**3.2. Thermal decomposition**

of the particles with size below 100 nm are needed. Magnetite (Fe3

most commonly used in medical applications.

chemical precipitation of iron salts [35–39].

**3.1. Precipitation method**

) have attracted particular attention because, under certain synthesis conditions, they

are superparamagnetic, being also biocompatible, thus becoming the magnetic nanomaterials

Hereinafter, the most popular synthesis methods used for obtaining M-IONPs will be described. After the chemical surface modification of magnetic nanoparticles by binding drugs, proteins, enzymes, antibodies, etc., they can be directed to an organ, tissue or tumor with the help of an external magnetic field. The methods described below allow to obtain magnetic nanoparticles with narrow size dimensions, desired shape and morphology, by changing the conditions and/or parameters of the synthesis. The most used and popular method for the synthesis of magnetite, being in the same time simple and efficient, is the

The first synthesis of superparamagnetic iron oxide nanoparticles was reported by Massart, and the method consists in mixing two salts of Fe3+ and Fe2+ in a molar ratio of 2:1 in aqueous medium

atmosphere or at elevated temperature, resulting a black magnetic precipitate [40]. The equation of the chemical reaction which underlies the formation of magnetite may be written as Eq. (1):

Magnetite is not stable at room temperature, being sensitive to oxidation in contact with air,

*O*<sup>4</sup> + <sup>1</sup>⁄<sup>2</sup> *O*<sup>2</sup> → 3*γ* − *Fe*<sup>2</sup>

The precipitation process is based on two steps regarding the formation of the solids [41, 42]: (i) nucleation—a very short period, occurs only when the concentration of the constituent species reaches suprasaturation and (ii) slow controlled growth of the preformed nuclei, by diffusion from the solutions to the surfaces of the crystal. To avoid the formation of polydispersed nanoparticles, it is necessary that the two stages to be separated, i.e., nucleation does not take place simultaneously with crystal growth. By controlling the two processes, monodispersed magnetic particles can be obtained. If the nuclei start to form in the same time, the growth of these nuclei leads to particles with very narrow size distribution. Therefore, the size of the obtained particles can be controlled but only in the nucleation step because the size of the

It has been shown that by controlling both the pH of the reaction medium and the ionic strength, it is possible to control the mean size of the particles. Jiang et al. have demonstrated that the size of the particles has an inverse proportionality with the pH and the ionic strength of the precipitation medium [43]. These two parameters (pH and the ionic strength) also affect

the chemical surface of the crystals and the electrostatic surface charge [44].

followed by precipitation of these salts using a precipitating agent (a base – NH3

*Fe* 2+ + 2*Fe* 3+ + 8*OH*<sup>−</sup> → *Fe*(*OH* )2 + 2*Fe*(*OH* )3 → *Fe*<sup>3</sup>

easily transforming into maghemite, according to Eq. (2):

particles does not change during the growth process.

2*Fe*<sup>3</sup>

(γ-Fe<sup>2</sup> O3

236 Iron Ores and Iron Oxide Materials

O4

*O*4↓ + 4 *H*<sup>2</sup>

*O*<sup>3</sup> (2)

) and maghemite

) under inert

*O* (1)

Thermal decomposition of organometallic compounds in high boiling organic solutions in the presence of stabilizers is also a popular method for the synthesis of the spinel structured Fe3 O4 and a very promising technique for obtaining high-quality superparamagnetic iron oxide nanoparticles. The magnetic nanoparticles obtained by this method proved to be superior to those obtained by precipitation, because the nucleation process can be separated by the growth process and the hydrolysis reaction is avoided [48].

The method is based on the decomposition of an iron precursor at high temperature in the presence of solvents which contain stabilizing surfactants (such as oleic acid or oleylamine) [49–51]. By varying the reaction mixtures and modifying the synthesis condition, it can be obtained M-IONPs with controlled size, size distribution and composition. The most commonly used precursors employed to prepare monodispersed M-IONPs with diameter ranging from 3 to 50 nm are of the form: (I) metal acetylacetonate—[M(acac)n] (where M = Fe, Co, Ni, Mn, Cr; n = 2 or 3) [52]; (II) metal cupferronates—[M<sup>x</sup> (cup)x ] (where cup = N-nitrosophen ylhydroxylamine); (III) metal oxalate—[M(C<sup>2</sup> O4 ) <sup>n</sup>•2H2 O]; (IV) metal carbonyl—Fe<sup>3</sup> (CO)12 [53] or Fe(CO)<sup>5</sup> [50]; (V) metal acetate—[M(CH<sup>3</sup> COO)n]; (VI) metal carboxylate, (VII) metal-urea complex—[Fe(CON<sup>2</sup> H4 ) 6 ](NO3 ) 3 [54]; (VIII) Prussian Blue—Fe<sup>4</sup> [Fe(CN)<sup>6</sup> •14H2 O] [55, 56]; (IX) metal chloride and (X) ferrocene—Fe(C<sup>2</sup> H5 ) 2 [57].

and poly-vinylpyrrolidone (PVP). Throughout time, the microemulsion method proved to be a simple and versatile method for fabrication of nanosized magnetic nanoparticles [61–65].

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

According to the literature, the size of the resulted nanoparticles can be controlled if the surfactant is proper chose and also by varying the ratio of water/oil/surfactant, the initial concentration of the reactants and the droplet size and by controlling the reaction temperature and time [66, 67]. The size of the synthesized nanoparticles can also be controlled in suitable

Lu et al. demonstrated that the surfactant nature has an important role on the final properties of the nanoparticles [64]. The authors have investigated the effect of SDS (anionic surfactant), DTAB and CTAB (cationic surfactants) and non-ionic surfactant on the preformed crystal, on

O4

in the case of using the cationic surfactants also obtained a good saturation magnetization,

Okoli et al. have prepared M-IONPs by the two types of microemulsion (water/oil and oil/ water), to be used in binding and separation of proteins. The authors demonstrated that by using a water/oil microemulsion, it can obtain magnetic iron oxide nanoparticles with a surface area

emulsion [68, 69]. The M-IONPs specific surface area is inversely proportional with the size of nanoparticles, the higher is the specific surface area the smaller nanoparticles size is obtained.

The advantage of this method is the fact that it can be obtain magnetic nanoparticles with uniform morphology and controllable size; but the major drawbacks are the requirements of

In case of these methods, the reaction takes place in aqueous medium (the hydrothermal method) or in organic medium (solvothermal method), in reactors or autoclaves, at temperatures between 130 and 250°C under high vapor pressure, in the range 0.3–4 MPa [70–72]. Using this method, it can be obtained magnetic iron oxide nanoparticles with tailored properties (size and shape) by tuning the reaction conditions. The hydrothermal method is known as an environment-friendly process for the obtaining of M-IONPs, due to the raw materials used

Lin et al. [74] has used hydrothermal and solvothermal methods to obtain hollow M-IONPs.

acetate and urea were used to guide the formation of hollow magnetite spheres. After homogeneous dispersion, the mixture is transferred to a Teflon-lined stainless steel autoclave and

by the Mössbauer measurements. Tian et al. synthesized ultra-small monodisperse Fe3

nanoparticles, with precise size control of 1 nm, by solvothermal method [75]. They used

as iron source, n-octanol as a solvent and n-octylamine as a reductant. The authors

nanoparticles with a size range from 4 to 6 nm, by varying the volume ratios

sealed to heat at about 200°C for 8–24 h. The authors demonstrated that the Fe3+

(as source of iron), ethylene glycol (as reducing agent), ammonium

O4

a large amount of solvent and the excess of surfactant that has to be eliminated.

such as sulfates and chlorides—as cation source, dissolved in water [73].

the surface of the hollow spheres exist in the form of Fe3

O4

http://dx.doi.org/10.5772/intechopen.74176

nanoparticles with size less than 16 nm, but

/g for the magnetic nanoparticles obtained by oil/water micro-

nanoparticles.

239

ions on

O4

, and the results are confirmed

narrow range by carrying out the reaction in nanoreactor [62, 64, 67].

In all the cases, the authors have obtained Fe3

/g compared to 304 m2

**3.4. Hydrothermal and solvothermal methods**

Briefly, they used FeCl<sup>3</sup>

O4

Fe(acac)3

obtained Fe3

of 147 m2

which is an essential parameter for biological applications.

stoichiometric situations and on the magnetic properties of the resulted Fe3

Using the thermal decomposition method, it can be easy to control the size and morphology of magnetic nanoparticles by controlling the ratio of the starting reagents, i.e. the ratio between the organometallic compounds, surfactant and solvent. Reaction time, temperature and aging period are equally important for the control of size and morphology. Hyeon obtained monodispersed iron oxide nanoparticles with size range from 4 to 20 nm by thermal decomposition of Fe(CO)<sup>5</sup> in the presence of oleic acid at 100°C. Initially, he obtained an iron-oleic acid complex, which was leaved to aging at high temperature (300°C) [50].

Pérez-Mirabet et al. used oleylamine both as stabilization agent (for the stabilization of the particles in solution) and as capping ligand (for the control of particles size), respectively, by one-pot thermal decomposition of Fe(acac)3 and M(acac)2 (M = Co, Mn, Cu and Zn) in oleylamine. They obtained magnetic spinel ferrite nanoparticles with average size of 12 nm and a saturation magnetization Ms = 76 emu/g, very close to the bulk magnetite (92 emu/g) [58].

This method is also suitable for synthesis of nanocubes and nanospheres, which are magnetic nanoparticles as well. Amara et al. synthesized Fe<sup>3</sup> O4 nanocubes and nanospheres by a new simple and single-step process [59]. They used various mixtures of ferrocene and polyvinylpyrrolidone (PVP) by solventless thermal decomposition. Lynch et al. obtained magnetic colloidal iron oxide nanoparticles by thermal decomposition. They generated gas bubbles (Ar) by boiling solvents. Their results illustrated that the argon bubbles had a stronger effect on the nucleation process of magnetic iron oxide nanoparticles than on their growth process [60]. Due to the nucleation process that involves boiling solvents, most often the accurate shape of the magnetic iron oxide nanoparticles is not fully reproducible using the thermal decomposition method.
