**1. Introduction**

Due to the wide potential of applications in various fields, such as biotechnology, biomedicine, magnetic fluids, catalysis, magnetic data recording and storage media, magnetic resonance imaging, magnetic fluid hyperthermia, magnetic drug delivery, cell separation, magnetic paper and more recently in environmental protection, magnetic iron oxide nanoparticles (M-IONPs) are the main components of the modern technology [1–15]. In nature, many forms of iron oxides are found, but the most technologically used are the magnetite (Fe3 O4 ), maghemite (γ-Fe<sup>2</sup> O3 ) and hematite (α-Fe<sup>2</sup> O3 ) (**Figure 1**).

Magnetite (Fe3 O4 ), a natural mineral known as the black iron oxide, is relatively stable at room temperature, very quickly transforms in maghemite and shows the strongest magnetism compared to other transition metal oxides [16]. Fe3 O4 has an inverse spinel structure with all the Fe2+ ions and half of the Fe3+ ions distributed in the octahedral sites and the other half of the Fe3+ ions distributed in the tetrahedral sites being surrounded by four oxygen atoms [17].

Spin magnetic moments of Fe3+ ions distributed in octahedral positions are parallely aligned, as well as those of Fe3+ ions distributed in tetrahedral positions but in the opposite direction, leading to an antiparallel coupling. Therefore, the spin moments of all Fe3+ ions mutually cancel out and do not contribute to the net magnetization of magnetite (**Figure 2**). All Fe2+ ions have magnetic moments aligned in the same direction so that their total magnetic moment is responsible for the net magnetization of magnetite. Therefore, the saturation magnetization of magnetite corresponds to the product between the spin magnetic moment of each Fe2+ ion and the number of Fe2+ ions, which corresponds to the mutual alignment of all Fe2+ ions in magnetite.

As magnetite, maghemite (γ-Fe<sup>2</sup>

**Property Oxide**

Molecular formula Fe3

Density (g/cm3

(Ms

Saturation magnetization

Standard Gibbs free energy

0 ) [kJ/mol]

/kg]

) at 300 K [A·m<sup>2</sup>

of formation (Δ*Gf*

O3

closely packed cubic lattice and the iron ions located at interstices. In γ-Fe<sup>2</sup>

O4 γ-Fe<sup>2</sup>

) 5.18 4.87 5.26

Type of magnetism Ferrimagnetic Ferrimagnetic Weakly ferromagnetic/

92–100 60–80 0.3

Crystallographic system Cubic Cubic or tetrahedral Rhombohedral, hexagonal

Structure type Inverse spinel Defect spinel Corundum

Lattice parameter (nm) α = 0.8396 α = 0.83474 (cubic);

**Table 1.** Physical and magnetic properties of iron oxides [22].

−1012.6 −711.1 −742.7

α = 0.8347; c = 2.501 (tetragonal)

Color Black Reddish-brown Red

Melting temperature (°C) 1583–1597 — 1350 Hardness 5.5 5 6.5

Curie temperature (K) 858 820–986 956

**Magnetite Maghemite Hematite**

O3 α-Fe<sup>2</sup>

Preclinical Aspects on Magnetic Iron Oxide Nanoparticles and Their Interventions as Anticancer…

**Figure 2.** Spin magnetic moment distribution of Fe2+ and Fe3+ ions in the elemental cell of magnetite.

) has a spinel structure with the oxygen ions disposed in a

O3

anti-ferromagnetic

α = 0.5034; c = 1.375 (hexagonal); αRh = 0.5427; α = 55.3° (rhombohedral)

O3

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not all the sites

Magnetite is oxidized in the presence of air to maghemite, which is also ferrimagnetic, but has a slightly lower magnetic response. This process is called maghemitization and occurs at the surface of the crystals. Crystal centers are also oxidized, and the process is being carried out by diffusion of Fe2+ ions from inside to the surface of the crystals, where they are converted to Fe3+. The rate of the oxidation process is determined by the diffusion rate of Fe2+ ions and the distance to the surface. Therefore, the particles remain unaffected by the phenomenon of maghemitization, while the small ones are susceptible to oxidation even at room temperature.

**Figure 1.** Crystal structure of: A—hematite, B—maghemite and C—magnetite (the blue sphere is Fe2+/Fe3+ and the red sphere is O2−). The structures were adapted after the structures found in the Crystallography Open Database (http:// www.crystallography.net).

Preclinical Aspects on Magnetic Iron Oxide Nanoparticles and Their Interventions as Anticancer… http://dx.doi.org/10.5772/intechopen.74176 231

**Figure 2.** Spin magnetic moment distribution of Fe2+ and Fe3+ ions in the elemental cell of magnetite.

**1. Introduction**

230 Iron Ores and Iron Oxide Materials

maghemite (γ-Fe<sup>2</sup>

www.crystallography.net).

Magnetite (Fe3

O3

pared to other transition metal oxides [16]. Fe3

O4

) and hematite (α-Fe<sup>2</sup>

Due to the wide potential of applications in various fields, such as biotechnology, biomedicine, magnetic fluids, catalysis, magnetic data recording and storage media, magnetic resonance imaging, magnetic fluid hyperthermia, magnetic drug delivery, cell separation, magnetic paper and more recently in environmental protection, magnetic iron oxide nanoparticles (M-IONPs) are the main components of the modern technology [1–15]. In nature, many forms of iron oxides are found, but the most technologically used are the magnetite (Fe3

) (**Figure 1**).

temperature, very quickly transforms in maghemite and shows the strongest magnetism com-

Fe2+ ions and half of the Fe3+ ions distributed in the octahedral sites and the other half of the Fe3+ ions distributed in the tetrahedral sites being surrounded by four oxygen atoms [17].

Spin magnetic moments of Fe3+ ions distributed in octahedral positions are parallely aligned, as well as those of Fe3+ ions distributed in tetrahedral positions but in the opposite direction, leading to an antiparallel coupling. Therefore, the spin moments of all Fe3+ ions mutually cancel out and do not contribute to the net magnetization of magnetite (**Figure 2**). All Fe2+ ions have magnetic moments aligned in the same direction so that their total magnetic moment is responsible for the net magnetization of magnetite. Therefore, the saturation magnetization of magnetite corresponds to the product between the spin magnetic moment of each Fe2+ ion and the number of Fe2+ ions, which corresponds to the mutual alignment of all Fe2+ ions in magnetite.

Magnetite is oxidized in the presence of air to maghemite, which is also ferrimagnetic, but has a slightly lower magnetic response. This process is called maghemitization and occurs at the surface of the crystals. Crystal centers are also oxidized, and the process is being carried out by diffusion of Fe2+ ions from inside to the surface of the crystals, where they are converted to Fe3+. The rate of the oxidation process is determined by the diffusion rate of Fe2+ ions and the distance to the surface. Therefore, the particles remain unaffected by the phenomenon of maghemitization, while the small ones are susceptible to oxidation even at room temperature.

**Figure 1.** Crystal structure of: A—hematite, B—maghemite and C—magnetite (the blue sphere is Fe2+/Fe3+ and the red sphere is O2−). The structures were adapted after the structures found in the Crystallography Open Database (http://

O4

), a natural mineral known as the black iron oxide, is relatively stable at room

has an inverse spinel structure with all the

O3

O4 ),

> As magnetite, maghemite (γ-Fe<sup>2</sup> O3 ) has a spinel structure with the oxygen ions disposed in a closely packed cubic lattice and the iron ions located at interstices. In γ-Fe<sup>2</sup> O3 not all the sites


**Table 1.** Physical and magnetic properties of iron oxides [22].

are occupied, Fe3+ ions are regularly distributed in only two-thirds of the sites and the rest of the sites remain vacant. After two sites filled with Fe3+ ions follows one vacant site [18, 19]. Maghemite is a metastable oxide, product of magnetite oxidation or a product resulting from the heating of other iron oxides.

**2.2. Size**

conditions, such as inflammations or tumors [28].

reticulum system [28].

the circulatory system [28].

**2.3. Charge**

The size and the size distribution of superparamagnetic iron oxide nanoparticles are important parameters for their biological application. Also, their magnetic properties are in close touch with their size. It has been demonstrated that the magnetic dipole-dipole interactions are significantly reduced in superparamagnetic iron oxide nanoparticles due to their scale of r6, r being the radius of the particle [28]. The advantages of using magnetic nanoparticles with sizes smaller than 100 nm are due to their surface efficiency to easily attach ligands and small settling velocities which give a high stability in suspension and improve tissue diffusion. Particles should be small enough to bypass the endothelial reticule system. They are supposed to remain in circulation after injection and be able to pass through the capital systems, organs and tissues, avoiding the embolus. Particle size is also important for getting an effect of improved permeability and retention. For example, particles larger than 10 nm may not penetrate the endothelium in physiological conditions, but can enter in pathological

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When magnetic nanoparticles loaded with medicinal substances are injected into the systemic circulation, size, morphology and surface charge are the three important parameters for their behavior in the bloodstream. Kupffer cells in the liver are very sensitive to both microorganisms and nanoparticles. Plasma proteins can easily adsorb onto their surface nanoparticles, depending on their size, surface charging and their morphology. Particles with sizes larger than 200 nm or below 10 nm are not suitable due to their absorption by the endoplasmic

Loading surface and biodistribution of superparamagnetic iron oxide nanoparticles play an important role in the colloidal stability. Surface charging can be described qualitatively by the nature and behavior of surface groups in the solution at a given pH and in the presence of an electrolyte. In terms of quantity, it can be measured as an electric potential in the double layer of the interfacial surface of the nanoparticles found in a suspension state. A high value of zeta potential is an indication of stability in dispersion of superparamagnetic iron oxide nanoparticles due to electrostatic interaction. Composition and structure of nanoparticles are very important for their interaction with biological fluids. In a known environment, superparamagnetic nanoparticle characteristics, such as the chemical composition, both core and neural crest cells, its size and size distribution, shape and angles of curvature, its crystalline structure, smoothness or surface roughness and hydrophobic or hydrophilic levels, are important for their *in vivo* applications. These features can determine their stationary time in

Osaka and his colleagues [29] have reported a correlation between surface charge of magnetite nanoparticles and their cellular absorption efficiency on different cell lines. For example, a superparamagnetic particle with positive charge showed a greater internalization in human breast cancer cells in comparison with those charged negatively, while there was no difference

At temperatures over 300°C, magnetite is oxidized to hematite (α-Fe<sup>2</sup> O3 )—an anti-ferromagnetic iron oxide. Hematite (α-Fe<sup>2</sup> O3 ) has a corundum crystal structure with Fe3+ ions distributed in octahedral sites and oxygen ions in hexagonal close-packed arrangement. α-Fe<sup>2</sup> O3 , the final product of the transformation of other iron oxides, is a red powder when it is finely divided, very stable at room temperature and very widespread in rocks and soils (**Table 1**) [20, 21].
