerium having a higher activity. For example, in the case of ATP derivatives, at pH 7 and 30°C, 3′,5′-cyclic monophosphates of adenosine and guanosine are promptly hydrolyzed by Ce(NH4)2(NO3)6 (10−2 M), with half-lives of 7 and 16 s, respectively [175]. The rate of hydrolysis has been shown to be proportional to the concentration of a catalytically active compound [Ce2(IV) (OH)4]4+ [176]. Moreover, for the lanthanide ions (especially La(III) and Ce(IV)), the ability to cleave the phosphate diester bond in DNA has been reported [177]. When reviewing the progress of the development of artificial analogues of phosphatases, Komiyama et al. [178] mentioned the activity of lanthanides: “The remarkable discovery that lanthanide ions catalyze the hydrolysis of DNA and RNA spurred the trend.” Ce(IV) ion accelerates the rate of DNA hydrolysis faster than BNPP (by 1011 and 1010 times, respectively); the tetravalent cerium ion accelerates the hydrolysis of DNA better than all other metals, while the rate of hydrolysis of RNA is higher in the case of a trivalent cerium ion [157]. Ce(IV) complex with EDTA not only demonstrates phosphatase-like activity in DNA hydrolysis reactions but also is site selective [179–185]. Fig. 8.6 [174] shows the site of activity of the complex (terminal monophosphates). Such a Ce(IV)-EDTA complex artificial restriction DNA cutter (ARCUT) [186] can be used as a tool for gene manipulation. As a rule, binuclear complexes are more active [187]. In the case of a tetravalent cerium ion, the hydrolysis process is not oxidative, since it proceeds independently of the presence of oxygen or ROS in the system [157,188]. In the case of trivalent cerium ions, the hydrolysis process accelerates in an oxidizing environment [157]. Cerium (III) chloride efficiently hydrolyzes DNA at pH = 7 under aerobic conditions only. A titration study showed that in the reaction mixture, Ce(III) is oxidized to Ce(IV) and the resultant ceric ions are responsible for DNA hydrolysis [189]. Ln3+-dependent DNAzyme (RNA-cleaving DNA-based catalyst named Ce13d) was obtained through in vitro selection and was reported to be active with all the trivalent lanthanides down to 1.7 nM Ce3+ but has almost no activity with Ce4+ [190].

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Fig. 8.6  The terminal mono-phosphates are the target of the Ce(IV) complex with EDTA [174]. Reprinted with permission from W. Chen, T. Igawa, J. Sumaoka, and M. Komiyama, Monophosphate as eminent ligand to bind Ce(IV)/EDTA complex for site-selective DNA hydrolysis. Chem. Lett., 33(3) (2004) 300–301. Copyright 2004 Chemical Society of Japan.

Thus cerium ions can act as a restriction enzyme mimetic. Complexes of lanthanide ions with metallopeptides serve as full-fledged enzymes. Lim and Franklin [191,192] investigated the properties of such chimeric endonucleases and showed the possibility of creating Ln-containing enzymes and their prospects in biochemical and clinical applications. It should also be taken into account that according to the previously described mechanism of restriction, cerium compounds (especially tetravalent ones including nanoceria) are capable of damaging the DNA of living beings [193]. The noncleaving interaction of cerium ions with phosphate groups of nucleotides can affect the conformation of DNA; thus Ce3+ causes a reversible transition of branched DNA from the right wound B-form to the left-sided Z-shape of the helix [194]. The reverse transition is observed when cerium ions are removed by EDTA. At the same time, Ce3+ ions can relieve the destruction of Hg2+ on the DNA structure (the chain’s fragmentation and untwisting) in a fish intestine [195] or DNA damage caused by Cd2+ in a fish kidney [196]. Phosphatidylinositol is an important component of intracellular signaling pathways of eukaryotic cells, and phospholipase C is a key enzyme in the metabolism of phosphatidylinositol. Matsumura et al. showed that cerium ions (and ions of other lanthanides) are able to perform the functions of this enzyme and catalytically decompose phosphatidylinositol [197], thus participating in the transduction of intra- and intercellular signals, including processes in human erythrocytes [198]. Ce4+ complex with the chelating agent bis-tris propane has been shown to be a good lysosomal phospholipase mimetic [199]. Diseases associated with a lipid metabolism (e.g., Niemann-Pick disease) may cause an imbalance of pulmonary function, with frequent respiratory infections. In this case, a large amount of phosphatidylcholine accumulates in lamellar granules and lysosomes of lung cells. One possible approach to the treatment of this dysfunction involves the use of a catalyst for the preferential hydrolysis of phospholipid phosphate ester bonds in lysosomes. For this purpose, Kassai et al. investigated the hydrolysis of phosphatidylcholine in the presence of various metal salts. It was shown that among the 12 investigated salts (including salts of lanthanides), only the salts of tetravalent cerium provide the required level of hydrolysis [200]. During the inhalation of submicron CeO2 particles, cerium (IV) species have been shown to be

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also localized in the lysosomes of alveolar macrophages of Wistar rats [201] and may provide a treatment for this disease. Since many cell membranes consist mainly of phosphatidylcholine, the phospholipase-like activity of cerium compounds should be taken into account when studying the behavior of nanoceria and other cerium compounds on biological membranes. Cerium salts can also affect the intake of phosphorus-containing substances to the cell, in particular, the transportation of nutrients through the membrane. For example, one of the most common mechanisms of nutrient component transport in bacteria is the phosphoenolpyruvate-phosphotransferase system (PEP-PTS), which enables the selective transport of phosphorylated forms of d-glucose, d-galactose, d-fructose, some pentoses, glucosides and galactosides and other carbohydrates, and accumulation of high concentrations of saccharophosphates in the cytoplasm. Zholobak et al. [202] analyzed the different sensitivity of microorganisms to nanoceria and cerium compounds and showed that pathogenic microorganisms that use the PEP-PTS as the main mechanism of carbohydrate transport are significantly more sensitive to its toxic effect. For environmental microorganisms, which virtually do not use PEP-PTS for the transport of nutrients, cerium compounds were either nontoxic or provided a growth-stimulating effect. The participation of cerium ions in the phosphorylation reaction, as well as their competition with Mg2+ ions for the active center of the enzyme, could be the key reasons for the different toxicity effects of cerium for different groups of microorganisms. The data on nanoceria phosphatase-like activity are controversial: some authors proposed a Ce4+-mediated process of phosphate bond hydrolysis [203,204], but Kuchma et at. reported that phosphatase-like activity depends on the presence of Ce3+ sites on the surface of nanoparticles, and it is inhibited when Ce3+ is converted to Ce4+ [154]. The ability of lanthanide ions to eliminate the phosphate group from various substrates and the difference in the phosphatase-like activity of Ce3+ and Ce4+ ions can be explained from the chemical point of view, since LnPO4 are barely soluble compounds (pKa = −24). This allows for the safe clinical application of lanthanide compounds in the therapy of hyperphosphatemia [205]: lanthanum carbonate is manufactured under the trademarks Renalzin (for cats) and Fosrenol (for human) for chronic kidney disease. Phosphate of tetravalent cerium is far less soluble (even in comparison with the oxide and hydroxides of Ce4+); pKa = −90.1 [206]. Thus the formation of cerium (IV) phosphate on the surface of nanoceria decreases the availability and reactivity of cerium ions, so the biological activity of nanoceria falls. Similarly, the ability of nanoceria to interact with organophosphates (phosphatase-like activity) decreases. With an excess of inorganic phosphates, even in the acidic medium (e.g., in phosphoric acid), cerium (IV) ions are much less prone to reduction, which can be used for the determination of the oxidation states of cerium in nanoceria [38]. In turn, under these conditions, SOD-like activity significantly decreases. Nevertheless, due to the high oxyphilicity of cerium, its ability to form peroxocomplexes without changing the degree of oxidation is partially retained; for example, H2O2 can replace DNA on the nanoceria surface [207], which is fixed via phosphate groups. Catalase-like activity of cerium compounds is also partially retained, as confirmed by the data obtained by Singh et al. [208,209]. However, nanoceria protects DNA from oxidative damage in sulfate and TRIS buffers, but not in

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a phosphate-buffered saline [210]. Medium composition also affects the antibacterial activity of nanoceria [211]; for example, ceria nanoparticles demonstrate cytotoxicity to Escherichia coli in normal saline systems and no toxicity in phosphate-buffered saline systems [212]. These facts should also be taken into account when choosing buffer solutions to study the properties of nanoceria (exposure to cell cultures, catalytic activity studies, etc.).

8.4.3 Cerium ions as mimetics of other enzymes Besides the oxidoreductase-like and phosphatase-like activities, cerium compounds are able to perform functions of other enzymes, primarily endonucleases, although information on these activities is rather scarce. The restrictase-like activity of Ce(IV) ions has already been noted earlier. Complexes of Ce(III) are able to perform the function of proteases, (as in the example of lysozyme protein in chicken eggs) [213].

8.4.4 Cerium ions and the activity of natural enzymes 8.4.4.1 Common enzymes in vitro In addition to their own enzyme mimetic properties, cerium compounds can affect the activity of natural enzymes. This influence is primarily due to free cerium ions that are capable of replacing metal ions in the structure or in the active center of the enzyme. To a lesser extent, this is also true for nanoceria particles, although their effect either is nonspecific due to conformational phenomena only or arises from the dissolution of nanoceria and the presence of free cerium ions in the system. For example, urease adsorbed on nanoceria changes its secondary and tertiary structure, the catalytic activity of the enzyme decreases, and its thermal stability increases [214]. In turn, when ultrafine nanoceria is stabilized by citrate, cerium solubility increases, and this leads to some synergy between the activity of catalase or SOD and nanoceria [215]. As a rule, the influence of lanthanide ions on the activity of enzymes is unfavorable a priori. It is believed that when the lanthanide ion replaces the metal ion, which determines the structure of the enzyme, the enzymatic activity either does not change or changes insignificantly; in turn, when the Ln3+ ion replaces the metal ion in the active site, this leads to the inhibition of enzymatic activity [216,217]. Ln3+ ions also reduce enzymatic activity when they replace the calcium ion involved in the attachment of the enzyme to the substrate [70]. The ability of cerium ions to inhibit enzymatic activity can be used in therapy. Thus, xanthine oxidase is involved in various pathological processes, for example, tissue damage due to ischemia followed by reperfusion. Kaya et al. [218] showed that cerium vanadate can be used as a therapeutic drug, being an efficient alternative to xanthine oxidase inhibitor Allopurinol. Xuefeng et al. [219] investigated the effect of cerium (III) chloride on the activity of α-amylase from a pig’s pancreas. It was shown that low concentrations of Ce3+ (0.5–10 μM) increase the activity of α-amylase, while high concentrations (10 μM) lead to the opposite effect. α-Amylase contains five centers for Ca2+ ion binding, and

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with an increase in the concentration of cerium, it successively replaces calcium in the structure of the enzyme. Fricker [220] noted that if the calcium ion is replaced by a lanthanide ion, the activity of the enzyme decreases when calcium performs a catalytic function and increases or does not change when the role of calcium is only structural. This phenomenon underlies the technique of studying the functions of metal ions (­primarily Ca2+) in natural enzymes [216,217]. Interestingly, when the removal of the metal (calcium) ion from the active center of the enzyme causes the loss of enzymatic properties, the subsequent introduction of the lanthanide ion often leads to the restoration of enzymatic activity. A few decades ago, the activation of the enzyme by a cation having an atomic number >55 was considered impossible [221], while partial reactivation of previously demetallized enzymes by lanthanide ions had been experimentally registered. The degree of reactivation depends on the ionic radius; for example, for α-amylase, activity increases with a decrease in the radius of the lanthanide ions, while the activity of trypsinogen increases with an increase in the Ln3+ ionic radius, approaching the activity of the enzyme [222]. Moreover, in a number of cases, upon spontaneous replacement of the native metal ion in the enzyme with the lanthanide ion, the activity of the resulting species exceeds the activity of the pristine enzyme. Most frequently, this is observed for cerium ions, since their ionic radii correspond well to the site of the original ion in the enzyme and their charge density is larger than that of the original ion, especially for Се4+. The influence of several lanthanide ions (La3+, Ce3+, and Nd3+) on the activity of Cu,Zn-SOD was investigated in the autooxidation of pyrogallol in 0.1-M Tris-HCl buffer (pH 8.2) at 25°C. It was shown that lanthanum and neodymium ions inhibit SOD activity in the entire concentration range, while in the case of cerium, the activity of SOD first increases and then decreases [223]. The effect of Ce3+ ions on the activity of SOD isolated from murine erythrocytes has also been studied in vitro [224]. Similarly, it has been shown that low concentrations of Ce3+ significantly increase, while higher ones decrease the activity of SOD (see Fig. 8.7A). Upon interaction with cerium ions, the secondary structure of SOD changes, which is associated with the coordination of the cerium ion in the metal active center. In other words, in this case, replacing the original metal ion in the active center of the enzyme with the cerium ion leads to an increase in enzymatic activity: “It is implied that the Ce3+ coordination is created by a new metal ion active site form in SOD, thus leading to an enhancement in SOD activity” [224]. King [225] investigated the activity of aryl-β-d-glucosidase in the hydrolysis of substrate and transfer of the glucosyl moiety to primary alcohols. No cofactor participated in the hydrolysis, but the Ce4+ ion appeared to be an absolute requirement for transglucosidation. Other cations and anions either inhibited the transfer reaction or did not affect the process; the dependence of the activity of the enzyme on the concentration of the Ce4+ ion (as CAN) was also nonlinear (see Fig. 8.7B). Lanthanide ions increase the activity of lactate dehydrogenase from a murine heart (LDH, EC1.1.1.27), and cerium ions provide maximum activity, as well [226]: “Our results showed that La3+, Ce3+, and Nd3+ could significantly activate lactate dehydrogenase (LDH) in vivo and in vitro; the order of activation was Ce3+ > Nd3+ > La3+ > control.” This effect can be due to changes in the secondary structure of the enzyme. The cofactor is also not

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Fig. 8.7  The influence of cerium ions on the activities of some natural enzymes. (A) SOD [224]; (B) aryl-β-d-glucopyranoside methanol glucotransferase [225]; (C) alanine aminotransferase [228]; (D) RuBisCO [229]. (A) Reprinted with permission from: J. Liu, L. Ma, S. Yin, and F. Hong, Effects of Ce3+ on conformation and activity of superoxide dismutase. Biol. Trace Elem. Res., 125(2) (2008) 170–178; Y. Liu, Z. Deng, and Y. Wang, The effects of Lanthanum chloride on neural stem cell proliferation. Exp. Lab. Med., 5 (2008) 004, Copyright 2008 Springer; (B) reprinted with permission from K.W. King, Ceric ion activation of aryl-β-d-glucopyranoside methanol glucotransferase. Arch. Biochem. Biophys. 95(2) (1961) 320–322, Copyright 1961 Elsevier; (C) reprinted with permission from N. Li, Y. Duan, C. Liu, and F. Hong, The mechanism of CeCl3 on the activiation of alanine aminotransferase from mice. Biol. Trace Elem. Res. 136(2) (2010) 187–196, Copyright 2010 Springer; (D) reprinted with permission from C. Liu, F.S. Hong, Y. Tao, T. Liu, Y.N. Xie, J.H. Xu, and Z.R. Li,The mechanism of the molecular interaction between cerium (III) and ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). Biol. Trace Elem. Res. 143(2) (2011) 1110–1120, Copyright 2011 Springer.

required for horseradish peroxidase, while it is well known that, for example, the manganese ion increases peroxidase activity. Other ions were shown not to affect or to inhibit enzyme, and only cerium increased peroxidase activity [227]. Cerium ions were also shown to increase the activity of alanine aminotransferase [228]. The dependence of the activity on cerium concentration was nonlinear too (see Fig. 8.7C). It should be noted that the dependence of enzymatic activity on the concentration of lanthanides is similar to the curve of hormesis, albeit the bimodal effect of cerium on the activity of isolated enzymes (outside biological systems) cannot be judged as the manifestation of hormesis, merely by definition of this term.

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Gould [230] investigated the effect of thorium, zirconium, titanium, and cerium salts on the activity of amylase, invertase, phosphatase, and trypsin. All the salts (except cerium salts) significantly reduced the activity of the enzymes studied. In the case of amylase, cerium showed 30% activation over the control. In the case of invertase, cerium also increased the activity of the enzyme by about 15%–20%. The effect of Ce3+, Cd2+, and Hg2+ ions on trypsin activity was also studied by Fashui et al. [231]. It was established that cerium (0.5–5 μM) significantly increased the activity of trypsin, while mercury and cadmium decreased its activity. Interestingly, cerium (unlike Cd and Hg) did not affect either the UV spectra or the secondary structure of trypsin. Changes in enzyme activity in the presence of cerium salts were observed not only in vitro but also in vivo; in the latter case, unfortunately, it is difficult to explain unambiguously the mechanism of this influence. Yang et al. [232] studied the effect of cerium nitrate on the activity of some ion-dependent ATPases in vivo (Ca2+-ATPase, K+/Na+-ATPase, and Mg2+-ATPase). The results obtained showed that after the recurrent intraperitoneal administration of low doses of cerium nitrate (1 mg/kg), the activity of ATPases was increased in the liver, kidneys, and heart of the rats, but no changes in activity were observed after the administration of high doses of cerium nitrate (50 mg/kg). Cerium chloride has been shown to significantly increase the activity of acetylcholinesterase and nitric oxide synthase in silkworm larvae infected with a nuclear polyhedrosis virus [233]. Zhao et al. [234] studied the effect of cerium nitrate on the activity of the enzyme system in testicular cells of male mice—LDH, sorbitol dehydrogenase (SODH), succinate dehydrogenase (SDH), and glucose-6-phosphate dehydrogenase (G-6PD). It was shown that cerium nitrate at low doses (15 mg/kg) activated the metabolism of enzymes (LDH, SODH, SDH, and G-6PD) and enhanced the proliferation of testicular cells, whereas high doses (60 mg/kg) promoted the opposite effect. Low concentrations of cerium ions can enhance the activity of natural enzymes above the basic pristine level, and the excess of free cerium ions reduces the activity of enzymes. Cerium ions bond in nanoceria and are inaccessible to the metallocenters of enzymes but are still capable of interacting with ROS, thus protecting enzymes from thermal/mechanical damage and oxidation. For example, nanoceria in the shell of LBL microcapsules protects encapsulated firefly luciferase against degeneration by hydrogen peroxide [173].

8.4.4.2 Enzymes and biologically significant molecules of plants In the agriculture of the People’s Republic of China, lanthanides have long been used as microfertilizers [235]; the annual consumption of REE by the agrochemical sector of China today is calculated in millions of tons [236]. It has been shown in both in vitro and in vivo studies that lanthanides can affect enzymes and biologically significant molecules in plants. For example, cerium nitrate promotes floral initiation and reproductive growth of Arabidopsis thaliana [237]. Recently, to increase the growth of plants, the use of nanoceria has been proposed: it has been shown that under conditions of abiotic stress in Arabidopsis thaliana, photosynthesis can be partially restored with nanoceria stabilized by polyacrylic acid [238,239]. The quantum yield of photosystem II also i­ncreased by 19%, the degree of carboxylation of ribulose-1,­5-bisphosphate

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c­ arboxylase/oxygenase (Rubisco) increased by 61%, and the degree of assimilation of carbon increased by 67%. In another study, bare and PVP-stabilized CeO2 nanoparticles at a concentration of 100 mg/kg of dry soil increased the carboxylase activity of soy Rubisco by 32% and 27%, respectively, and inhibited this activity at >500 mg/kg [240]. Hu et al. [241] found that low concentrations of ceria nanoparticles (1 mg/L CeO2) enhanced the net photosynthesis rate of plants in constructed wetlands, while exposure to a high concentration (50 mg/L CeO2) inhibited photosynthesis. Nanoceria effectively protected Chlorella vulgaris cells from the damaging effect of excess UV radiation in a silica gel block [242] and in the form of a coating [243]. Rico et al. showed that low concentrations of nanoceria (62.5 and 125 mg/L) reduced the level of hydrogen peroxide in the roots and stem of rice, while a high concentration of nanoceria (500 mg/L), on the contrary, increased oxidative stress [244]. Cerium chloride protects rape [245] and soybean seedlings [246] from UV irradiation (UV-B, 280–320 nm), presumably through the activation of the plant’s autoprotective system and the enhancement of photosynthesis. Other lanthanide ions are also known to be able to inactivate ROS in plants too [71,247,248].

Artificial introduction of lanthanide ions: Rubisco and chlorophyll Rubisco is one of the major enzymes in plants, cyanobacteria, and chemoautotrophic proteobacteria. It plays a central role in the mechanism of inorganic carbon supply to the biological cycle and is considered to be the most widespread enzyme on the Earth. Lei et al. isolated the Rubisco/Rubisco activase complex from spinach and treated it with lanthanum chloride or cerium chloride; it was found that the enzymatic activities of the complex in the plants treated with La3+ and Ce3+ were 1.8 and 2.8 times higher than in control samples [249]. The results obtained show that not only cerium but also its redox inactive neighbor, lanthanum, enhanced the enzymatic activity of Rubisco. Liu et al. investigated the chemical mechanism of interaction between Ce3+ ions and Rubisco in  vitro. It was shown that the carboxylase activity of the enzyme increased significantly at low cerium concentrations and decreased at higher ones [229]. The position of UVB absorption bands of Rubisco did not depend on the concentration of cerium, but the intensity of the bands increased proportionally. Ce3+ ions also did not affect the position of λmax in the fluorescence spectra of Rubisco, but the intensity of the bands increased in a dose-dependent manner too. These data, as well as X-ray studies, suggest that cerium is directly coupled with the enzyme (1.52 binding sites per protein, see Fig. 8.7D), with the Ce3+ ion coordinating eight Rubisco oxygen atoms in the first shell and six oxygen atoms in the second shell. Gong et al. showed in vivo that under the condition of manganese deficiency, Rubisco activity and nitrogen metabolism in maize can be restored by treatment with cerium [250,251]. The expression of Rubisco mRNA of small (rbcS) and large subunits (rbcL), as well as activation subunit (rca), was significantly increased in cerium-treated corn. Rubisco, as an enzyme, requires the presence of a Mg2+ ion in the active site. Magnesium ions are also required for the normal operation of the main plant energy source, chlorophyll. Lanthanides have a beneficial effect on chlorophyll formation and activity too [252]. Under the condition of magnesium deficiency, spinach had reduced chlorophyll content and a high level of ROS in chloroplasts. Treatment with cerium

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salts made it possible to compensate for the lack of magnesium and to lower the level of ROS. Recent studies have revealed that cerium is able to replace magnesium in the porphyrin cycle of spinach chlorophyll [253,254]. Zhou et al. cultivated corn in Hoagland solution with magnesium deficiency, while cerium restored the synthesis of chlorophyll and activated photophosphorylation and cofactor Ca2+-ATPase [255]. The authors also came to the conclusion that cerium is able to replace magnesium in chlorophyll. Cerium salts favorably affect plants with a deficiency of other ions involved in the enzymatic system of photosynthesis—for example, manganese or calcium. Redox inactive lanthanum is also capable of successfully replacing magnesium in chlorophyll (the LaN bond length is 0.253 nm in the porphyrin cycle), substantially accelerating the formation of photosystem II and increasing the intensity of photosynthesis of spinach. Goecke et al. studied the effect of rare-earth chlorides on the growth parameters of the yellow-green alga Trachydiscus minutus (Eustigmatophyceae, Ochrophyta) and the green alga Parachlorella kessleri (Trebouxiophyceae, Chlorophyta) under various illumination conditions. In the control experiments, the growth rate of P. kessleri was approximately three times higher than that of T. minutus and did not depend on the content of lanthanides. With the introduction of Ce3+, the growth rate of T. minutus increased sharply and reached P. kessleri values given the same light intensity. This was accompanied by an increase in concentration of the major pigments, such as lutein, violaxanthin, β-carotene, or chlorophyll, while the addition of Pr3+ and Lu3+ led to their decrease [256]. Řezanka et al. studied the effect of REE on Desmodesmus quadricauda [257]; after lanthanide treatment, the total amount of chlorophyll increased by up to 21% relative to the control. Moreover, when the heavy isotopes of magnesium (25Mg and 26Mg) were used to preform chlorophyll, the addition of lanthanides reduced the content of these isotopes in the algae, indicating the replacement of magnesium by lanthanides in chlorophyll. Wang et al. demonstrated that the supplemental feeding of Anabaena flosaquae with Ce3+ in the concentration range 0.05–0.1 mg/L stimulated growth and increased chlorophyll-α content and the activity of the antioxidant system (SOD, catalase, and peroxidase), whereas concentrations above 5 mg/L were found to be toxic for cyanobacteria [258]. Lanthanides can stimulate the activity of other processes in organelles of plants. They can affect seeds’ vigor and germination, when incorporated into the seeds’ treatment [259], especially aged seeds [260]. The treatment of aged rice seed with cerium nitrate enhanced respiratory rate and catalase, SOD, and peroxidase activities [260]. Microcalorimetric studies of the effect of cerium ions on mitochondria of rice 9311 (Oryza sativa L.) showed that mitochondrial activity increased significantly in the presence of 0–120 μg/mL of Ce3+ ions, while concentrations of cerium from 140 to 150 μg/mL had the opposite effect [261]. When growing rice under hydroponic conditions, Xu et al. investigated the effect of tetravalent cerium on the antioxidant system of this plant [262]. Ce4+ ions at a concentration of 0.02 mM increased the antioxidant capacity of reduced ascorbate and glutathione and the levels of SOD, ascorbate peroxidase, and catalase. As in the other cases, a high concentration of cerium (0.2 mM Ce4+) inhibited protective reactions and caused peroxide oxidation of membrane lipids. In the pot experiments, Pak choi plants (Brassica rapa subsp. chinensis) were sprayed

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with cerium nitrate and yttrium nitrate solutions [263]. The dry weight, chlorophyll content, photosynthesis rate, catalase, peroxidase, SOD, and ascorbate peroxidase activities peaked at the 300-mg/L REE concentration, and the effects of Ce3+ were better than those of Y3+.

Natural sources of REE and the enzymatic system of plants The soil of some regions of China is naturally enriched with REEs, and endemic free-growing plants have the opportunity to involve REE in their metabolism. Thus samples of the perennial fern Dicranopteris, harvested from a REE-enriched field, contained an increased concentration of lanthanides [264–267], Dicranopteris dichotoma being a “hyperaccumulator,” ΣREE = 3358 μg/g of leaves [268]. The photosynthesis activity of the D. dichotoma samples grown in the zone of the REE deposit was much higher than that of the same plant taken from other regions. Lanthanides were isolated from the chloroplasts of Dicranopteris linearis leaves collected in areas of mining of REEs in the South Jiangxi region (southern China); similar artificial complexes of chlorophyll and lanthanides have been synthesized and studied 264]. The FTIR spectra confirmed that lanthanides are bound to chlorophyll porphyrin rings; the intensity ratios of the Soret band to the Q-band of Ln-chlorophyll-α in UV-visible spectra were higher than those of the pristine chlorophylls, indicating that Ln-chlorophyll-α has a much stronger absorption in the ultraviolet region of the solar spectrum. Probably, the plants containing Ln-chlorophyll can more effectively assimilate UV radiation. Concentrations of lanthanum and cerium in plants were found to be 10–100 times higher than concentrations of other REEs [269]. Thus the results of many studies demonstrate that cerium ions increase the activity of a wide range of enzymes when administered in vitro and in vivo at a certain concentration; when cerium is available in the natural environment, plants readily include it in their metabolism. Recently, a natural enzyme was discovered whose activity requires the presence of the lanthanide (cerium) ion in the metal center. “The unexpected discovery of lanthanide-dependent biochemistry in living organisms highlights the existence of substantial gaps in our knowledge of the role of metals in Life” [270].

8.4.4.3 Lanthanides’ microbiology: PQQ and XoxF Quite recently, in Italian hot volcanic reservoirs, acidophilic methanotrophic, and methylotrophic microorganisms that use cerium as an essential element were discovered [271]. A well-known MxaF-type methanol dehydrogenase enzyme (e.g., MxaF-MDH in Methylobacterium extorquens AM1) uses a calcium ion in the cofactor system. Unexpectedly, the Methylacidiphilum fumariolicum SolV bacterium contains a complex of pyrroquinoline quinone (PQQ) with a cerium ion (Fig. 8.8) in the main structural center of this enzyme (XoxF-MDH, Fig. 8.9). PQQ is an essential cofactor for many of the dehydrogenase enzymes in bacteria; it is also likely to be important in mammals [272]. Quinoproteins (PQQ-containing enzymes) are widespread, from bacteria to mammalian organisms, and occur in several classes of enzymes [273]. PQQ by itself is known to participate in oxidation-reduction reactions of the mitochondrial respiratory chain [274] and is also a potent plant growth factor [275].

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Fig. 8.8  PQQ with cerium ion.

Fig. 8.9  General view of XoxF-MDH and cofactor structure (protein databank code: 4MAE).

It is the lanthanide-PQQ complex that provides enhanced catalytic properties of the enzyme and allows bacteria to survive in harsh abiotic conditions. The methanol affinity constant in such XoxF-MDH (Fig. 8.9) is 10 times higher than that of MxaFMDH; in contrast to the calcium-containing enzyme, the cerium-containing enzyme catalyzes a deeper oxidation of the alcohol, (not to formaldehyde, but to formate) [276,277]. A model molecule (benzyl alcohol) was successfully dehydrogenated using the functioning model of the lanthanide-containing enzyme [277]. The gene encoding the methanol dehydrogenase of the SolV strain, identified as the XoxF ortholog, is phylogenetically closely related to MxaF. Further metagenomic studies have led the authors to absolutely striking results: XoxF-type methanol dehydrogenase is not unique, inherent only in this type of endemic microorganism; it is also found in other methylotrophs. Moreover, the XoxF-type is more widespread in nature than the conventional MxaF-MDH, “XoxF gene encoding an alternative MDH (which requires lanthanum or cerium for activity) is found in all known proteobacterial methylotrophs” [278], wherein XoxF acts as the predominant methanol dehydrogenase and micromolar amounts of lanthanides are sufficient to suppress MxaFI expression [279] (the socalled REE switch [280]). In other words, a large number of microorganisms are able

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to use lanthanides as key elements of the enzymatic system. The genes of XoxF are present in Rhizobiales, Burkholderiales, Nitrosococcales, Actinobacteria, and many others [270], and PQQ-bound enzymes are found not only in Archaea but also in Eukaryote—for example, in Coprinopsis cinerea oxidoreductase [281]. Some important mammalian enzymes are reported to be quinoproteins (contain PQQ) [282]. For example, choline dehydrogenase from dog’s liver mitochondria [283] or rabbit muscle LDH [284] has been proved to be quinoproteins. Today, numerous studies of cerium-­ containing enzymes in various organisms have been reported [285–287]. Cerium increased the activity of MDH in Methylobacterium radiotolerans, Methylobacterium fujisawaense, and Methylobacterium zatmanii by a factor of 4–6 in comparison with calcium, suggesting the induction of latent genes [288]. When the ethanol dehydrogenase ExaF from M. extorquens contains a lanthanide ion in the active site, its enzymatic activity increases by 900 times as compared with the enzyme obtained when growing the culture on a medium containing no REE [289]. A metaproteogenomic approach identified XoxF as one of the most common proteins in the plant phyllosphere [290] and rhizosphere [291]. In the phyllosphere of the above mentioned A. thaliana “XoxF was even detected exclusively, that is, no MxaF was detectable” [290]. The article named “Just add lanthanides” was published in Science [292]: the bacteria of the plant phyllosphere collected on the campus of San José University showed more active growth on standard agar medium in the presence of lanthanide ions. During the blowout of the Deepwater Horizon (DWH) well, a decrease in the methane concentration was observed in the submerged hydrocarbon plume, with a sharp decrease in the concentration of light lanthanides in water; metagenomic sequencing of samples from the anomalous zone showed the presence of XoxF-MDH [293]. “Moreover, sequence analyses suggest that XoxF-MDHs represent only a small part of putative REE-containing quinoproteins, together covering an unexploited potential of metabolic functions” [276]. This discovery will inevitably affect many questions of natural science. According to Shiller et al. [293], the biological uptake of REEs is “an overlooked aspect of the oceanic geochemistry”. Today, the main indicator of paleoceanographic conditions is the cerium anomaly. Because “PQQ may have been present throughout early biological conception and evolution” [275], if the distribution of cerium depends not only on physicochemical but also on biological factors, it will be necessary to revise many conventional data on the evolution of the Earth. The question of significance (or even presence) of lanthanide-dependent enzymes in Eukaryotes is currently under debate; however, the influence of lanthanides on various types of macroorganisms seems to be mediated via symbiotic microorganisms in some cases. For instance, it was known long ago that cerium fertilizers are beneficial for rice (O. sativa) cultivation [294,295]; later, Minamisawa et al. found that symbiotic methanotrophs are key microbes for nitrogen acquisition in paddy rice root, and the most abundant of them use REE-binding XoxF-MDH [296]. REE may enhance nitrogen fixation by Azotobacter species too [297]. Nakagawa et  al. suggested the probable symbiotic relationship between many plants and REE-dependent methylotrophs [298], including nitrogen fixers. Rzigalinski et al. demonstrated that supplementation of nanoceria leads to an increase in the life span of the fruit fly Drosophila

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melanogaster [299]; later, Shin et al. showed that commensal bacterium Acetobacter pomorum, essential for insulin signaling activation, regulation of host homeostatic programs, and normal development of the fruit fly, contains PQQ-dependent alcohol dehydrogenase [300]. One more example is the anaerobic fermentation of plant biomass in the rumen of cattle that results in the production of methane; the conversion of CH4 by ruminants is both an economic and an environmental task for both more effective feed digestibility and the reduction of the eructation of greenhouse gases. “The concept that CH4 eructated from cattle is actually a result of active methanogenesis versus methanotrophy in situ is highly intriguing” [301]. PCR amplification with specific primers has demonstrated the methanotrophic bacteria attached to the rumen epithelium [301,302]; the abundance of methanogenic and methanotrophic bacteria in the rumen’s microbial community is diet dependent [303,304]. Lanthanides affect rumen fermentation: supplementing cerium chloride in the ration of beef cattle increases fiber digestibility and microbial nitrogen flow and decreases CH4 production [305]. Similarly, lanthanum chloride decreases CH4 production by ruminants through manipulating the rumen’s microbial flora without negatively affecting feed digestion [306]. REE supplementation has been shown to improve rumen fermentation and feed digestion in sheep. Xun et al. demonstrated that dietary REEs stimulated rumen microbial activity, digestive microorganisms, or enzyme activity in a dose-dependent manner; the optimum supplemental dose of dietary REE-citrate in sheep was about 200 mg/kg of dry matter [307]. The metabolism of some Pseudomonas [287] or Bradyrhizobium is influenced by lanthanides [308] too. REEs have recently been shown to be involved in the activation of silent or poorly expressed genes in bacteria [309,310]. Rare-earth chlorides cause antibiotic overproduction by 2- to 25-fold when added at a low concentration (10–100 μM) to the cultures of Streptomyces coelicolor A3(2) (actinorhodin ­producer), S. antibioticus (actinomycin producer), and S. griseus (streptomycin producer), whereas other metals (Cu, Zn, Mn, Ni, and Co) have been shown to be ineffective [311]. The ability of lanthanides to enhance enzyme production and secondary metabolism has also been observed in Bacillus subtilis; they stimulated the production of both α-amylase and bacilysin at the transcriptional level [312]. The ability of REEs to affect the production of biologically active substances with bacteria can be used as a new strategy for drug discovery: “Rare-earth microbiology” may thus offer new insight into entirely unknown regulatory events that occur in all organisms [309]. In his “Biochemistry of the Lanthanides”, Evans wrote, “In addition, lanthanides sometimes bind to unique sites on proteins which are not known to accept other metal ions” [70]. In the Protein Data Bank database, among the 100,000 three-dimensional structures of known biologically active compounds, only seven substances contain cerium ions [313]. Despite this, Martinez-Gomez et al. predicted that these data are only the beginning of new discoveries associated with new Ln-dependent enzymes [286]. Chistoserdova noted that the discovery of the properties of lanthanides as a critical cofactor of enzymes posed a number of important fundamental questions [270]: Why do living organisms prefer REEs in the presence of an excess of common chemical elements? What are the competitive advantages of Ln-dependent enzymes and biologically active proteins (regulators, transporters, sensors, etc.)? How widespread and how

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important are Ln-dependent enzymes and other bioactive molecules on Earth, and how can we recognize them? Nakagawa et al. wrote that rare earths are likely to have more important and universal biological significance, and further progress in elucidating the function in the life activities of the future rare earths can be expected to open the door to the new “rare-earth world” [298].

8.5 Effects in biological systems ex vivo and in vivo: Cerium ions versus nanoceria Since the most interesting and unusual property of nanoceria is its ability to have a beneficial effect on biological systems via protection against oxidative stress and other unfavorable factors, let us consider this phenomenon and compare it with known data on the behavior of cerium ions in more detail.

8.5.1 Nanoceria and cerium ions in regenerative medicine Nanoceria is considered to be a potential therapeutic agent in regenerative medicine [25]. For example, it stimulates the proliferation of fibroblasts in  vitro [314–316] and accelerates the healing of model lesions in  vivo [317], which is promising for wound therapy [318,319]. Nanoceria-functionalized polycaprolactone-gelatin fiber mesh [320], chitosan-coated cerium oxide nanocubes [321], and ceria-decorated mesoporous silica nanoparticles [322] have been demonstrated to have a substantial potential for wound healing applications. The use of nanoceria is also a perspective for the healing of type 2 diabetic foot wounds [323]. The effect of cerium ions on the regeneration of integumentary tissues was discovered >25 years ago: thus the commercial preparation Flammacerium, intended for the treatment of burn wounds, contains cerium nitrate [324–327], which accelerates the recovery of fibroblasts in the zone of the scab and the epithelization of the wound. Today, as a wound dressing material, a collagen matrix containing cerium ions is proposed [328]. Low concentrations of cerium (III) chloride stimulate the proliferation of cardiac fibroblasts in Wistar rats; the concentration dependence is nonlinear, and a stimulatory response at low levels of cerium has been observed with a peak at 0.5 μM [329]. Shivakumar et  al. investigated the effect of cerium ions on the synthesis of collagen in cultured cardiac fibroblasts and explants [330]. It was shown that low concentrations of cerium (100 nM) enhanced the synthesis of collagen, and high concentrations (100 μM) inhibited it. At a concentration of 100 nM, cerium ions did not affect the rate of DNA synthesis in fibroblasts; however, the incorporation of uridine (labeled with tritium) in RNA was markedly increased. Shivakumar et al. concluded that the stimulating effect of cerium on the synthesis of collagen and noncollagen proteins was manifested at the level of transcription; the authors described the results of nonmonotonic dependence as “paradoxical.” Cerium (1.3-mg/kg body weight CeCl3 i.v.) has been seen to significantly stimulate protein synthesis in the cardiac muscle of Wistar rats in vivo [331], accelerate the healing of wounds, and increase the proliferation of

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human foreskin fibroblasts [332]. Extracellular calcium-sensitive receptors (CaSR) are critical in the signal pathway of epithelial cells; it has been shown that lanthanides are able to activate CaSR in the absence of calcium. On the other hand, all lanthanides activate the proliferation of stromal cells (fibroblasts) at low concentrations [333,334]. Nanoceria protects the mesenchymal stem cells of human dental pulp from oxidative stress [335]. Rocca et al. investigated the ability of nanoceria to inhibit the adipogenic differentiation of mesenchymal stem cells (MSCs) in vitro, used as a model of adipogenesis [336]. Cerium salts have also been shown to stimulate osteogenic and inhibit adipogenic differentiation of mesenchymal stem cells at the cellular level [337,338]. Rocca et al. observed the effect of the inhibition of adipogenesis by cerium oxide [336] and suggested nanoceria as a promising antiobesity drug [339]. Hu et al. showed that low concentrations of cerium ions (0.001-μM CeCl3) increase the viability of mesenchymal bone marrow stem cells (BMSC) and ALP activity, with both decreasing at higher concentrations (10-μM CeCl3) [340]. Cerium species can influence the expression of osteogenic transcription factors (Runx2, Satb2, and OCN) and promote the migration of BMSC by increasing the expression of SDF-1 mRNA. The authors concluded that cerium, being a promoter of the phosphorylation process, promotes migration and osteogenic differentiation of BMSC stromal cells along the Smad1/5/8 signaling pathway [340]. The effect of cerium on osteo- and adipogenesis is unlikely to be related to its redox properties in the process of ROS inactivation, since redox inactive lanthanum likewise influences differentiation [207]. The effect of cerium chloride on proliferation, osteogenic differentiation, and mineralization of mouse preosteoblasts (MC3T3-E1 cell line) was studied at the cellular and molecular levels in vitro [341]. It was shown that concentrations of 0.0001-, 0.001-, 0.01-, 0.1-, and 1-μM CeCl3 accelerated these processes, and 10, 100, and 1000 μM inhibited them. Zhang et  al. investigated the effect of cerium ions on the proliferation, differentiation, adipocytic transdifferentiation, and mineralization of primary mouse osteoblasts [342]. It has been shown that cerium ions improved cell proliferation in the whole range of concentrations (10−9, 10−8, 10−7, 10−6, 10−5, and 10−4 M) studied and inhibited differentiation in concentrations of 10−5 and 10−4 M. In the case of nanoceria, proliferation, osteogenic differentiation, and adipogenic differentiation of BMSCs were significantly influenced by both concentration and duration of cultivation [306].

8.5.2 Nanoceria modulates the level of cytokines and reduces the inflammatory response 8.5.2.1 Nanoceria reduces the level of proinflammatory cytokines Cerium oxide nanoparticles possess antiinflammatory properties. For example, nanoceria reduces the production of inflammatory mediators by stimulating the macrophages of mice 774A.1 [343]. In a model of human immunity in vitro, Schanen et al. showed that treatment with CeO2 nanoparticles induced APCs (antigen-presenting cells) to secrete the antiinflammatory cytokine, IL-10, and induce a TH2-dominated T cell profile [344]. In the model of nonalcoholic fatty liver disease (NAFLD) in rats, Kobyliak et  al. showed that nanoceria reduces inflammatory processes in the

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blood of rats, and this can prevent complications from obesity and liver damage. Ceria nanoparticles were shown to reduce the levels of proinflammatory cytokines (IL-1β, IL-12Bp40) in rat serum and to restore the level of antiinflammatory cytokines (IL-4, IL-10, and TGF-β) to control values [345]. A single intravenous dose (0.5 mg/kg) of CeO2 nanoparticles decreased the expression of proinflammatory cytokines in polymicrobial, insult-induced splenic damage in Sprague-Dawley rats [346]. During the long-term application of cerium nitrate in the treatment of burn wounds, it was found that the main function of cerium is immunomodulation [51,347]. Thus it was noted that topical cerium nitrate restored the immune function suppressed by the burn injury [348]. “Specific studies show the effect of cerium nitrate on improvements in immune response has been successful and was first reported in mice, while data on human patients show promise” [349]. “These studies suggest that topical Ce may have potential as an immunomodulator in the treatment of burns” [350]. In these cases, cerium binds and denatures the lipid-protein complex (LPC), which is released from the burned skin and is responsible for deep immunosuppression with burns [324,325]. The value of cerium as an immunomodulator in burns lies in its ability to neutralize or inactivate the lipoprotein or suppressor active peptide complexes in the wound site [347]. Cerium reduces the release of histamine in human granulocytes, blocking the activity of calcium-dependent ATPase and also effectively inhibits this enzyme in the epidermal Langerhans cells, which play an important role in atopic eczema and skin immune responses [351,352]. In cell culture, lanthanides inhibit lymphocyte activation by blocking calcium-dependent processes and calcium channels [347]. Treatment by immersion in a solution of cerium nitrate significantly reduces the activation of leukocytes and the inflammatory response in the burn area [353]. In this case, burn mortality after treatment with cerous nitrate is much lower than that anticipated, which cannot be related only to a decrease in the bacterial load or to an increase in epithelialization of the wound. Additional studies conducted to clarify these paradoxical effects have shown that treatment with cerium nitrate 30 min after a burn decreased leukocyte activation and reduced alarm cytokine levels, macromolecular leakage, and burn edema formation [354]. In the case of thermal damage, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are important mediators of acute and severe inflammatory response. Immersion treatment with cerium nitrate in the early period after thermal damage has been shown to allow the concentration of TNF-α and IL-6 to be restored to a level that can only be achieved by surgical treatment of the wound [355]. The immunomodulating properties of cerium in burns are also reflected in its ability to neutralize or inactivate LPC or serum amyloid protein complexes in the wound zone. For CeO2 nanoparticles, it has also been shown in  vitro (macrophages RAW264.7) and in  vivo (Sprague-Dawley rats) that treatment with nanoceria reduces the level of IL-6 and inflammatory markers in the blood of mice and reduces the release of ­lipopolysaccharide-induced cytokines and activation p65-nuclear factor-κB (NF-κB) in cultured RAW264.7 cells [356]. Nanoceria treatment has been shown to be able to reduce metabolic syndrome and inflammation induced by air pollution in Nrf2deficient mice; inhibition of astrocytes activation related NF-κB and enhancement of Nrf2 by cerium oxide nanoparticles have been observed both in vivo and in vitro, suggesting nanoceria inhibited inflammation and nerve injury by affecting hypothalamic neuroendocrine alterations and decreasing glial cell activation [357].

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Nesmerak noted that lanthanides inhibited lymphocyte activation, chemotaxis and neutrophil aggregation, Kupffer cell activity, and histamine secretion from mast cells and also reduced histamine- and serotonin-induced vascular permeability and inflammation caused by carrageenan. On the other hand, in low doses, lanthanides seem to enhance the immune response, leading to antibody formation and lymphocyte activation [358]. Experimental studies in mice have demonstrated that cerium nitrate (with or without sulfadiazine) can suppress delayed hypersensitivity reactions to 2,4-­dinitroaminobenzene and restore lymphocyte homeostasis [350,359,360]. It is known that allergic inflammation develops as a result of the interaction of cellular receptors with various allergens, resulting in the release of numerous inflammatory mediators (cytokines, leukotrienes, adhesion molecules, factors of eosinophils, and mast cells). According to the studies of Luo et al., cerium nitrate successfully inhibits allergic rhinitis in guinea pigs caused by 2,4-toluene diisocyanate [361]. Application of cerium compounds at the site of skin lesions allows exclusion of the development of allergic urushiol contact dermatitis; interestingly, the detoxification activities of soluble cerium salts and insoluble oxide (hydroxide) are the same [362]. Lanthanides inhibited angiotaxis and oedema in rats following the injection of inflammatory agents: rare-earth complexes of pyrocatechol disulphonate proved to be very effective in counteracting inflammatory reactions in rats induced by subplantar injection of bee venom or cobra venom; with high doses of 250–350 mg/kg, the inhibition of the edematous swelling may even exceed 80% [363]. Nanoceria protects mammals against autoimmune diseases associated with oxidative stress. Thus ceria nanoparticles stabilized with citrate/EDTA (mean size 2.9 nm, ζ-potential −23.5 mV) have been shown to reduce ROS levels and also remove clinical signs and motor deficiency in mice in the model of multiple sclerosis [364]. Similar prospects for the therapy of autoimmune diseases have been repeatedly noted for lanthanide ions. Thus Sturza noted: “As an endocrinologist, I was daily confronted with pathologies such as autoimmune thyroiditis, a situation where the body produces antibodies against its own structures: these cases were unexpectedly solved with the help of lanthanide-compound-based remedies” [365]. “Ce(NO3)3 was able to modulate the levels of the inflammatory cytokines IL-2 and TNF-α associated with toxicant-­ induced liver damage suggesting that Ln3+ may be able to modulate the inflammatory process in rheumatoid arthritis” [220]. “The treatment of rheumatoid arthritis—an inflammatory disease characterized by a progressive erosion of the joints resulting in deformities, immobility, and a great deal of pain—is a very promising field for lanthanide-­based chemotherapeutics” [358]. Upon selecting a carrier for drug delivery, the ability of metal oxide nanoparticles (including silicon, zinc, and cerium oxides) to induce apoptosis of cells in vitro and an inflammatory response in rats in  vivo was investigated [366]. A549 and H1299 cells were exposed to nanoparticles for 12 h; the rats were injected with nanoparticles (20 mg/kg) for 1, 7, 14, or 28 days. Unlike with nanoparticles of zinc and silicon oxides, autophagy and apoptosis were not detected 12 h after the exposure of cells to 100 μg/ mL of nanoceria. The genes associated with autophagy, LC3, atg5, beclin1, and bcl2, did not change at ceria concentrations from 0 to 200 μg/mL. It was shown in vivo that only 4 of the 27 cytokines (IL12P70, RANTES, IL-X, and MIP-1α) were changed on day 28 after exposure to cerium oxide nanoparticles (20 mg/kg). Yang et al. noted nanoceria to be the “ideal vehicle” for targeted drug delivery both in vivo and in vitro.

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The ability of lanthanide compounds (primarily cerium compounds) to decrease the activity of the reticuloendothelial system can also be used for organ transplantation and prosthesis implantation. For example, the incorporation of CeO2 in hydroxyapatite coatings for orthopedic implants can be a good strategy to promote osseointegration and reduce implant-induced inflammatory reactions [367].

8.5.2.2 Nanoceria increases the activity of interferons Interferons have a variety of biological activities that manifest themselves in antiviral, antitumor, and immunostimulating effects: they block intracellular replication of the virus, suppress cell division, stimulate the activity of natural killers, and increase the phagocytic activity of macrophages and the activity of surface antigens of histocompatibility; at the same time, they inhibit the maturation of monocytes in macrophages. The influence of nanoceria on the activity of interferons (IFN) has been studied recently [368–371]. Shydlovska et al. showed that the use of nanoceria in combination with IFN significantly increases the interferon response in mice compared with unmodified IFN, while the TNF production level does not increase, which indirectly indicates the safety of such a complex [369]. During the treatment of a viral infection (herpes simplex HSV-1), it was shown that ­nanoceria-activated IFN is a more effective antiherpetic drug than the traditional acyclovir. The corresponding composite is claimed for practical use [371]. Previously, Sedmak et al. investigated the effect of cerium (and other lanthanides) on the activity of various interferons. The addition of REE salts increased the initial activity of leukocyte (α), fibroblast (β), and immune (γ) human interferons by a factor of two or more, as well as the activity of murine L-cells interferon [372–375]. In the presence of 0.002–0.01 M lanthanides, β-interferon maintained its activity after 4 days of heating at 37ºC and also after shear, although, to a lesser extent, α-interferon was also significantly stabilized. Moreover, it was found that such a stabilized interferon had a higher titer and more actively bound to the corresponding receptors of the cell membranes [373]. The use of iodine-labeled (125I) human and murine ­β-interferons showed that treatment with lanthanides increased binding to human A549 cells and murine L-cells at 0ºC by 20–30 times and also enhanced antiviral activity in homologous cells. Interestingly, binding sites of cells with pristine and ­lanthanide-modified interferons are different; such interferons do not compete for receptors but exhibit synergism. The method of stabilizing an interferon with lanthanide ions is claimed to be of practical importance [376].

8.5.2.3 Nanoceria as an oral immunomodulator Recently, Jiangxi Medical College Hospital and Department of Immunology examined the correlation between the state of the human immune system and the content of lanthanides. The latter was measured by the ISP-MS method, and the functions of cellular and humoral immunity were determined by flow cytometry and turbidimetric immunoassay, respectively. It has been shown that in a REE-supplemented group (102 people), immunity was better than in the control group (52 people). The authors concluded that lanthanides exert a stimulating effect on the human immune system [377].

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It is known that low doses of lanthanides, orally administered, cause a beneficial response in laboratory and farm animals and birds, (weight gain, egg production, digestibility of feed, etc.). The use of lanthanides as feed additives has been practiced in Europe for more than a decade (e.g., cerium-lanthanum citrate Lancer [378]) and in China for more than half a century [379]. Kroth demonstrated that such ­lanthanide-supplemented feeding affects the state of the intestinal microbiota of animals, improving the assimilation of nutrients and protein and energy accumulation [380]. The immune level of the animals significantly increased. Thus, the addition of 2, 20, or 200 mg/L of cerium nitrate to drinking water for 50 days increased nonspecific immunity in mice [381], the maximum effect being observed at a 20-mg/L concentration [382]. REE supplementation increased blood immune-related cell population and decreased fecal emission gases in finishing pigs [383]. Absorption of orally administered lanthanides is low, >95% being excreted in the feces [379], even in the case of a readily soluble cerium citrate [384]. Thus, with this method of application, cerium compounds primarily affect the intestinal microbiota; at least a part of this microflora is PQQ dependent [300,385,386]. Cai et al. demonstrated that diets with lanthanides improved both fecal Lactobacillus counts and growth performance, digestibility, and blood lymphocyte counts in pigs [387]. Zholobak et al. demonstrated that in the presence of citrate-stabilized nanoceria, the probiotic properties of Lactobacillus species were significantly increased; simultaneous oral administration of Lactobacillus delbrueckii subsp. Bulgaricus and nanoceria significantly activated the immune systems of mice [202].

8.5.3 Nanoceria as a neuroprotective agent Beginning with the pioneer works [388,389], nanoceria has demonstrated a great perspective in the therapy of neurodegenerative dysfunctions [390,391]. In the recent report of Rzigalinski et al., citrate-stabilized nanoceria, as a neuroprotective agent, was intravenously injected to mice (0.05–50 mg/kg); 5 days later, Parkinson’s disease was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and the development of the disease was evaluated after 7 days. It was shown that doses of 0.05–5 mg/kg of nanoceria prevented a decrease in the level of dopamine in the corpus striatum and retained dopaminergic neurons in substantia nigra, while a higher dose (50 mg/kg) was ineffective [391]. Hegazy et  al. caused Parkinson’s disease in the rats by administering 6-hydroxydopamine in the corpus striatum; subsequent intraperitoneal administration of 0.5 mg/kg nanoceria significantly improved neurobiochemical parameters and motor functions (open field, RotaRod, and stepping tests). It was noted that higher (1 mg/kg) and lower (0.1 mg/kg) doses were not effective enough [392]. The use of a single dose of nanoceria at a nanomolar concentration had a significant neuroprotective effect on neurons in the spinal cord of adult rats [24]. In the ischemia model in vitro, the concentration of nanoceria of 0.2–1 mg/L significantly reduced cell death, and at concentrations above and below (0.1 and 2.0 mg/L) cell death was at the control level [393]. During in vivo experiments, in a model of induced ischemic stroke in rats, with intravenous administration of nanoceria at low doses (0.1 and 0.3 mg/kg), the size of the ischemic zone was not affected, and at concentrations of 0.5 and 0.7 mg/kg, the zone size was significantly reduced, >50% from the control (P < .05) [394]. At the same time,

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higher doses (1.0 and 1.5 mg/kg) also failed to provide a protective effect against stroke. D’Angelo et al. studied the influence of nanoceria on the development of Alzheimer’s disease, which was modeled by treatment of human neuroblastoma cells SH-SY5Y in vitro with beta amyloid (Aβ). It was found that the viability of the cells could be restored only when using 100-mg/L concentration of nanoceria; lower concentrations were ineffective, and higher concentrations were toxic [395]. In neuroblastoma neuro2A cell culture, 10-nm nanoceria particles have been shown to be toxic in concentrations above 10 mg/L [396], and 23-nm ceria nanoparticles are toxic in concentrations above 25 mg/L [397]. In a cell culture of the cortical neurons of the cerebral cortex, nanoceria has shown the highest neuroprotective activity at a concentration of 100 nM, and at micromolar concentrations, ceria particles have been found to be toxic [397]. Singh et al. showed that a single dose of 10-nM nanoceria with an average size of 10 nm prolonged life span and preserved the function of neurons in a culture of brain cells [398]. Moreover, the treatment of a cell culture of astrocytes of rats’ cerebral cortex by nanoceria in the same ultralow concentration of 10 nM protected cells from death caused by γ-irradiation by 40%–70% [388]. Chen et al. studied the ability of nanoceria to slow the development of blindness caused by the destruction of photoreceptors by excessive bright light [399]. Two important facts were established during the study: (1) the neuroprotective effect is observed at least 8–10 days after nanoceria administration, and (2) nanoceria is effective at very low concentrations. The working concentration of nanoceria in a rat’s vitreous body was ~6.3 ng/mL, 1000 times lower than the lowest dose in many toxicity studies. Thus from the analysis of a large body of experimental material, we can conclude that the neuroprotective effect of nanoceria is manifested in a narrow range of low concentrations, at a level of micromolar and lower. Moreover, both lower and higher cerium concentrations are ineffective; in the latter case, the nanoparticles, instead of a neuroprotective action, demonstrate a neurotoxic effect. A similar peculiarity is observed for lanthanide salts. Unfortunately, it is not possible to make an adequate comparison of nanoceria and ionic cerium species, since in the latter case, most reports published are devoted to acute and chronic neurotoxic effects of high concentrations of REEs. Thus intraperitoneal administration of cerium and lanthanum chlorides, at a dosage of 20 mg/kg of body weight daily for 14 days, to ICR mice caused multiple brain damage, oxidative stress, LPO, an increase in the level of glutamic acid, and a decrease in the activity of acetylcholinesterase [400]. Daily intragastric administration within 60 days of cerium chloride to ICR mice, at doses of 0, 2, 10, and 20 mg/kg of body weight, caused a deterioration in learning ability, which was due to a disruption in the homeostasis of trace elements, enzymes, and neurotransmitter systems in the brain [401]. Upon intragastric administration of 1, 2, and 5 CeCl3 mg/kg of body weight for 90 days, significant accumulation of Ce in the hippocampus was observed in ICR mice, which resulted in neuritis and deterioration of spatial memory [402]. Long-term exposure of rats to LaCl3 solutions (0.25%, 0.50%, and 1.0%) in drinking water had a neurotoxic effect [403]. In a cell culture of astrocytes, concentrations of LaCl3 above 250 μM caused a dose-dependent apoptosis [404]. In experiments with low concentrations (2.5-μM LaCl3), lanthanum improved the proliferation of neural stem cells in  vitro [405]. Similarly, in in  vivo experiments,

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a single intravenous injection of 5 mg/kg LaCl3 in male Sprague-Dawley rats had a neuroprotective effect, preventing apoptosis of cells after temporary focal cerebral ischemia [406] (a model similar to that used for nanoceria studies [394]). La3+ reversibly and noncompetitively regulates neuronal α2β4 nicotinic acetylcholine receptors; the inhibition of acetylcholine response was independent of the membrane potential [407]. Intragastric administration of lanthanum acetate (3 mg/kg of body weight, once a day) was found to suppress the development of ischemia-induced neuronal damage in Wistar rats [408]. It is worth mentioning that redox inactive lanthanides (e.g., lanthanum) possess a neuroprotective action, as cerium does. These data contradict the assumption that the key mechanism of nanoceria’s neuroactivity is switching between stable valence states of cerium. Despite the fact that nanoceria protect neurons from free radical damage [398], apparently, it seems more correct to judge nanoceria not as a simple antioxidant, but as a mediator of signal transduction involved in the mechanism of neuronal death and protection [395]. In other words, the main function of nanoceria is the modulation of intracellular signaling pathways; hence, the effect should depend on the type and state of cell health [57]. The last assumption relies on the experimental data indicating that nanoceria is effective at extremely low concentrations (up to 10–20 ng/mL) and the effect varies according to bimodal law: A positive effect is observed at low doses, and a neutral or negative effect is observed at high doses. In addition, the effect of nanoceria on the living system is observed after a latent period (at least 1–2 h). It should be especially noted that ROS plays an important role in the regulation of signaling pathways, and their overinhibition also hinders normal cell functioning; this is especially relevant for nervous system cells. Thus, nanoceria in the dose range of 5–100 μg/mL after 48 h does not exhibit cytotoxicity to neural progenitor cells of C17.2 mice and dose dependently protect them from ROS, but inhibits differentiation and axonal targeting (axonal guidance signaling) [409].

8.5.4 Nanoceria and cerium ions in oncology Nanoceria is considered to be a promising drug for the treatment of tumors [410–414]. CeO2 nanoparticles exhibit cytotoxicity and an antiinvasive action against tumor cells of SCL-1 carcinoma, being less toxic to stromal cells [415]; similarly, nanoceria are toxic to cultures of human cervical cancer cells (HeLa) and nontoxic to normal fetal lung fibroblasts HFL-1 [416]. It has been shown that CeO2 nanoparticles reduce the viability of human hepatocellular carcinoma cells SMMC-7721 and cause their morphological damage and apoptosis by the mechanism of oxidative stress [417]. Alili et al. demonstrated the possibility of using cerium oxide nanoparticles to destroy human melanoma cells (A375) in vitro and for melanoma redox therapy in vivo in immunodeficient (nude) mice [418]. Nanoceria has been shown to cause the destruction of tumor cells of human melanoma due to oxidative stress and related genotoxic effects [419]. The phenomenon of selective toxicity is probably associated with the pH-dependent antioxidant properties [100,414]. Another mechanism of nanoceria selective toxicity to malignant cells may be associated with the greater sensitivity of their DNA to damage [57]—especially from the point of view of the possible restrictase-like activity of cerium (vide supra).

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Cerium oxide nanoparticles (20-nm size) at concentrations of 3.5, 10.5, and 23.3 μg/mL have exerted a prooxidant effect on A549 human lung cancer cells [420]. Xiao et al. found that nanoceria at low concentrations inhibited the migration of gastric cancer cells; at higher concentrations (10 μg/mL), CeO2 hindered proliferation of the cells [421]. DHX15 is an ATP-dependent RNA helicase, which inhibits carcinogenesis; it has been shown that nanoceria increases the expression of DHX15 and tumor suppression; thus the use of nanoceria can be a promising approach to the treatment of gastric cancer by increasing the expression of DHX15 [421]. Giri et al. demonstrated that nanocrystalline cerium oxide in vitro reduces the migration and invasion of human ovarian cancer cells SKOV3 and A2780 by SDF1, HB-EGF, VEGF165, and HGF [413]. Sack-Zschauer et al. investigated the ability of nanoceria of different sizes (4.5–188.6 nm) to inhibit cancer cells and to protect normal cells [422]. The smallest nanoparticles obtained by the “soft” method proved to be the most toxic to tumor cells but nontoxic to normal cells. It is interesting that the larger nanoceria, which underwent heat treatment, did not react with hydrogen peroxide (in contrast to the smaller ones); these are unsuitable for biomedical use. The use of cerium ionic compounds in the therapy of malignant neoplasms has a long history [70,220,338,358,423–425]. For example, it was the beginning of the 20th century when cerium iodide (Introcid brand [426]) was used to treat lymphogranulomatosis and inoperable solid tumors. Antitumor activity of cerium nitrate has been noted [427]: in concentrations exceeding 0.64 mM, cerous nitrate inhibited the growth and proliferation of HeLa, SGC-7901, B16 tumor cells, Lewis lung carcinomas, and K562 and H22 cells in vitro; in turn, the toxicity of cerium nitrate to normal FL and L929 cells was low. The antitumor activity of cerium nitrate has also been investigated in vivo [428]. It was shown that cerium nitrate inhibited the growth of the tumor through activating the immune functions of mice and promoting capabilities on antioxidation. Cerium chloride suppresses the proliferation of PAMC82 and K562 tumor cells [429,430]. The probable mechanism of its action is the decrease in the concentration of calmodulin and increased expression of some genes (p53 and p21) in tumor cells. The growth rate of melanoma cells in the presence of 1-mM Ce3+ ions (and in the presence of a number of other lanthanides) was significantly lower than in the control; cell cycle studies have shown that lanthanide ions inhibit the transition from stage G0/G1 to stage S [431]. Ce3+ (and calmodulin) has been observed to promote the proliferation of primary hepatocytes, modulate the cell cycle, and reduce the rate of apoptosis while inducing apoptosis of hepatocarcinoma cells [432]. The action of some antitumor drugs (paclitaxel) is based on the stimulation of assembly and stabilization of microtubules from the dimers of tubulin, which leads to suppression of cellular functions at the stage of mitosis and interphase of the cell cycle; it has been shown that lanthanide compounds also affect the stability of microtubules, increasing their ordering in PAMC82 cells [153,430,433]. Telomerase is a good target for the development of anticancer drugs because it is expressed in the majority of cancers, while normal human cells, including stem cells, have lower telomerase activity; another anticancer mechanism of lanthanides involves downregulation of tumor telomerase activity [434,435].

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Treatment with 2-mM CeCl3 solution selectively inhibited the proliferation of leukemic cells of NB4 and, after 72 h, caused their apoptosis [436]. Hao et al. confirmed the dose-dependent apoptosis of K562 cells induced by cerium chloride [437]. A single injection of ethylcarbamate (urethane) intraperitoneally provoked carcinogenesis in mice. The addition of light REEs to drinking water (1.0%, 0.25%, or 0.0625%) within 110 days of the introduction of a carcinogen significantly reduced the development of lung cancer (11.6% … 31.3%) and adenomas (35.7% … 58.0%) and increased the activity of natural killers (NK cells, 46% … 85%) [433]. Palizban demonstrated that the antitumor activity of cerium ions increases in the presence of certain proteins, for example, transferrin, and that REE compounds (32 mg/kg) inhibit the growth of sarcoma S180 and Lewis lung cancer in vivo by 39.87% and 36.82%, respectively [438]. REEs promote the proliferation of embryonic membrane cells (FL) and suppress human leukemia (K562) cells in vitro [439]. Cerium complex with porphyrin, which causes apoptosis of tumor cells, has been recently patented as an antitumor agent [440]. As a promising cytostatic, a coordination compound of cerium with 1,10-phenanthroline (Gl50 = 0.98 μM, TGl = 15.1 μM, and LC50 = 63.1 μM on 40 lines of malignant human cells) has been claimed [441]. The complex of Ce(IV) with mitoxantrone has been shown to possess a higher lethality to Ehrlich ascites tumor cells [442], probably due to the restrictase-like activity (see in the preceding text) of ceric ions, which enhances the binding of mitoxantrone with DNA. A significant problem in the development of antineoplastic drugs based on lanthanides is that their antiproliferative activity is manifested at high concentrations only (more than millimoles), whereas concentrations below micromoles stimulate proliferation, that is, an opposite effect takes place [338,443,444] and the same is observed for ceria nanoparticles [445]. Rubio et al. reported the protective effect of nanoceria in five human tumoral cell lines [446]; the authors concluded that the tumoral state of the cells is not a general argument to explain the antioxidant/prooxidant properties of nanoceria. In the development of drugs, selective toxicity plays an important role; in oncology, where relatively high concentrations of cytotoxic substances are used, this factor is the key one. There are many reports in the literature about the affinity of lanthanide compounds for tumors in vivo [447]. Nanoparticles of cerium oxide are of undoubted interest in oncology, since in high concentrations, they are much less toxic to normal cells than free ions. Moreover, it is easier for them to be functionalized by ligands for targeted accumulation in the tumor zone (in order to increase the active concentration above the threshold)—for example, using folate to increase tumors’ affinity [448,449]. The toxicity of Ln chelates is several orders of magnitude lower than that of inorganic compounds and complex compounds of lanthanides thus deserve much attention [424]. Preclinical studies of Ce3+ complexes and coumarin derivatives showed that most of these compounds have an antiproliferative effect on various cancer cell lines (e.g., Burkitt P3HR1 lymphoma, THP-1 myeloid leukemia, and Ehrlich ascites carcinoma). Numerous antitumor rare-earth drugs in China are mainly composed of heterocyclic compounds [450] and complexes [451]. Curiously, according to the results of surveys conducted by the Beijing Institute of Labour Hygiene and Occupational Disease, workers employed in the production of

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REE have a comparatively low incidence of cancer, the standardized mortality ratio (SMR) is 0.282 (P = 0.01) [439,452].

8.5.5 Nanoceria and cerium ions in diabetes therapy Diabetes mellitus is a metabolic disorder characterized by hyperglycemia and inadequate secretion or action of endogenous insulin. Pourkhalili et al. showed the prospects of using nanoceria (together with sodium selenite) for the treatment of diabetes in vitro and in vivo [453,454]. Dysfunction of the nervous system can have various causes: high levels of glucose and toxic by-products are the important causes of neuropathy in diabetes and are observed in 50% of patients; in diabetic neuropathy, nanoceria have been found to improve histopathology and reduce morphological disorders of neurons in the spinal ganglion of rats [455]. Type 1 diabetes is usually caused by the destruction of pancreatic endocrine cells; the toxic effect of the insecticide diazinon on mammals is primarily due to the destruction of the pancreas; the possibility of protecting rats in vivo from the action of diazinon with nanoceria was studied by Khaksar et al. [456]. As a result of nanoceria action, hyperglycemia caused by diazinon was eliminated; insulin, proinsulin, C-peptide, and ATP/ADP levels were improved; caspase-3 and caspase-9 activities were restored; pancreatic islet apoptosis was reduced; and biomarkers of oxidative stress were reduced. Khurana et al. [457] studied the effects of nanoceria in streptozotocin-induced type 1 diabetes. It was shown that nanoceria treatment significantly reduced glucose levels and diabetogenesis to 50% at 0.2 mg/kg and 37.5% at 2.0 mg/kg doses in Swiss mice. Obtained data established the antidiabetic potential of nanoceria, which may become a novel strategy to combat type 1 diabetes. Type 2 diabetes is the most common form of diabetes, which is associated with elevated serum Cu2+ levels, hyperglycemia-induced oxidative stress, and β-cell ­apoptosis. Zhai et al. found that nanoceria can inhibit Cu2+/H2O2-evoked hydroxyl radicals and the oxidative stress of β-cells [458]. Ceria nanocubes with two different sizes (5 and 25 nm) were used as an antioxidant for controlling oxidative stress-induced pancreatic β-cell damage [459]. Nanoceria with a smaller particle size demonstrated stronger antioxidant and antiapoptotic effects. Vafaei-Pour et al. studied nanoceria for amelioration of diabetic embryopathy in streptozotocin-induced gestational diabetes [460]. It was found that diabetes acted as a teratogen agent for fetal development, and nanoceria treatment significantly inhibited embryonic oxidative stress and pathologic changes in diabetic female mice. Eighty years ago, Fischler and Roeckl noted that intravenous injection of REE salts (chlorides, acetates, and nitrates) caused a reversible decrease in sugar in the blood, which was associated with enzymatic processes in the liver [461]. Schurig et al. showed that the effect of light lanthanide salts on gluconeogenesis was manifested in a decrease in the activity of pyruvate carboxylase and phosphoenolpyruvate carboxylase, whereas only a slight effect was observed on glucose-6-phosphatase and fructose-1,6-diphosphatase [462]. Oberdisse et al. confirmed that REEs were able to inhibit the synthesis of these two key enzymes of liver gluconeogenesis, did not affect renal gluconeogenesis, and increased the concentration of insulin in the blood [463]. Lanthanides have been shown to stimulate insulin secretion in β-cells of the

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­pancreatic Langerhans islets [464] and improve its adsorption [465]. The inhalation route of insulin administration has an advantage over oral administration but is inferior to injection efficacy, and lanthanides can be used to solve the problem of noninvasive methods of diabetes therapy, as they improve the transmembrane transfer of insulin macromolecules [466]. Ln3+ interacts directly with insulin, changing its conformation and aggregation. Depending on the concentration, lanthanides bind to the monomer (Ins) and reversibly replace zinc in the hexamer (Ins)6-2Zn2+ [465], thus modulating hypoglycemic activity. Fox proposed the use of cerium compounds with derivatives of sulfonylurea (­glyburide and tolbutamide) as an oral hypoglycemic agent for reducing blood sugar in the treatment of diabetes [467]. Glipizide—another oral hypoglycemic agent of the sulfonylurea group—has been found to stimulate insulin secretion by β-cells of the pancreas and increase the release of insulin. In order to create an oral agent for the treatment of a new generation of diabetes medicines, Prakash et al. synthesized and examined the glipizide complex of cerium [468].

8.5.6 Nanoceria and cerium ions in other biomedical applications Lung et al. found that cerium oxide nanoparticles reduced the development of atherosclerosis in apolipoprotein E-deficient mice grown on a high-fat diet [469]. Nikolov et al. showed that lanthanum carbonate significantly reduced the calcification of blood vessels and the risk of developing arteriosclerosis, in the same mice [470]. Lanthanum salts (chloride and acetate) have been seen to prevent the calcification of rat calcifying vascular cells (CVCs) by hydrogen peroxide in vitro [471] and vascular calcification in rats by nicotine + vitamin D in vivo [472]. It is known that drugs that inhibit the calcium mineralization of the lumen in the arteries suppress atherogenesis. Oral lanthanum chloride administration has been found to significantly and dose dependently reduce the development of atherosclerosis in rabbits under conditions of artificial hypercholesterolemia [220,473]; “LaCl3-treated rabbits exhibited histologically less severe coronary artery and mitral valve atherosclerosis” [474]. Previously, the ability of lanthanides to reduce the development of atherosclerosis was associated mainly with anticoagulant and antiatherosclerotic activity (but these applications were accompanied by some side effects [458]). The ability of cerium to prevent the coagulation of blood was found long ago. Thus it was shown that lanthanides (including cerium), in a dose-dependent manner, increase the clotting time of normal human plasma when clotting is induced either by thromboplastin or kaolin in the presence of cephalin and Са2+ [475]. Cerium salt of p-­aminobenzenesulfonic acid was developed for human antithrombotic use [51,363]. Former commercial ­lanthanide-based anticoagulants Helodym 88 or Thrombodym (salts of acetylpropionic or sulfo-isonicotinic acids) are able to inhibit the gross increase of vascular permeability caused by inflammatory agents [363]. Lanthanides have an inhibiting effect on platelet aggregation and prolong the coagulation time of plasma enriched with platelets, which is caused by the activated factor X. Amidolytic activity of activated factor X and thrombin has been shown to decrease dose dependently with an increasing concentration of lanthanides. These results

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s­uggest that REEs exhibit an anticoagulant effect by mechanisms that partially inhibit the enzymatic activity of both activated factor X and thrombin [476]. Hara et al. showed that lanthanides inhibit blood coagulation in vitro by acting on prothrombin in the blood and inhibiting its activation into thrombin and in vivo by the inhibition of prothrombin production in the liver cells [477]. In rats treated orally with 0.2–20.0 mg/kg of body weight/day of CeCl3, an increase in both hemoglobin in erythrocytes and oxygen affinity of hemoglobin was observed. Deconvolution of FTIR spectra indicated that the secondary structure of hemoglobin significantly changed: depending on the dose and duration of cerium intake, the content of α-helix decreased. The change in affinity to oxygen was attributed to the binding of Ce(III) to hemoglobin and interaction with 2,3-diphosphoglyceric acid (2,3-DPG) in erythrocytes. Conformational changes in hemoglobin and hydrolysis of 2,3-DPG, respectively, as well as a partial conversion from heme-Fe(II) to heme-Fe(III), occurred in this case [478]. Obviously, cerium compounds could be used for angioplasty, for example, ceria-coating of stents for vascular prosthetics (or the introduction of REE in the composition of the stent itself as a mischmetal). Nanoceria is promising for the treatment of eye diseases caused by intracellular ROS and oxidative stress [399]. Cerium ions (chloride) loaded into mesoporous silica nanoparticles protect human epithelial cells from oxidative stress too [479] and demonstrate good results in preventing the development of diabetic cataracts [480]. It was shown by Rzigalinski et al. that the use of nanoceria as a food supplement leads to an increase in the life span of the fruit fly Drosophila [299]. Previously, Xiaoyong et al. studied the effect of cerium chloride oral administration on the life span of the fruit fly and silkworm [481]. Similarly, it was shown that CeCl3 increased the life expectancy of female fruit flies in a concentration of 133 mg/L and male fruit flies in a concentration of 266 mg/L (P < .05). Cerium ions in 4, 8, 16 mg/L concentrations increased the life span of the silkworm, and, in 16 and 32 mg/L concentrations, increased the weight of the cocoon (P < .05) [481]. In a certain concentration range, Ce(IV) sulfate, along with nanoceria, has been shown to protect fruit flies from oxidative stress, including that caused by hexavalent chromium salts [482]. Wang investigated the effect of Ce(IV) on the development of D. melanogaster, wherein various concentrations of Ce(SO4)2 were added to the culture medium and the activities of SOD and catalase were analyzed in third-stage larvae [482]. It was found that in the cerium (IV) sulfate concentration range of 1–16 mg/L, the activity of antioxidant enzymes increased significantly in comparison with the control but decreased in the concentration range of 64–1024 mg/L. Huang et al. showed that the Ce(IV) salt caused oxidative stress in the fruit fly in the entire range of concentrations studied (1, 4, 16, 64, 256, and 1024 mg/L of ceric sulfate) [482]. Males and females of different species (even classes) of animals have different sensitivity to cerium compounds, females being more sensitive to the toxic effect of lanthanides [481]. This pattern has been demonstrated both for cerium ions (rats, [485,486]) and for nanoceria (mice, [151]). Bruce noted that for female rats, the tolerant concentration of cerium species was of an order of magnitude that was smaller than for males [485]. Because of the significant gender difference in sensitivity to cerium compounds, the sex of the experimental animals should be taken into account and registered in all studies.

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8.5.7 Nanoceria, cerium ions, and radiation Nanoceria can modulate the effect of radiation on biological objects [487,488]: nanoceria generally protects living beings from UV irradiation, while the influence on the biological effects of ionizing radiation is ambiguous. The protective effect of nanoceria has been shown in vitro on ultraviolet [489–491] and X-ray [492,493] irradiation, as well as in vivo on ionizing radiation [487,494–496]. A number of papers on radiotherapy have shown the ability of nanoceria to enhance the destruction of tumors under the action of X-ray radiation [497–499]. It is obvious that in the first case, cerium compounds (including nanoceria) interact with the products of radiolysis of water and biological molecules, eliminating ROS, and in the latter case, they directly interact with radiation, generating ROS and Auger electrons. The ability of cerium compounds to sensitize or to protect from radiation depends on the following: ●

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●

●

●

●

●

the type of radiation the nature of the biological object the microenvironment (pH/oxygenation of the medium) the nature of the cerium compounds (including anions and ligands) their concentration the valence state of cerium in the compound the catalytic activity of cerium species (especially important for nanoparticles).

The main mechanisms of the action of radiation on the cell and the possible functions of cerium compounds are shown in Fig. 8.10. 1. Radiation directly destroys biological objects and damages DNA; irreparable DNA damage causes cell death via necrosis/apoptosis. 2. Radiation initiates the formation of ROS and free radicals that cause secondary (or ­oxidative) damage to cellular DNA. 3. Cerium species shield the biological object physically from radiation due to absorption and/or scattering, with safe dissipation of the energy of radiation taking place. 4. Cerium species neutralize the toxic factors arising from the interaction of radiation with matter (ROS, free radicals, etc.)—for example, the products of water photolysis (radiolysis). 5. Cerium species enhance the destructive effect of radiation due to the fact that they can transfer radiation energy to other toxic species (ROS, Auger electrons, etc.). 6. Cerium species reduce the resistance of cells to the destructive effect of radiation. 7. Cerium species are directly (or through cellular mechanisms) involved in the restoration of damaged biological objects (e.g., involved in DNA repair), increase cell proliferation, reduce the level of inflammatory cytokines, reduce apoptosis, etc.

The protection of living cells by cerium compounds from ROS and free radicals produced by UV, X-ray, or gamma radiation does not fundamentally differ from the previously described defense mechanisms from ROS formed in other processes (4). The restoration of biologically significant molecules, and regeneration/reparation using cerium compounds (including nanoceria) are similar in most cases (7). The inhibition of oncogenesis with cerium compounds (8) is also independent of irradiation. The main difference lies in the interaction of radiation with different cerium compounds (3, 5).

320 Cerium Oxide (CeO2): Synthesis, Properties and Applications

Fig. 8.10  NanoCeO2 effects on interaction between irradiation and cellular DNA.

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Tetravalent cerium ions in the near UV range have an extinction about an order of magnitude greater than the extinction of Ce3+ ions. For most compounds of tetravalent cerium, the value of the molar extinction coefficient is about ~5000 M−1 cm−1, depending on the anion and on the medium. For example, the molar extinction coefficient of 2–6-nm ceria nanoparticles is about 4000 M−1 cm−1, and the molar extinction coefficient for cerium (IV) sulfate solutions is 5580 M−1 cm−1 [500]; Ce4+ ions in glasses have a molar extinction coefficient of 3500–6000 M−1 cm−1 [501]). The molar extinction of organic UV filters is much higher, in some cases by an order of magnitude. With increasing size and crystallinity of nanoceria, screening ability increases due to light scattering, but the ability to damage organic compounds and biological objects due to photocatalytic properties and phototoxicity also increases. Thus the extinction coefficient and shielding ability for nanoceria and cerium (IV) ions are nearly the same, while water-soluble salts are one order of magnitude more toxic. Thus the use of stable complex compounds of tetravalent cerium may be promising, for example, those containing ligands, which are already used as UV filters (acetylacetonates, cinnamates, salicylates, etc.), because a mixture of UV filters is more effective and a mixture of organic and inorganic filters should be generally preferred [502]. Some cerium compounds possess photocatalytic properties, primarily solid semiconductors (including cerium oxide). To a lesser extent, this applies to ions. Thus, in the photodegradation reaction of the Orange-II dye, Ce3+ ions exhibit activity over the whole pH range, and Ce4+ ions are inactive in neutral and alkaline solutions, at pH values higher than 5.6 [503] (see Fig. 8.11). At pH values <5.6, tetravalent cerium ions can be reduced to more photoactive Ce3+ [503]. At the nanoscale, the photocatalytic properties (i.e., the ability to oxidize organic compounds under irradiation) of nanoceria increase with increasing particle size [489]. Despite the fact that nanoceria heat treatment reduces specific surface area (increases the particle size), the rate of ceria-assisted photodegradation of the organic dyes increases: the rate of methylene blue photodecomposition before ceria annealing was 0.00636 min−1, while heat treatment at 400°C, 600°C, and 800°C increased the rate to 0.00719 min−1, 0.00855 min−1, and 0.00939 min−1, respectively [504]. Similar results were reported for the photodegradation of methyl orange dye by nanoparticles of different sizes, obtained under different annealing conditions (see Fig. 8.12) [489]. Fig. 8.12 also shows the rate of photodegradation of the dye in the absence of cerium compounds, making it clear that in a certain size range, nanoceria protects the organic molecules, while in the other, it accelerates the decomposition process. Nanoceria doping with other trivalent lanthanides (Sm, Gd) also increases the rate of photodecomposition of the methylene blue dye [505]. These data can be useful when choosing nanoceria for certain applications. For example, under UV irradiation, PVP-stabilized nanoparticles of cerium oxide exhibit different photocytotoxicity relative to normal and malignant cells (the latter are more sensitive), which can be used for tumor therapy [506]. This effect is probably due to the decrease in the pH value of cancer cells. It is well known that for the microenvironment of many malignant cells in the tumor zone, the pH <7 (in contrast to normal cells, where pH ≥7)—this fact is usually taken into account when explaining the mechanisms of selective toxicity of nanoceria [414].

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Fig. 8.11  Effect of pH on the photocatalytic activity of cerium ions [503]. Reprinted with permission from Q. Cheng, S.H.I. Wei, D.U.A.N. Lian, S.U.N. Binzhe, L.I. Xiaoxia, and X.U. Aihua, A comparison between Ce(III) and Ce(IV) ions in photocatalytic degradation of organic pollutants. J. Rare Earths 33(3) (2015) 249–254, Copyright 2015 Elsiever.

Fig. 8.12  The effect of annealing temperature and particle size on the photocatalytic activity of ceria nanoparticles [489]. Data adapted from N.M. Zholobak, V.K. Ivanov, A.B. Shcherbakov, A. S. Shaporev, O.S. Polezhaeva, A.Y. Baranchikov, … and Y.D. Tretyakov, UV-shielding property, photocatalytic activity and photocytotoxicity of ceria colloid solutions. J. Photochem. Photobiol. B Biol. 102(1) (2011) 32–38.

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For trivalent cerium ions, the ability to radiosensitize tumors is also observed both in vitro and in vivo. Hao et al. showed that cerium (III) chloride enhances the damaging effect of gamma irradiation [507]. Additionally, in the acidic microenvironment of the tumor, tetravalent cerium is more readily reduced to trivalent; the latter possesses enhanced photo- [503] and radiolytic [507] activity and is able to damage DNA and to promote lipid peroxidation [193]. Floersheim et al. showed in vivo that in low concentrations, cerium (III) nitrate reduced postradiation mortality, while at high concentrations enhanced it [508]. In the radiation treatment of tumors, nanoceria behaves similarly, providing sensitization of malignant cells to radiation and simultaneously protecting normal stromal cells [498]. Synergy in the combined use of radiation and nanoceria for tumor therapy has also been investigated [499,509] and patented [510]. Treatment with nanoceria before radiotherapy markedly enhances apoptosis of cancer cells and also increases the inhibition of pancreatic tumor growth, without damaging normal tissues [499]. In the example of radiation-resistant cells of gliosarcoma 9 L, it has been shown that cerium oxide nanoparticles protect cells and increase their survival under high-energy X-ray radiation [511]. In turn, low-energy X-ray radiation not only generates ROS but also interacts with CeO2, forming a flux of Auger electrons decreasing the viability of the cells; in this case, nanoceria acts as a radiosensitizer. It should be noted that the radioprotective concentrations of nanoceria in vivo are very low in most cases (e.g., 15 nM [512] or 200 nM [495] intraperitoneal injections in mice); such quantities of nanoparticles obviously cannot protect biological tissue from X-ray or gamma radiation via the simple mechanical shielding. The interaction between radiation and matter depends on such characteristics of the substance as its density, atomic number, and average ionization potential. The density of a CeO2 nanoparticle is considerably higher than the density of biological media containing dissolved cerium ions. The larger ceria nanoparticles can generate more free radicals and Auger electrons under the action of ionizing radiation; for hydrated cerium ions in low-concentration aqueous solutions, this effect is almost negligible; therefore, the protective effect prevails.

8.6 Toxicity of nanoceria and cerium ions Cerium salts are generally more toxic than CeO2 nanoparticles (vide supra). The interaction of trivalent cerium ions with hydrogen peroxide can proceed according to the Fenton mechanism, to form hydroxyl radicals [107,113]. Toxicity of water-soluble Ce(IV) compounds is associated mainly with the high redox potential of tetravalent cerium ions and their ability to oxidize biological molecules. Thus the standard electrode potential of the Ce4+/Ce3+ pair (+1.72 V, 1 M HClO4) is much higher than the oxidation potential of most organic compounds (e.g., for DMEM growth medium, this value ranges from −0.38 to +0.34 V [513]). However, for both nanoceria and cerium water-soluble salts, the redox potential depends on the pH: in neutral (and especially in alkaline) media, the oxidizing properties do not appear. In addition, the redox potential of cerium salts depends strongly on the ligand and can differ by several volts [514].

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Studies of the absorption of coarse-grained and nanosized CeO2, as well as free cerium ions, have shown that endocytosis is the main mechanism of cerium uptake in plants [515] and in animals (clathrin-mediated and caveolar ones) [516,517]. The biological barriers of plants are probably less prone to nanoparticle translocation than mammalian ones [518]. The transfer of ions of tetravalent cerium into the cell is possible with the help of transport proteins of the transferrin family, while the ions of lanthanides themselves are unable to penetrate cell membranes [358]. It is believed that transferrin in vivo cannot be the lanthanide transporter, since its affinity to Fe3+ is greater than to Ln3+ [70], but not to Ce4+. Thus, in their studies, Baker et al. [519] showed that Ce4+ ions replaced Fe3+ ions in lactoferrin, while Ce3+ was more readily oxidized to Ce4+ in the lactoferrin [520]. Fig.  8.13 shows the structure of this lactoferrin. Similarly, in the case of transferrin, the calculated stability constant of the complex with the Ce4+ ion is close to the value for iron (log K ≈ 21), while the stability constant of the similar complex Ce3+ is significantly less [521]. For transferrin and nanoceria, the probable pathway of cerium migration is shown in the diagram (Fig. 8.14). Transport protein captures cerium ions and is absorbed by the cell through receptor-mediated endocytosis. In endosomes, due to the reduced pH, the cerium ions are detached from the transferrin and are released into the cytoplasm, and the transport protein returns to the intercellular media. The complex of cerium ions with transferrin can play an important role in cytotoxicity. It is well known that low pH of the medium facilitates the prooxidant properties

Fig. 8.13  The structure of cerium-containing lactoferrin (protein databank code: 1FCK).

Fig. 8.14  Cellular uptake of ceric ions via transferrin-mediated pathway.

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of Ce4+ ions [7], which could be important, for example, in oncology [414]: thus transferrin increases the toxicity of ceric ions in the gastric adenocarcinoma cell system [522,523] or breast cancer cells MCF-7 [524]. Upon intravenous administration of cerium chloride, LD50 in mice is ~13 mg/kg [525], LD50 in rats is 50–60 mg/kg [526], and LD50 in rabbits is 35 mg/kg [527]. In turn, the dose of 100 mg/kg of CeO2 nanoparticles of 5-, 15-, 30-, or 55-nm size is well tolerated [528]. Upon intraperitoneal administration of cerium chloride, LD50 in mice is 352.34 ± 30.38 mg/kg, and LD50 in guinea pigs is 109.66 ± 17.58 mg/kg [529]. Bruce et al. investigated the acute toxicity of lanthanide compounds, including cerium nitrate and CeO2 [485]. LD50 of cerium nitrate in female rats orally is 4200 mg/kg, LD50 of cerium nitrate in female rats intraperitoneally is 290 mg/kg, LD50 of cerium nitrate in female mice orally is 4200 mg/kg, and LD50 of cerium nitrate in female mice intraperitoneally is 470 mg/kg. For adult female rats, LD50 of cerium nitrate intravenously is 4.3 mg/kg; for adult male rats, LD50 of cerium nitrate intravenously is 49.6 mg/kg. It was noticed that for females, the tolerant concentration of cerium salts was of an order of magnitude smaller than for males. In comparison with cerium ions, cerium oxide (including at a nanoscale) was much less toxic. Cerium oxide did not cause death in female rats at doses of >1000 mg/kg in either mode of administration. Upon oral administration, cerium oxide nanoparticles in the doses studied (up to 2000 mg/kg) did not cause toxic effects in Wistar rats [530]. LD50 of bulk cerium oxide (CAS 1306-38-3) in rats orally is 5000 mg/kg, LD50 of bulk cerium oxide in rats dermally is 1000–2000 mg/kg, and LD50 of bulk cerium oxide upon inhalation of dust is 5.05 mg/L [531]. As a rule, the toxicity of condensed matter in the form of nanoparticles is much higher than that of a coarse crystal; the toxicity of nanomaterials is observed even when the corresponding bulk material is comparatively safe for living organisms [532]. This trend was reported for gold, platinum, graphite, titanium oxide, and silicon. As the particle size of the coarse-grained cerium oxide is reduced down to the nanometer range, its toxicity also increases at first [533]; see Fig.  8.15, Section C, [151]. Unexpectedly, with a further decrease in size, the toxicity of ceria paradoxically decreases (see Fig. 8.15, Section B), until an ionic solution forms at which point the toxicity rises sharply (see Fig. 8.15, Section A). As shown earlier, an increase in the size of nanoparticles of nanoceria leads to a decrease in their solubility, according to Ostwald’s exponential law. Since cerium ions are more toxic, an increase in size should be accompanied by a reduction in toxicity throughout the nanometer range. Generally, as the temperature of synthesis of nanoparticles increases, the amount of hydroxide groups and defects on the surface decreases, which also leads to a decrease in solubility, so toxicity should also decrease. However, the toxicity of nanoceria follows the opposite trend [8]. Previously, it was assumed that with a decrease in the size of ceria nanoparticles, their nonstoichiometry and, accordingly, the Ce3+ fraction in their composition increase, which increases the antioxidant properties of nanoparticles. This approach could provide a formal explanation for the reduction in toxicity with a decrease in the size of nanoceria (see Fig. 8.15, Section “B”). This hypothesis is one of the reasons for the conclusion drawn by Reed et al. about the preferred size of particles for biomedical applications

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Fig. 8.15  Schematic dependence of nano-ceria toxicity on particle size.

(2–3 nm) [8]. However, recent studies have unambiguously demonstrated that the stoichiometry of ceria particles does not depend on their size; moreover, in the absence of external reductants under normal conditions in an oxygen atmosphere, nanoceria of any particle size does not contain Ce3+ ions [39], and the hydroxylation of the surface also does not lead to the reduction of Ce4+ ions [10]. The annealing of CeO2 nanoparticles at high temperatures increases their crystallinity and reduces the number of defects, while the number of active forms of oxygen (in particular, superoxide [534]) on the surface increases [535] and, accordingly, prooxidant activity increases. This explains the observed directly proportional relationship between the annealing temperature and the toxicity of nanoceria [2]. According to Karakoti et al. [536], the temperature of ceria nanoparticles’ synthesis determines their behavior in biological systems, including toxicity. In the nanometer range, the photocatalytic properties also increase with increasing particle size [489]. The homeostatic system of a living being could transform CeO2 nanoparticles via the dissolution-condensation process, to decrease their size and toxicity. Intravenous administration of nanoceria causes early prooxidant effects in the Sprague-Dawley rat brain, followed by a transition to oxidative stress and then, unexpectedly, reverts back to a no stress state after 90 days [48]. Large ceria nanoparticles (cubes with [100] crystal faces and a size of 31 ± 4 nm) have been shown to undergo a size transformation inside the liver, as demonstrated by the formation of very small 1–3-nm nanoceria having antioxidant properties. Nanoceria pharmacokinetics is quite different from those of the cerium ion [537]. Generally, any kind of nanoparticle possesses two kinds of toxicity: nonspecific and specific. The first does not depend on the properties of the particle material and is related to the protective reaction of the biological system to an external (mechanical) stimulus. When nanoparticles are introduced into a culture, they interact with membranes, activate endocytosis, and induce oxidative stress, which determines nonspecific toxicity in vitro [538,539]. When introduced into the body, nanoparticles interact with a mononuclear phagocytic system and cause an inflammatory response in vivo.

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The nonspecific toxicity of nano- and microparticles is used, for example, in the development of vaccine adjuvants to enhance immune response [540]. In other words, cerium oxide nanoparticles as abiotic foreign bodies have also been shown to possess toxicity. For example, nanoparticles of biologically neutral latex [107] or silica [541] have been shown to induce ROS formation in the cell culture. The same silica nanoparticles, when administered to mice at 50 mg/kg intraperitoneally, have been seen to activate peritoneal macrophages, which cause an inflammatory response, leading to an increase in the level of IL-1, TNF-α, and nitric oxide in the blood. Obviously, cerium oxide nanoparticles cause the same nonspecific response, while ROS formation and inflammatory processes are partially excluded, due to the specific properties of cerium species. When ceria nanoparticles additionally possess catalytic (prooxidant) properties or release insufficient ions to compensate for inflammation, the toxic properties predominate. Moreover, too intense a release of cerium ions also intensifies toxicity. Due to their high biological activity and reactivity, when injected at adequate (low) concentrations, cerium ions often do not reach the targeted zones, but with increasing concentration, they are retained along the whole transport chain, are accumulated, and cause side effects (primarily toxic ones). Thus cerium oxide nanoparticles can be judged as a very effective carrier of the specific medication: cerium ions.

8.7 Executive summary ●

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Cerium oxide nanoparticles (nanoceria) predominantly catalyze oxidation reactions. The catalytic activity of nanoceria causes oxidative stress and is the major source of their toxicity. Annealed, well-crystallized ceria particles in the size range of 10–60 nm cause enhanced oxidative stress and have the highest toxicity among other nanoceria preparations. Both nanoceria and cerium ions possess oxidoreductase-like and phosphatase-like properties. Favorable biological effects of nanoceria and cerium ions are mostly identical. Favorable biological activity of cerium ions is observed in the low-concentration range, at the solubility level of nanoceria. Cerium ions are responsible for the biological activity of nanoceria, including cerium ions on the surface of nanoparticles. Many lanthanides have a similar effect on living beings, while due to the properties of the tetravalent cerium ion in oxide/hydroxide compounds, it is most suitable for biomedical applications. Cerium has a number of unique properties associated with the stable state of Ce(IV): redox activity, small ionic radius, and high charge density. Soluble cerium salts have a relatively high toxicity. Upon intravenous administration, soluble ionic cerium species are an order of magnitude more toxic than nanoceria [542]. Trivalent cerium ions are able to participate in the Fenton reaction; reduced nanoceria with a high Ce3+ content can participate in the Fenton reaction too. Tetravalent cerium ions can cause direct oxidation (especially in an acidic media), which also depends on the ligands and on the environment; nanoceria in an acidic media possesses oxidative properties (oxidase- and peroxidase-like). In high concentrations, cerium ions inactivate enzymes and inhibit biologically active molecules; in the corresponding (low) concentrations, cerium ions can enhance activity of some enzymes.

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There is a recently discovered group of lanthanide-dependent natural enzymes. The lanthanide-dependent enzymes are mainly found in microorganisms. Very low amounts of lanthanides are sufficient to suppress the usual enzymatic metabolism of microorganisms and to activate lanthanide-dependent one (so-called REE switch [280]). Cerium species can affect the biology of plants and animals indirectly through commensal microbiota (symbiotic microorganisms). In many animal species, males are more tolerant to cerium, so higher cerium concentrations are required for therapy. In males, the toxicity threshold is also higher than in females. Coordination Ce4+ compounds have, as yet, been little investigated [543]. Until new preparations of Ce4+ (nanoparticles, polymers, complexes, MOFs, polyoxometallates, etc.) are proposed for biomedical applications, cerium oxide nanoparticles remain the best choice. For biomedical purposes, it is better to use fine (<10 nm) hydrated CeO2 nanoparticles obtained using “soft” methods from aqueous solutions. The toxicity of nanoceria depends on localization within the cell, which in turn depends on the nanoceria surface charge [544]. As a rule, positively charged particles are more toxic. Nanoceria is an ideal carrier for drug delivery [366], including the following: drug carrier and inhibitor of ROS formation in ophthalmology; drug carrier and promoter of ROS formation in oncology; carrier of drugs, genes, and analogue of restriction enzymes in gene therapy; carrier of drugs and modulator of signal transduction in neurology; drug carrier and adjuvant in immunology and antiviral therapy; prebiotic for the intestinal microflora and an oral immunomodulator. ●

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