Involvement of Lanthanides in the Free Radicals Homeostasis

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Current Topics in Medicinal Chemistry, 2014, 14, 000-000 1

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Involvement of Lanthanides in the Free Radicals Homeostasis

Maria Valcheva-Traykova1, Luciano Saso

2 and Irena Kostova

3,*

1Department of Pharmacology and Toxicology, Medical Faculty, Medical University of Sofia,2 Zdrave St,

Sofia 1431, Bulgaria; 2Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza

University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy; 3,*

Department of Chemistry, Faculty of

Pharmacy, Medical University, 2 Dunav St., Sofia 1000, Bulgaria

Abstract: Lanthanides are group of rare-earth elements with growing applications both in the industry and

healthcare. Their unique properties impose various possibilities for involvement in electron transfer reac-

tions essential for the cellular survival and health on general. The intensified contact of people with lantha-

nides and the expanding medicinal applications of their compounds insist more profound knowledge on the involvement

in biologically relevant electron transfer reactions. It is well known that the balance between formation and elimination of

free radicals in a living body is essential for its health and survival. Any internal or environmental factor that alters this

balance alters the homeostasis and this way altering the health status. In the present review, the possibilities of changing

the balance between formation and elimination of free radicals, due to introduction of different lanthanides and their com-

plexes with organic ligands, were explored, based on the available information in the literature. It was observed that lan-

thanides may act either as antioxidants or pro-oxidants, depending on the environment, the nature of the bonding in their

compounds, and concentration in the tissues. The opportunities for their application in medicine were related with the

abilities to control over their involvement in the overall oxidative status of the body.

Keywords: Antioxidants, complexes, electron transfer reactions, free radicals, lanthanides, pro-oxidants.

1. INTRODUCTION

The ability to maintain a healthy balance between forma-

tion and elimination of free radicals is essential for the sur-

vival and wellbeing of a living system. Any internal or envi-ronmental factor that alters the free radicals homeostasis has

an impact on the control over normal or pathological proc-

esses in the body. Introduction of active substances with po-tential to change the level of the free radicals may influence

biologically relevant electron transfer reactions. The lantha-

nides (Ln) are rare-earth elements with growing industrial and medicinal applications. As a result of this, living bio-

logical systems (plants, animals, humans) are in contact

more frequently with these elements. The variable valent states and coordination numbers of lanthanides, along with

the similar ionic radii with those of ions being essential for

the living body, all this determines the involvement of the rare-earth elements in various biologically relevant chemical

reactions.

The medicinal applications of the lanthanides resumed and intensified the research on their chemistry and biocom-patibility. The extensive exploration of possible applications of lanthanides as anti-inflammatory, anti-viral and anticancer agents defines the necessity of detailed investigation on their involvement in the homeostasis. A possible involvement in the balance between formation and elimination of free

*Address correspondence to this author at the Department of Chemistry,

Faculty of Pharmacy, Medical University, 2 Dunav St., Sofia 1000, Bul-

garia; Tel: 359 2 92 36 569; Fax: 359 2 987 987 4;

E-mail: [email protected]

radicals in living systems may determine the action of lantha-nides as in vivo antioxidants or pro-oxidants. The information on this matter is essential for determining the boundaries of their medicinal applications. In the last Lately a great atten-tion was paid to the chemical properties of lanthanides com-plexes in aqueous solutions. The Lanthanides' complexes are promising anticancer agents. The instability, strong oxophilic-ity, the very fast exchange reaction, the variability of their coordinative number, and the non-directionality of their coor-dination, altogether lead to the bioactivity of lanthanide com-plexes. The oxophilicity of Ln is in the base of their involve-ment in the free radicals homeostasis of a living body. As far as by scavenging free radicals Ln produce nontoxic com-pounds with completed electron pairs lanthanides may act as in vivo antioxidants. But the same oxophilicity is at least in part responsible for the competitive biding of Ln to proteins, which alters various biologically relevant electron transfer pathways and results in toxicity. Evidently, the medicinal application of Lanthanides requires that the antioxidant activ-ity prevails the toxic effects.

2. LANTHANIDES - GENERAL INFORMATION

2.1. Structure of the Electron Shells

Unlike all other elements (except actinides), lanthanides are arranged in a row instead of column, forming a group. The chemistry of individual element in the row is very simi-lar to this of the other members in this row, similar to ele-ment in the same column in the periodic table. The lantha-nides possess partially filled f orbital, which is responsible for the uniformity in their oxidation states.

2 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 Valcheva-Traykova et al.

Almost all lanthanides exist in the +3 oxidation state, be-cause they easily lose two s electrons and one d electron.

The occupied f electron orbitals are deeply situated in the electrons shell and unutilized for bonding, and therefore hardly affected by ligands. The three-valent lanthanide cations exhibit a-class (hard acid) properties and preference for O-donor ligands. Although Lanthanides prefer chelated

ligands, some of them may be attached to the central Ln ion.

Lanthanide metals commonly form 6 to 12 coordinate complexes, but many 8 and 9 coordinate compounds are formed too. The coordination bonding is primarily of ionic origin. The complexes undergo rapid ligand exchange. An-other important trait is the lanthanide contraction. Lantha-nides are relatively rare compared to other elements. The limited data available show that the variety in number of 4f electrons results in various biological effects.

2.2. Abundance of the Lanthanides

In the nature the lanthanides may be found as phosphates, carbonates, fluorides and silicates. Trivalent ions may move from the minerals in the underground water at low pH. Many lanthanum compounds are part of the environmental pollu-tion due to human activities: coal and uranium mining (espe-cially using solvents), ceramic and cement industry, refine-ment of oils and gasoline, NMR imaging in medicine, mass production of phosphate fertilizers, air pollutants in urban areas, disposal of electronic parts, etc. [1, 2]. Lanthanides' cations are absorbed by halloysite, kaoline and other clay minerals, from where they are easily released. The lantha-nides' cations in the water are accumulated in the bodies of aquatic life forms and in the plants living on the ground. This way the lanthanides penetrate the food chain and are digested from the humans with the food and water.

2.3. Biological Activities of the Lanthanides

In general, the biological activities of Ln may be related with the similarities of their ion radii and coordination num-bers with these of other essential for the cell survival ele-ments, such as Ca, Mn, Mg, Fe and Zn, the variability of the Ln ionic charges, as well as the ability of Ln ions to make stable complexes with organic molecules. [3]. The main bio-logical activities, as described in [1, 3] are illustrated in Fig. (1). They may affect the living body directly and indirectly. The chemical interactions of Ln with biologically active molecules may result in altered enzymatic activities, substi-tution of essential metal ions from their ion-binding proteins, polymerization of macromolecules. Their chelation with ion binding sites of proteins and ion channels may alter the spe-cific permeability of the cellular membranes, resulting in shortage or excess of ions in the intracellular and extracellu-lar voids. The lanthanide ions may interfere with the immune defense, with the function of the liver, spleen, brain, heart and blood vessels.

These activities may modify great variety of biologically active molecules, resulting in alteration of many processes involved in the cellular homeostasis and survival [1, 3, 4].

2.4. Toxicology

The extended use of lanthanides in the industry, healthcare and farming, as well as the environmental pollu-

tion intensified the contacts of humans with lanthanides in the last 15 years. The exposure of living biological systems with lanthanides cations and aerosol particles are inevitable in urban areas and industrial regions today. The ever expand-ing practical application of lanthanides and their potential as medicines or environmental pollutants lead to the extensive investigation of their toxicity [1, 2]. If administered through the food chain and for a short time, all lanthanides were con-sidered as low toxic [5, 6] especially if digested with mate-rial that has low water solubility.

Fig. (1). Main biological activities of lanthanides in a living body.

The oral toxicity of lanthanide oxides is as low as this of the table salt [6]. Because of this low toxicity Lanthanides have been used as markers in nutritional studies. The patho-genic potential of lanthanides dusts is mild, compared with this of the fibrogenic powders such as quartz and silica [7, 8]. The poor absorption by the digestive system was not enough to prevent the penetration of small amounts of lanthanides into the blood stream and the prolonged exposure resulted in slow and steady accumulation of these elements in the living body. Lanthanides may enter into the blood stream through gastroin-testinal introduction or via intravenous administration [3, 4, 9], rapidly living this compartment and redistributing in the or-gans (liver, bones, brain, spleen, etc). Their insoluble phos-phates and carbonates [10, 11] tend to accumulate in the re-ticuloendothelial system in the liver [4]. Most lanthanides eas-ily accumulate in the bones and teeth, and are very hard to excrete [4, 9, 12] because of the very close ion radii and coor-dination numbers with these of calcium [13, 14]. Ln also cross the blood-brain barrier and accumulate in the brain [2, 15-17]. Long term consumption of low doses of lanthanides has sig-nificant negative impact on the signal conduction velocity of the brain [18] resulting in diminished cognitive abilities of humans [2, 15- 17] and experimental animals [16, 17]. The aerosol particles are inhaled with the polluter air and accumu-late in the lungs [1]. The lanthanide ions competitively replace not only Ca, but also Fe, Zn, Mn and Mg ions from their bind-ing sites on proteins [1, 2, 4]. The metal cations contents in the blood are regulated by the homeostasis of the whole body, and elemental changes in the body parts can be reflected by changes of the metal cations contents in the blood serum [19]. Using animal model, [2] found significant alterations of the contents of Ca, Mg, Mn, Fe and Zn in the blood serum after altering these cations in the brains and other organs, due to Yb exposure. Investigations on model animals reveal that that gadolinium inhibits the mitochondrial function, induces oxida-

Involvement of Lanthanides in the Free Radicals Homeostasis Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 3

tive stress, and this triggers apoptosis of neurons [20]. It is well known that lanthanide ions can occupy the Ca

2+ binding

sites in proteins, resulting in abolished biological activity of the ion-binding molecules [1, 4]. In many types of cells lan-thanides block various routes of calcium influx including both voltage- and receptor- dependent neurotransmitter release [21]. Hence, the toxicity of lanthanides is being associated with long term exposure to small doses via food chain and water consumption, venous introduction and inhalation of polluted air. Lanthanides enter the food chain via polluted water from aquatic plants and animals. The intravenous intro-duction of these elements is related with medical procedures. The inhalation is almost inevitable in urban, industrial and mining environment. The toxicity is as acute as high is the possibility for lanthanides to contact metal binding proteins, to occupy cellular ion channels, and to alter the homeostatic lev-els of the metal ions essential for signal conducting and cellu-lar survival. The adverse effects of lanthanides are strong if they are introduced as simple salts (chlorides, nitrates), and very mild if lanthanide complexes with organic molecules are used. The acute toxicity of lanthanides is manifested as blood pressure drop, fallowed by a cardiovascular collapse and pul-monary paralysis. The chronic toxicity is commonly associ-ated with hepathotoxicity and edema.

Chronic toxicity may also result in a decreased learning ability and other neurological alterations.

2.5. Medicinal Applications

Lanthanides have various medicinal applications [3, 22]. They are used as contrast materials in the NMR imaging, as wound healing and bactericidal agents. Their potential appli-cation in antiviral, anti-inflammatory, anticancer therapies and in detoxification is extensively explored. The explora-tion of lanthanides in the abolishment of cancer development and inhibition of carcinogenesis has been expanded.

According one hypothesis the tumorogenesis may be trig-gered by iron overload [23] and iron- mediated generation of free radicals. The excessive free radicals inflict intranuclear damage, resulting in disturbed cell proliferation, differentia-tion, and inhibited apoptosis. Altered signal transduction, dis-arrayed cell cycle and impaired immune functions are typical events during cancer development. As far as Ln competitively suppress iron uptake, inhibit ROS formation by binding to hydroperoxides, and mask the free radicals via magnetic inter-action, intervening signal transduction, the compounds of lan-thanides are expected to possess anticancer activity. Despite the encouraging results, the application of Ln as anticancer agents is still questioned by a series of problems, mainly re-lated to the duality and variety of the biological effects. It needs no discussion that the lanthanides, still scantily investi-gated and described in the literature, provide new opportuni-ties for research on their medicinal applications.

3. INVOLVEMENT OF LANTHANIDES IN ELEC-

TRON TRANSFER REATIONS

3.1. Characteristics of Lanthanides that Determine their

Effects in Biologically Relevant Electron Transfer Reac-

tions

Most of the reactions in the living body proceed with transfer of electrons. The balance between different systems

which release or accept electrons is a delicate one and insists constant readjustments in accordance with the ever changing effects of the environment. Any replacement or structural alteration of any structural part of the living system results in a biological outcome, a new change in the balance between systems exchanging electrons. The main features that affect the biological outcome to the lanthanides are the unaccom-plished 4f electron shells [24], the variable ion charges [25], the similarities of their ion radii and coordination numbers [26-30] with those of some metal ions of great importance for the homeostasis (such as these of Ca, Fe, Mg, Mn and Zn) and the effects of the lanthanide cations on the electron transfer abilities of their ligands in lanthanides complexes [24]. Moreover, the ratio between different valence states may be crucial for the biological effect of a Ln [31]. Some of the characteristics of Ln cations are listed in Table 1.

All lanthanides form stable triple charged cations (Ln3+

) with 4f electron configurations extending from 4f0 (La

3+) to

4f14 (Lu3+

). The atoms of the 4f elements from Cerium to Lutetium possess between 2 and 14 electrons. The filling up of the 4f orbital is regular with one exception: Europium has the outer electronic structure of [Xe]4f`

75s

25p

65d

06s

2 and the

next element gadolinium has an extra electron in the 5d shell, [Xe] 4f`

75s

25p

65d

16s

2 (when all seven 4f shells are

singly occupied, a degree of stability is conferred on the atom). Ytterbium has a full complement of 4f electrons ([Xe]4f`

145s

25p

65d

06s

2) and the extra electron in the lutetium

atom enters the 5d shell ([Xe] 4f`14

5s25p

65d

16s

2). Except

lanthanum, gadolinium and lutetium, all other lanthanides do not have electrons on their 5d orbitals. Each lanthanide dif-fers from its immediate predecessor in having one or more electron in the 4f (though there are some exceptions) and an extra proton in the nucleus of the atom. The 4f electrons con-stitute inner shells and very ineffectively screen the nucleus. This results in a gradual increase in the attraction of the nu-cleus to the electrons in the outermost shell as the nuclear charge increases, and a consequent progressive contraction in the atomic radius with increasing in the atomic number, from lanthanum (La

+3 = 0.115nm) to Lutetium (Lu

+3 =

0.093nm). As the ionic radii contract along the lanthanide series, the ability to form complex ions increases.

They generally adopt high coordination numbers, between 9 and 12 (Table 1). Lanthanides exhibit a main oxidation state of +3 which contain an outer shell consisting in 8 electrons and an underlying layer of up to 14 electrons. In agreement with Hund’s rule, the electron configurations 4f0 (La

3+), 4f

7

(Gd3+

) and 4f14 (Lu

3+) which possess respectively an empty, a

half-filled, and an entirely filled 4f level are in a stable state. The cations having 4fn electron occupancies close to the stable configurations may very easily change their valences in order to obtain the closest stable electron configuration. Cerium can exist in an oxidation state of +4. In this state it has the same electronic structure with La

+3 (an empty 4f level-noble gas

configuration) Ce3+

(4f1) – e- ? Ce4+ (4f0).

Also, Tb4+

is present, having the same electronic struc-ture as Gd

3+ (a half- filled 4f level). An empty, a half-filled

and a completely filled 4f shell confers some extra stability on a particular oxidation state. The Eu

+2 is isoelectronic with

Gd+3

too.

Eu3+

(4f6) + e- ? Eu

2+ (4f

7)

4 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 Valcheva-Traykova et al.

Table 1. Ionic charge (Z), occupancies of the 4f electron shells (4fn), Shannon ionic radii (R), and coordination numbers (CD) of

lanthanides cations according to literature data [26,32].

Ln3+

Z 4f n R, pm CD

La3+ 3+ 4f0 103.2-136 6,7,8,9,10,12 [32]

La3+ 3+ 4f0 103-136 6-9 [26]

Ce3+ 3+ 4f1 101-120 [26],101-134 [32] 6-9 [26], 6,7,8,9,10,12 [32]

Ce4+ 4+ 4f0 87-114 [32] 6,8,10,12 [32]

Pr3+ 3+ 4f2 99 [2], 112,6-117.9 [32] 6 [26], 8,9 [32]

Pr4+ 4+ 4f1 85- 96 [32] 6,8 [32]

Nd2+ 3+ 4f4 129-135 [32] 8,9 [32]

Nd3+ 3+ 4f3 98-116 [26], 98.3-127 [32] 6-9 [26],6, 8, 9, 12 [32]

Pm3+ 3+ 4f4 97 [26], 97-114.4 [32] 6 [26], 6, 8, 9 [32]

Sm3+ 3+ 4f5 95.8 [26] 6 [26], 6,7,8,9,12 [32]

Sm2+ 2+ 4f6 122-132 [32] 7,8,9 [32]

Eu3+ 3+ 4f6 94.7 [26], 94.9-112 [32] 6 [26], 6,7,8,9 [32]

Eu2+ 2+ 4f7 117-135 [32] 6,7,8,9,10 [32]

Gd3+ 3+ 4f7 93.8 [26], 93.8-110.7 [32] 6 [26], 6,7,8,9 [32]

Tb3+ 3+ 4f8 92.3 [26], 92.3-109.5 [32] 6 [26], 6,7,8,9 [32]

Dy3+ 3+ 4f9 91.2 [26], 91.2-108.3 [32] 6 [26], 6,7,8,9 [32]

Dy2+ 2+ 4f10 107-119 [32] 6,7,8, [32]

Ho3+ 3+ 4f10 90.1 [26], 90.1-112 [32] 6 [26], 6,8,9,10 [32]

Er3+ 3+ 4f11 89 [26], 89-106.2 [32] 6 [26], 6,7,8,9 [32]

Tm3+ 3+ 4f12 88 [26], 88-105.2 [32] 6 [26], 6,8,9 [32]

Tm2+ 2+ 4f13 103-109 [32] 6,7 [32]

Yb3+ 3+ 4f13 86.8 [26], 86.8-104.2 [32] 6 [26], 6,7,8,9 [26]

Yb2+ 2+ 4f14 102-114 [32] 6,7,8 [32]

Lu3+ 3+ 4f14 86.1 [26], 86.1-103.2 [32] 6 [26], 6,8,9 [32]

Yb

+2 is isoelectronic with Lu

+3 (4f145s25p6) meaning an

entirely filled 4f level. In addition, +2 and +4 states exist for lanthanides that are close to these states.

The examples above illustrate the high probability for Ln3+ having on electron more than a stable 4f configuration to loose an electron resulting a higher valent state (Ce

3+? Ce

4+)

[33], while if missing one electron from a stable 4f configura-tion it might accept an electron, transferring to a lower valence state (Eu

3+? Eu

2+) [34]. The ability of Ln ions themselves to

exchange electrons with the environment allows them to par-ticipate in electron transfer reactions taking place in the sur-rounding media. In particular, they may affect many biological processes that require exchange of electrons.

In general, lanthanide compounds are predominantly ionic and usually contain lanthanide +3 ion, corresponding to the most stable oxidation state. Ln2+ and Ln4+ are less sta-ble. For instance Ce

4+ and Sm

2+can be converted to +3 state -

the most stable oxidation state. That is why Ce4+

is strongly

oxidizing and Sm2+ is strongly reducing agent. Ln3+ Ions form complexes with high coordination numbers. The coor-dination numbers for [Ln( OH2 )n]

3+ in water solution are up

to 9 for the early lanthanides and 8 for the later smaller members. The variability of charges, coordination numbers and coordination symmetry of lanthanide cations increase their ability to bind to proteins, forming stable complexes at various environmental conditions. This is a prerequisite for competitively bonding with ion binding proteins and this way altering some cations- related pathways of biologically relevant processes in a living body. The cation radius, charge and coordination number may affect the electron distribution within organic ligands in lanthanide complexes, increasing the involvement of the ligands in electron transfer reactions. The similarities of the ion radii and coordination numbers of lanthanide cations (Table 1) these of Calcium, Iron and Zn cations (Table 2) allow the lanthanides to replace them com-petitively in the ion binding proteins, resulting in biological effects in living systems [4, 29, 35, 36].

Involvement of Lanthanides in the Free Radicals Homeostasis Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 5

Table 2. Shannon ionic radii (R) and coordination numbers

(CD) of Ca, Fe and Zn ions according literature data

[26,32]: data are provided for coordination numbers

corresponding to these of the lanthanides, as given in

Table 1.

Cation R, pm CD

Ca2+ (3p6) [26,32]

100 6

106 7

112 8

118 9

123 10

134 12

Fe2+ (3d6) [32] 78 6

92 8

Fe3+ (3d5) [32] 78 8

Zn2+ (3d10) [32] 90 8

In a living biological system, chemical species possess-

ing unpaired electrons are constantly formed and eliminated [37]. These chemical species, known as free radicals [38], both benefit and harm the living body [39, 40]. To control over the harmful effects of the free radicals, the living sys-tems developed an antioxidant defense, consisting in mole-cules synthesized by the body (endogenous antioxidant de-fense) and received from the environment (exogenous anti-oxidant defense). The antioxidant effect of a substance (molecule, natural product, food additive or component of the food chain) may be achieved through many possible pathways (Fig. 2).

Usually the direct antioxidant effects are related with pathways for scavenging of the free radicals, chelating of metal cations with variable valent states and stimulating en-dogenous antioxidant enzymes.

The indirect antioxidant effects are related with either stimulation of systems that control the performance of direct antioxidants, or suppression of systems that stimulate free radicals production. Some substances may act as antioxidant through more than one pathway. The properties of the Ln cations may prerequisite their involvement as pro- oxidants or antioxidants in a living biological system. As lanthanides and their compounds are promising as antiseptic, antiviral, anti-inflammatory and anticancer agents, their abilities to act as antioxidants are important to be analyzed.

3.2. Solutions of Simple Salts of Lanthanides

The effects of the aqueous solutions of simple lanthanide salts (chlorides, nitrates) have been extensively examined, as the lanthanides tend to accumulate in a human body through the food chain [41]. It has been found that the systemic ac-cumulation of lanthanides has negative impact on the IQ of the affected population. Most of the lanthanides effects were related with the abilities of the Ln cations to bind with cation binding proteins, this way incapacitating their biological activities [4, 20, 35, 36, 42-45]. The main pro- and antioxi-dant effects of the aqueous solutions of Ln chlorides and nitrates are presented in Fig. (3).

Some of the potential involvements of lanthanide salts in the homeostasis of free-radicals production-elimination are mentioned in [3]. In vivo experiments on animal models permitted to associate some positive effects of lanthanide salts with their antioxidant action. They may decrease the inflammatory oxidative stress both directly (by scavenging free radicals) and indirectly (by decreasing the expression of inflammatory cytokines and TNF-?). They may depress the atherogenic plaque deposition by diminishing the LDL

Fig. (2). Some pathways of the antioxidant effect of a molecule.

6 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 Valcheva-Traykova et al.

Fig. (3). Possible prooxidant and antioxidant effects of the aqueous solutions of Ln chlorides and nitrates.

oxidation (via free radicals scavenging) and by altering the Ca

2+-associated platelets aggregation. Some of the antioxi-

dant effects of the Ln solutions were associated with their abilities to interact with hydroperoxides and to suppress the Fe intake [29]. Indeed, by interacting with hydroperoxides, Ln cations may act as scavenger of free radicals, while the suppression of the Fe uptake may diminish the chance for free radicals’ production via Fenton reaction. In the work of Liu et al. [24] was pointed out that tumor growth due to phagocytosis- induced oxidative stress may be suppressed by Ln, and that LnCl3 in low concentrations may decrease the O2?- induced DNA damage. All authors that stress antioxi-dant effects of lanthanide cations in solutions stress that this effect is being observed at low concentrations (doses below 20 mg/kg). At high concentrations or doses (20 mg/kg and above) the prooxidant effects prevail. The pro-oxidant ef-fects of the Ln cations are related with their abilities to com-petitively bind to ion-binding proteins. The main result of such binding usually is irreversible alteration of the quater-nary structure of the protein and loss of biological activity. The reversible binding to Ca ion channels leads to a de-creased Ca influx, with devastating consequences to the cel-lular survival [4, 27]. It was observed that the ion radius and the coordination number are important for the strength of this effect. As small the radius and as variable coordination number is, as much the Ln cation hinders the Ca influx through the ion channel. This is because the smaller the ra-dius and the larger the coordination number of the cation, the stronger the interaction with the Ca binding sites and the slower the penetration along the ion channel into the cellular interior. In general, lanthanides bound to Ca2+ binding pro-teins decrease the Ca content into the cell and generate ex-cess of extracellular Calcium, both generating increased free radical production within and out of the cell, with devastat-ing consequences for the cellular survival [24, 26, 46, 47]. The high doses of Ln chlorides have been accompanied with depletion of the total antioxidant status of rat spleen [24] and brain [26, 44, 45]. This effect decreased in the order:

Ce3+

>Nd3+

>La3+

. In the same order decreased the oxidative damage. Inactivation of the non-enzymatic antioxidants was observed, along with substantial decrease of the activity of the endogenous antioxidant enzymes. As the ion radii do not change in the above mentioned order, these effects might be related to the abilities of the ions to react with particular binding sites on the molecules taking part in the antioxidant defense. An indirect in vivo antioxidant effect of GdCl3 was related with the ability of the salt to inactivate Kupffer cells in the liver and mononuclear phagocytes in the lung. As re-sult of this, GdCl3 showed a protective effect against toxi-cant-induced liver damage and post-ischemic injury of lungs due to myeloperoxidase from activated mononuclear phago-cytes. The use of the Ln

3+ salts in medicine is restricted by

their strong adverse effects on the cardiovascular system.

3.3. Coordination Complexes of Lanthanides

The Ln3+

ions usually form complexes with F- and O-donor ligands, e.g. with H2O, EDTA, -diketonate, citric acid, oxalic acid ligands. Charged ligands have highest affin-ity for the smallest Ln

3+ ion. Typical illustrations of 6-

coordinated octahedral metal complexes are [[CeCl6]2-

and [Er(NCS)6]. Most of the complexes have coordination num-bers 8 or 9, e.g. [Nd(H2O)9]

3+ , [Sm(NH3)9]

3+.

Lanthanide ions are usually weakly colored in solution. Their complexes spectra show much narrower absorption bands which is associated with weak f-f transition. The f electrons are almost unaffected by complex formation and the color remains constant for a particular ion regardless of the ligands. It is well known that the bands due to f-f transi-tion are sharp compared to the broad bands for d-d transi-tion. Absorption bands due to 4f-5d transitions are broad because of the ligand environment. All Ln(III) ions (except La

3+ (f 0) and Lu

3+ (f 14)) show luminescence and between

them Eu3+

(f 6) and Tb3+ (f 8) show particularly strong emissions. This has been attributed to the large number of excited states which decays to the ground state with either

Involvement of Lanthanides in the Free Radicals Homeostasis Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 7

emission of energy (fluorescence) or non-radiative path-ways. The cause of this is f-f transition.

Lanthanide complexes with various large organic ligands are synthesized and examined as potential anticancer agents and antioxidants [28, 29]. The complexes with best charac-terized antioxidant properties, which permit to clarify the role of the cation in the antioxidant activity of the complex, are listed in Table 3.

Table 3. Lanthanides complexes whose antioxidant behavior

is being investigated.

Ligans Helators References

Coumarin derivatives Ce3+, La3+, Nd3+ [48,49]

5-orotic acid Ce3+, La3+, Nd3+ [50]

8-hydroxyquinoline-2-

carboxaldehyde + aroylhydrasides Tb3+ [51]

N, N'-bis-(1-naphtaldimine)-o-

phenylenediamine

Cd3+, La3+, Nd3+,

Dy3+, Pr3+, Tb3+,

Sm3+, Er3+

[30]

Chromones La3+, Eu3+, Sm3+ [52-55]

(2R, 3R)-diphenylethylenediamine,

(R being o-hydroquinone, p-

hydroquinone)

La3+ [56]

The investigations of coumarin derivatives showed that

Ln 3+

bind coordinatively to a deprotonated hydroxyl or car-bonyl group in the organic ligand (LO-). As strong the coor-dinative bond [Ln

3+...LO-], as weak the antioxidant effect of

the complex and as low the ability to provoke apoptotic cell death were in a model system, containing Xanthine and Xan-thine oxidase. As the ion radius of Ce

3+was larger than this

of Nd3+

, the [Nd3+

...LO-] interaction was stronger than this of the [Ce

3+...LO-] interaction in the respective complexes. This

was related with the higher toxicity of the Ce complex than this of the Nd complex toward the cancerous cells. On the base of the Ln complexes with 5-orotic acid, one more vari-able was observed to affect the antioxidant properties of the lanthanide complexes: the stability of the complex in a bio-logical environment. The research on the (8-hydroxyquinoline-2-carboxaldehyde + aroylhydrasides) complexes with Tb

3+ showed that the complexes containing

active phenolic group were better scavengers of OH? radi-cals, while complexes containing N-heteroatomic substitu-ents were better O2?- scavengers. It was found that the lan-thanide cation pulls electron density from the ligand, this way increasing the polarity of any O-H bond, increasing the possibility for this bond to break and donate proton to a free radical. In addition of being scavengers of hydroxyl and su-peroxide radicals, the Ln complexes with chromones bonded to the double DNA strands via intercalation. It was proposed that intercalation might provide additional protection against oxidative fragmentation of DNA, but at the same time it was pointed out that this may deeply alter the DNA secondary structure with major consequences for the DNA replication and transcription. The suppression of the hydroxyl radicals

decreased in the order EuL>LaL>L, while the superoxide diminishing ability decreased in the order LaL>EuL>>L. Evidently, the complexes were better scavengers than the ligands alone, and the active sites of scavenging activities were different for the hydroxyl radical and superoxide. The N, N'-bis-(1-naphtaldimine)-o-phenylenediamine complexes of Cd

3+, La

3+, Nd

3+, Dy

3+, Pr

3+, Tb

3+, Sm

3+, Er

3+ revealed that

they showed remarkable antioxidant effect against DPPH? radical. They found that the strength of the chelator to ligand interaction pooled electrons from the ligand toward the chelator, resulting an increased polarity of the O-H bonds in the ligand. This increased the chance of the ligand to partici-pate in HAT (Hydrogen Abstraction Type) reactions. As small the ion radius of the chelator, as strong the electron transfer from the ligand, as strong antioxidant effect toward DPPH? radical was. The possible antioxidant pathways of antioxidant action of the lanthanides’ cations complexes with organic ligands are illustrated in Fig. (4).

Not all complexes between lanthanum ions and antioxi-dant ligands resulted in antioxidant activities; in vivo applied quercetin decreased the MDA leveling animal model of non-alcoholic steatohepatitis [57], while the lanthanum complex of quercetin showed considerable toxicity, induced doxycy-cline (DOX)-dependent prooxidative effects and formation of single-strand and double-strand DNA brakes [58]. Thus, the antioxidant behavior of the complexes of lanthanide cations were related with the effect of the cation radius on the electron density distribution within the active sites in the ligand, the nature of the active sited of the ligands, and the stability of the ligand in the biological environment. A pro-spective lanthanide complex with anticancer and antioxidant activity will be able to travel intact to the target cancerous cells. The intact complex will provide antioxidant protection to the healthy tissues from oxidative damage. The complex would decompose when within the tumor, due to the altered environment. By decomposition in the tumor, it will release the toxic chelator to act as anticancer agent, while the free antioxidant ligands will eliminate the excessive free radicals.

3.4. Organometallic Compounds of Lanthanides

The term "organometallic" means that the lanthanide atom is bound to carbon through single -bonds or through multiple -bonding. Large variety of such derivatives have

been isolated and characterized [59]. The organometallic compounds of the lanthanides contain good donor ligands. The lanthanide complexes with acceptor ligands are rare. The 5d orbitals of lanthanides are empty and the 4f orbitals are suppressed. This limits the bonding modes that are avail-able to the lanthanide ions. On the other hand, the strong electropositive lanthanide ions insist good electron donors (e.g. alkoxide, amide and halide ligands which are both and donors), rather than good acceptor ligands (e.g. CO and phosphine ligands which are both donors and accep-tors). The type of bonding in the organometallic lanthanide

complexes is principally ionic, depending on the electrostatic and steric requirements. Almost all organometallic com-plexes are strong Lewis acids and they are usually sensitive to air and moisture.

For example, many cyclopentadienyl compounds as Ln(C5H5)3 and other complex species [60], have been made.

8 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 Valcheva-Traykova et al.

Fig. (4). Illustration of the main antioxidant actions of lanthanide complexes: Ln(III)- trivalent lanthanide ion; L- organic ligand.

These complexes contain Ln3+ ion with a small number of Ln2+

compounds. -Bonded alkyl groups are common with these containing cyclopentadienyl ligands tending to dominate.

In some of them the bonding involves Ln(0) atoms and -

bonded arene ligands [61]. These complexes, which are very sensitive to oxygen and water, have become a successful

field for research. Their potential application in catalysis as

well as organic synthesis reagents is connected with the ab-sence of a rigid stereo-chemical arrangement around the Ln

atom coupled with an inherent high reactivity.

3.5. The Lanthanide Nanoparticles - A New Source of Antioxidant Activity in Living Biological Systems

By combining the properties of solid compounds with mobility of individual molecules, the nanoparticles are prom-ising materials with possible applications in medicine [62]. At the same time, there are general concerns that the com-plicity of the interactions of nanoparticles with living sys-tems may result in unpredictable harmful effects [63]. The effects of the physical and chemical properties of the nanoparticles, as well as their interactions with living bio-logical systems were investigated, in order to better under-stand the mutual effects between nanoparticles and biologi-cal environment. The major variables of nanoparticles that affect the biological system are: physical dimensions (parti-cle size, shape) [25, 31, 64, 65], method of synthesis [64, 65], concentration [25, 64, 66], and method of application [67]. The properties of the nanoparticles may easily be al-tered by environmental changes [68-70]. All variables men-tioned in one of other way are related with the surface chem-istry and physicochemistry of the nanoparticles. The surface chemistry seems to be decisive for their interaction with the biological environment. So far the most promising lantha-nides nanoparticles for medicinal application are these of CeO2 (Nanoceria) [25, 31, 66, 68, 69, 70-77] and Eu(OH)3 [31, 78, 79]. Nanoceria showed outstanding antioxidant ef-fects, acting as well tolerated anti-aging anti-inflammatory agent [72, 76, 77]. They acted as powerful antioxidants by directly recombinating superoxide [25], by mimicking the catalytic activities of superoxide dismutase (SOD) and cata-

lase (CAT) [68, 69, 74, 77], as well as by actively participat-ing in the uptake-reuptake of the free intracellular oxygen [31]. In an in vivo experiment on fish model CeO2 treatment did not alter SOD activity in the liver [66]. The main feature responsible for these three antioxidant pathways was the Ce

3+/Ce

4+ ratio on the surface of the nanoparticle. As high

the relative amount of trivalent cerium ion on the nanoceria surface is, as strong the antioxidant effect of the nanoparti-cles. The possible mechanisms of the electron transfer reac-tions and oxygen transfer are illustrated in Fig. (5). The sur-face Ce4+ cations can accept electrons from superoxide radi-cals yielding Ce

3+ and O2. The surface Ce3+ participate in

the transformation of hydroxide radicals to water and oxygen atoms, latter occupying oxygen vacancies in the nanoceria crystal. The oxygen vacancies on the surface of the nanopar-ticle also are important for its biological activity. The Ce

3+/Ce

4+ ratio on the cerium oxide nanoparticles is of great

importance for the angiogenesis [31]. Ceria nanoparticles with 57% Ce

3+ are highly oxygen deficient and it was hy-

pothesized that these nanoparticles first extract and then lib-erate in catalytic cycle oxygen from the environment (Fig. 5). This hypothesis was supported by the observed transient hypoxia immediately after treatment of endothelial cells. The nanoceria particles stabilized HIF-? in endothelial cells and altered the regulation which induced pro-angiogenesis. In an in vivo mice model of age-related macular degeneration, nanoceria inhibited the pro-inflammatory cytokines and af-fected many genes involved in cell signaling and tissue de-velopment [73] (Fig. 5).

Recently it was observed that ceria nanoparticles not only catalytically interact with superoxide and hydroxyl radicals (Fig. 1), (mimicking SOD and CAT), but also stimulated the proliferation, dopamine production and differentiation of neuron- type cells P12 [77]. The transcriptional profiles of nanoceria pretreated P12 cells were different than these of the controls [76]. It was found that nanoceria not only acted as a strong exogenous antioxidant, but also up-regulated the transcription of genes involved in natural cellular defense pathways and neuroprotection, while down- regulating genes involved in the neurodegeneration. The most important bio-logical effects of the nanocetia are presented in Fig. (6).

Involvement of Lanthanides in the Free Radicals Homeostasis Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 9

Fig. (5). Participation of the nanoceria in intracellular oxygen and

electron transfer.

Fig. (6). The most important biological effects of the nanocetia.

The direct synthesis of nanoceria in polyethyleneglycol (PEG) solutions resulted in nanoparticles with even better antioxidant properties [75]. The PEGylated nanoceria reacted with H2O2 by forming a charge transfer complex governed by the PEG. This complex provides tunable oxidative state of CeO2, influencing the capacity of the active Ce3+. In con-trast with nanoceria, the Eu(OH)3 nanorods showed pro-oxidant properties [31, 78, 79] accompanied with pro-angiogenic effect through generation of high amounts of reactive oxygen species. The Eu(OH)3 nanorods increased the healing of diabetic wounds, in rat models. This beneficial biological effect depended on the shape of the nanoparticles: the nanorods were much more efficient than the standard Eu(OH)3 powders. The lanthanide nanoparticles are com-pletely new potential agents of medical application. They are subject of extensive research in the last few years. As seen on the example of nanoceria, they are very promising agents of antioxidant defense, acting both via direct and indirect pathways. So far, most of the biological experiments are performed on cell cultures. These experiments show the great potential of the lanthanide nanoparticles as healing agents, as they provide not only antioxidant protection, but additional benefits to the living cells. The importance of lan-thanides in clinical diagnostics, as well as anticancer agents, is increasing. Lanthanide complexes based X-ray contrast imaging probes and lanthanide chelates based contrast en-

hancing agents (lanthanide polyamino carboxylate-chelate complexes) for magnetic resonance imaging (MRI) are widely used in the in vivo radiological analysis.

The conjugated (with antibodies and other molecules) MRI contrast agents show improved relativity, functioning

in the body as carriers of medicines. The in vivo characteris-tics of this new generation of contrast agents depends not only on the properties of the lanthanides, but also on the in-duced hydrophobicity.

The high spin paramagnetism and long electron relaxa-tion times of Gd(llI) made it preferable contrast enhancing

agent for MRI [80].The conjugation of Gd(III)- polylysine chelate with anticarcino-embryonic antigen monoclonal anti-bodies resulted in a new MRI contrast agent [81].

CONCLUSION

In general, the catalytic activity of the lanthanides in biological environment is related with the completion of the 4f electronic shell (which determines the variability in ionic charges), the ion radius, coordination numbers and their variability, the redox potential (which determines how easy the electron transfer with the environment could be), and in the case of nanoparticles - the ratio between ions with different charges and the number of oxygen vacancies on the crystal surface. The similarities of ion radii and co-ordination numbers of lanthanides with the corresponding characteristics of Ca, Fe and Zn determine the ability of the former to competitively replace the latter in binding with proteins in biological solutions. This irreversibly alters and inactivates the ion binding proteins and many biological processes in living systems. Most of the resulting effects are not beneficial for the cell survival and allow the lantha-nide cations to be used as anticancer agents. The ability to change the valent state enables the lanthanide cations to exchange electrons with other chemical species in the envi-ronment, either generating, or recombinating free radicals. The prooxidant properties are additional benefit in tumor destruction, while the antioxidant properties benefit the survival of the healthy tissues. The nanoparticles provide an opportunity for reversible transitions between different ionic charges during electron transfer with the biological systems. This enables the lanthanides to act as powerful exogenous catalysts, mimicking the catalytic activities of endogenous antioxidant enzymes in the living biological systems. The nanoparticles with prooxidant properties offer benefits too, providing high amount of reactive oxygen species when needed for wound healing. The ion radius and variability of coordination numbers allow the lanthanides to form stable complexes with organic molecules, in which the ion modifies the electron density within the ligand, in-creasing the antioxidant activity of the latter. These com-plexes provide opportunity to transport the cytotoxic lan-thanide ions to the tumors and providing the healthy tissues with antioxidant defense. This benefit may be achieved if the complex is stable in homeostatic environment, but un-stable in altered homeostasis (as this in the tumor). It must be pointed out that in solutions, the similarity of the ion radius and coordination numbers of lanthanides with these of some cations essential for the cell survival (such as Ca) may allow the lanthanides to deplete the influx of these

10 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 22 Valcheva-Traykova et al.

ions trough the ion channels. This is one of the pathways of lanthanides cytotoxicity. The lanthanide nanoparticles pro-vide the benefits of the catalytic surface of a solid material with the mobility of an individual molecule, in a biological environment. The solid surface provides the stability of a high ratio between cations with different charges and oxy-gen vacancies, which can regenerate after electron or oxy-gen transfer with the biological environment. This may dramatically change the oxidative behavior of a lanthanide. For example, Ce

3+, acts as powerful pro-oxidant, on the

nanoceria surface determines the antioxidant properties. The ability to modify the biological effect of lanthanides may be illustrated on the example of Ce. The individual Trivalent cerium ion is powerful prooxidant. Its complex with 5-aminoorotic acid is a mild antioxidant. The powerful antioxidant action of nanoceria depends on how much tri-valent cerium is positioned on the nanoparticle's surface. On the base of the literature data it may be concluded that lanthanides, in their different forms of application, may provide benefits to the patients. The toxicity of the lantha-nide cations may be combined with the antioxidant activity of organic ligands to form complexes, which are stable in homeostatic environment, but decompose in the target tu-mors. There the Ln cations will kill the cancerous cells, while the free ligands may eliminate the excessive free radicals, saving the healthy tissues from oxidative damage. New nanoparticles can be explored for their potential medi-cal application. The nanoceria show great potential as ex-ogenous antioxidant and cellular protector.

LIST OF ABBREVIATIONS

CAT = Catalase

CD = Coordination number

DNA = Deoxyribonucleic acid

DOX = Doxycycline

DPPH = 2,2-Diphenylpicrylhydrazyl

EDTA = Ethylenediaminetetraacetic acid

HAT = Hydrogen abstraction type reactions.

HIF = Hypoxia-inducible factor

LDL = Low-density-lipoproteins

Ln = Lanthanides

MRI = Magnetic resonance imaging

PEG = Polyethyleneglycol

ROS = Reactive-oxygen species

SOD = Superoxide dismutase

TNF = Tumor necrosis factor

CONFLICT OF INTEREST

The authors confirm that this article content has no con-flict of interest.

ACKNOWLEDGEMENTS

This work was supported by the Medical University-Sofia Grant Commission.

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Received: April 05, 2014 Revised: August 27, 2014 Accepted: September 15, 2014