Applications and Toxicology of Iron Oxide Nanoparticles

Abstract

Iron oxide nanoparticles have been intensively studied in the last decade for their unusual physical and chemical properties owing to their extremely small size, large specific surface area and number of promising applications. In Medical applications including magnetic resonance imaging, cell separation and detection, tissue repair, magnetic hyperthermia and drug delivery, iron oxide nanoparticles (IONPs) have been extensively used due to their remarkable properties, such as superparamagnetism, size and possibility of receiving a biocompatible coating. The development of magnetic iron oxide nanoparticles with improved biocompatible surface engineering to achieve minimal toxicity, for various applications in biomedicine is much more inevitable. In this article Iron oxide and its applications were discussed when it is nano dimension with its nanotoxicology.

1. Introduction

The most important metal oxides are presently Titanium oxide (TiO₂), Zinc oxide (ZnO), Magnesium oxide (MgO), Copper oxide (CuO), Aluminium oxide (Al₂O₃), Manganese oxide (MnO₂) and Iron oxide (Fe₃O₄ and Fe₂O₃). Iron oxide is a range of chemical compounds made up of iron and oxygen. These are naturally occurring; some form in the soil or in chemical deposits in rocks or mountains. Not all oxides are functional to humans, but numerous metal oxide play prominent roles in industry, cosmetics, etc. Iron and its compounds are abundantly available in nature and readily synthesised in the laboratory. The two most commonly studied iron oxides have been magnetite (Fe₃O₄) and maghemite (γ-Fe₂O₃).

Magnetite (Fe₃O₄) is a black colour mineral, containing both Fe (II) and Fe (III) and exhibiting ferromagnetic behaviour. It develops in a variety of species and aids with orienting. Alternative names for magnetite include ferrous ferrite, iron (II, III) oxide, magnetic iron ore, black iron oxide, and iron oxide.

Maghemite (-Fe₂O₃) is an structural reddish-brown ferromagnetic mineral that is similar to magnetite but has a cation deficient site. It happens in soils as a weathering byproduct of magnetite or as a byproduct of heating other Fe oxides, typically in the presence of organic materials.

IONPs are naturally occurring particles in the environment that are produced during volcanic eruptions and air pollution. Particles of either Fe₃O₄ (magnetite) or -Fe₂O₃ (maghemite), can be formed as emissions from vehicles, manufacturing, and energy plants, but they can also be specially chemically synthesised for a number of uses. Various methods can be employed in their fabrication such as synthesis by water in oil microemulsion system, co-precipitation reactions in constrained environments, polyol method, flow injection synthesis and sonolysis [1, 2, 3].

As high magnetization values are needed for applications like as imaging and therapy, magnetic behaviour is a crucial factor in the design and synthesis of superparamagnetic iron oxide NPs (SPIONs). Although this may be achieved by applying the highest magnetic field permitted in clinical settings, it is also possible to manipulate the reaction conditions during the synthesis processes to produce particles with a large surface area and high magnetic susceptibility. Iron oxides are chemical compounds composed of iron and oxygen. Altogether, there are 16 recognised iron oxides and oxyhydroxides as shown inTable 1. The uses of these various oxides and hydroxides are tremendously diverse ranging from pigments in ceramic glaze, to use in thermite.

Type of iron oxide	Colour	Chemical formula	Mag. behaviour at room temp.
Goethite	Yellow brown	α-FeOOH	Antiferromagnetic
Lepidocrocite	Orange	β-FeOOH	Paramagnetic
Akaganeite	Brown to bright yellow	γ-FeOOH	Paramagnetic
Feroxyhyte	Red brown	δ-FeOOH	Ferrimagnetic
	Red brown	δ′–FeOOH	Superparamagnetic
		High pressure FeOOH
Ferrihydrate	Reddish brown	Fe5HO8·4H2O	Superparamagnetic
Bernalite	Greenish white	Fe(OH)3	Weakly ferromagnetic
		Fe(OH)2
Schwertmannite	Yellow	Fe16O16 (OH)y(SO4)·nH2O	Paramagnetic
Haematite	Red	α-Fe2O3	Weakly ferromagnetic
Magnetite	Black	Fe3O4	Ferromagnetic
Maghemite	Dark brown	γ-Fe2O3	Ferrimagnetic
		β-Fe2O3
		ε-Fe2O3
Wustite	Black	FeO	Paramagnetic

Table 1.

Recognised iron oxides in 16 forms.

Oxides:

• Iron (II) oxide, wustite (FeO)

• Iron (II, III) oxide, magnetite (Fe₃O₄)

• Iron (III) oxide (Fe₂O₃)

• Alpha phase, haematite (α-Fe₂O₃)

• Beta phase, (β-Fe₂O₃)

• Gamma phase, maghemite (γ-Fe₂O₃)

• Epsilon phase, (ε-Fe₂O₃)

  Hydroxides:

• Iron (II) hydroxide (Fe(OH)₂)

• Iron (III) hydroxide (Fe(OH)₃), (bernalite)

  Oxide/hydroxide:

• Goethite (α-FeOOH)

• Aakaganeite (β-FeOOH)

• Lepidocrocite (γ-FeOOH)

• Feroxyhyte (ε-FeOOH)

• Ferrihydrite (Fe₅HO₈·4H₂O or 5Fe₂O₃·9H₂O)

• High-pressure FeOOH

• Schwertmannite (ideally Fe₈O₈(OH)₆(SO)·nH₂O

With the formula Fe₂O₃, iron oxide, often known as ferric oxide, is an inorganic substance. It is one of the three primary forms of iron oxide; the other two are the uncommon iron (II) oxide (FeO) and the naturally occurring iron (II, III) oxide (Fe₃O₄) found in the mineral magnetite. Fe₂O₃ is the primary source of iron for the steel industry as the mineral haematite. Acids easily destroy the reddish-brown, paramagnetic Fe₂O₃. As rust and iron (III) oxide have similar compositions and share a number of features, it might be helpful to refer to rust by this name in some situations. Rust, also known as hydrated ferric oxide, is thought of as an ill-defined substance. Magnetite and maghemite are preferred in biomedicine because they are biocompatible and potentially non-toxic to humans. Iron oxide is easily degradable and therefore useful for in-vivo applications.

Generally, magnetite (Fe₃O₄) and maghemite (γ-Fe₂O₃) are the two main forms which have attracted widespread interest in biomedical applications due to their super paramagnetic properties. Fe₃O₄ exhibits the larger magnetism than γ-Fe₂O₃ because it is in a more stable form. It is also known as black oxide and contains both divalent and trivalent Fe ions. Maghemite (-Fe₂O₃) is a reddish-brown weathering by product of magnetite that is found in soil. The oldest iron oxide known is haematite (Fe₂O₃), which is also known as ferric oxide. These iron oxides are incredibly stable at ambient temperatures and frequently appear as the byproducts of the transformation of other iron oxides. Some of the physical and magnetic properties are presented in Table 2 [4, 5].

Property	Magnetite	Maghemite
Formula	Fe3O4	γ-Fe2O3
Lattice parameter (nm)	a = 0.8396	a = 0.8347
Crystallographic system	Cubic	Cubic or tetrahedral
Structural type	Inverse spinel	Defect spinel
Type of magnetism	Ferromagnetic or superparamagnetic	Ferromagnetic or superparamagnetic
Density (g/cm^3)	5.18	4.87
Melting point (°C)	1583–1597	—
Hardness	5.5	5
Type of magnetism	Ferrimagnetic	Ferrimagnetic
Curie temperature (K)	850	820–986
Ms at 300 K (A-m^2/kg)	92–100	60–80
Standard free energy of formation (kJ/mol)	−1012.6	−711.1

Table 2.

Physical and magnetic properties of iron oxide nanoparticles.

2. Magnetic properties of IONPs

The physical property of magnetic materials known as magnetism results from the mobility of electron orbitals or intrinsic spin caused by the existence of unpaired electrons (Figure 1). Unpaired electrons are required for iron and some materials containing iron to exhibit magnetic behaviour. Magnetic solids are better understood as a collection of magnetic dipole moments because of the abundance of electrons in materials.

Figure 1.

Magnetic moment of an electron. Source: https://www.embibe.com.

If a magnetic material is positioned in a magnetic field H, the individual atomic moments in the material contribute to induce the magnetic flux inside the materials can be written as

$$B={\mu }_o\left(H+M\right)$$E1

where μ_o is the vacuum permeability (12.566 × 10⁻⁷ VsA⁻¹ m⁻¹) and the magnetization M = m/V is the magnetic moment per unit volume, where m is the magnetic moment on a volume V of the material. In the regime, where the magnetization scales linearly with H, it is useful to define the magnetic susceptibility (χ) as,

$$M=\chi H$$E2

Fundamentally, there are two types of magnetic measurements for magnetic particles:

1. Magnetization as a function of applied field with temperature (M-H loop).

2. Magnetization as a function of temperature at a given magnetic field.

Figure 2 shows hysteresis loop of magnetic material at constant temperature. Magnetic hysteresis refers to the irreversibility of the magnetization and demagnetization process. The saturated magnetization (M_s) is the magnetic moment per unit volume of the material obtained when a sufficiently large magnetic field is applied to remove all domain walls and aligns the magnetization of the sample with the field. Remanent magnetization (M_r) is the magnetization that remains after an applied field has been removed. Coercivity (H_c) is the applied magnetic field required for reduction of a saturated magnetic material to zero magnetization.

Figure 2.

Hysteresis curve of a ferromagnetic material at constant temperature. Source: http://electrons.wikidot.com.

The ZFC-FC curve is obtained by measuring the magnetization, when cooling the sample to the low temperature in the same field as shown in Figure 3. In the ZFC and FC measurements, the field must be weak enough in comparison with the anisotropy field to guarantee that the ZFC-FC curve reflects the intrinsic energy barrier distribution.

Figure 3.

Typical ZFC-FC magnetization measurement of magnetic material. Source: Materia (Rio J.).

For the ZFC (Zero Field Cooled) curve, the sample is first cooled in a zero field from a high temperature well above blocking temperature (T_B), down to a low temperature much below T_B, where nanoparticles are in a ferromagnetic state, where they are in a superparamagnetic state. After that, a magnetic field is provided, and as the material is heated to a temperature well over the blocking temperature, the magnetization as a function of temperature is monitored.

3. Superparamagnetism

The magnetic behaviour of materials depends on the structure of the material and particularly on its electron configuration. There are several types of magnetism in materials identified as paramagnetism, ferromagnetism, superparamagnetism, antiferromagnetism and ferrimagnetism.

Superparamagnetic materials exhibit non-magnetic moment in the absence of an external magnetic field but can respond to the alignment of the magnetic dipoles along with the external magnetic field. On the other hand, in the presence external magnetic field, they can develop a net magnetic moment. Superparamganetism has a zero intrinsic coercivity, high saturation magnetization, no hysteresis nature like ferromagnetic and no remanence magnetism as presented in Figure 4. Generally, superparamagnetism takes place when the material is composed of very small crystallites, i.e. less than 30 nm. Since the particles are very small, no permanent magnetization experiences after the magnetic particles are isolated from the applied magnetic field.

Figure 4.

Hysteresis loop of superparamagnetic material. Source: https://doi.org/10.1063/1.4820992.

In a superparamagnetic material, Even though magnetic moments are forcing themselves to line up along the field direction, the thermal vibration energy of each particle has a magnitude similar to the magnetic energy, thus the magnetic moments shift their direction arbitrarily as a result. As a result, there is no net magnetic reaction, and the substance acts like a paramagnetic substance. The superparamagnetic materials may still react to an external magnetic field and yet have significant magnetic characteristics with a very high susceptibility. Because of the thinness of the hysteresis loop and lack of remanence or coercively in superparamagnetic materials. The facile resuspension, high surface area, slow sedimentation, stability and dispersion of magnetic force, and lack of magnetic remanence are some benefits of the superparamagnetic particles [6, 7, 8, 9, 10]. Subsequently, these advantages make iron oxide crystallites with smaller grain sizes to employ in many applications such as separation, purification, drug delivery device, cancer treatments through hyperthermia and as a contrast agent in Magnetic Resonance Imaging (MRI).

4. Applications of IONPs

Iron oxide nanoparticles (IONPs) are fairly a fascinating material have already found in many applications mainly due to large surface to volume ratio and extraordinary magnetic properties. IONPs exhibit sorbent properties, which were successfully tested on removal organic dyes and toxic inorganic metal pollutants from industrial waste water. Moreover, their magnetic properties and ability of the modified surface to selectively bind chemicals show promise of the future industrial interest in magnetically separable sorbents and filtration media.

Maghemite and magnetite NPs have been used in magnetic recording media such as tapes and HDDs. However, current industrial demand for higher recording density have reduced the size of used NPs. High susceptibility and low coercivity of superparamagnetic iron oxide NPs (SPIONs) and their biocompatibility and biodegradability show great potential for applications in biomedicine. In this thesis, some of the applications of IONPs have been discussed briefly which are relevant to our studies.

4.1 Biomedical applications of IONPs

Magnetically responsive nano and micro particles have been employed in various areas of biosciences, biotechnology and environmental technology. Biomedicine related applications are mainly based on the utilisation of selected properties, namely magnetic separation, magnetic targeting, hyperthermia, drug delivery, MRI contrast and antibacterial.

Target molecules, cell organelles, and cells can be quickly isolated using magnetic separation from complex biological mixtures and raw samples like blood, bone marrow, tissue homogenates, urine, stools, and other biological materials. Magnetic separation is a very straightforward, quick, efficient, and gentle technique. The chemicals and cells that magnetic separation isolates are often unmodified, pure, and viable. When there is a requirement for large yields of pure and physiologically active chemicals and biological structures on a small scale, gentle test tube magnetic separation is the method of choice.

Hyperthermia treatment is a gifted therapy for cancer where the temperature of the tumour tissue is raised slightly above physiological temperature, i.e. about 42–46°C by artificially. This is based on the fact that when magnetic materials are exposed to an AC magnetic field it generates heat. The heating occurs due to magnetic losses in the form of hysteresis loss. Both bulk magnetic materials and tiny magnetic particles can be employed. Yet due to their advantageous magnetic characteristics in connection to hyperthermia therapy and simplicity of delivery in the target tissues, tiny magnetic particles, especially nanomagnetic materials, have replaced bulk magnetic materials.

Iron oxide particles (IONPs) are routinely used in clinics as a contrast agent for magnetic resonance imaging (MRI). Tracking and monitoring of stem cells in-vivo after transplantation can supply important information for determining the efficacy of stem cell therapy. The most reliable and secure non-invasive method for tracking stem cells in living organisms is thought to be magnetic resonance imaging (MRI) in combination with contrast chemicals. Commercially available superparamagnetic iron oxide nanoparticles (SPIONs) have been used to identify stem cells with the use of transfection agents (TAs).

Magnetic iron oxide nanoparticles attached with drugs has been found that a perspective field of targeted drug delivery where distribution of drug attached with magnetic nanoparticles within the body is manipulated by external magnetic field. A more successful treatment outcome is anticipated if magnetic particles associated with medications can be condensed into the appropriate location by an external magnetic field and then subjected to an AC magnetic field. For the aim of delivering medications, liposomes have been widely used. Liposomes have also been utilised to distribute magnetic particles effectively (known as magnetoliposomes). Targeting of therapeutic agents is necessary for maximum utilisation thereby reducing dose and avoid unwanted adverse effects due to higher doses. Targeting through monoclonal antibody is also used for targeting different drugs/biological molecules to their desired site.

Antibacterial agents are crucial for the food packaging sector, the textile industry, and water purification. The toxicity of organic chemicals used for disinfection is one of its drawbacks. As a result, inorganic disinfectants like metal oxide nanoparticles (NPs) are becoming more popular. The inorganic nanostructured materials with effective surface modification show good antimicrobial inhibition activity. Such improved antibacterial agents locally destroy bacteria, without being toxic to the surrounding tissue. The iron oxide nanoparticles have been widely favoured as antibacterial agents because of low cytotoxicity, biodegradable and reactive surface that can be modified with biocompatible coatings. The mechanism of antimicrobial property of nanoparticle lies with the fact that the large surface area relative to the volume, which effectively covers the microorganisms and reduce oxygen supply for respiration.

4.2 Heavy metals and dye removal from water

Water resources become critical important to living things, but there is a major environmental concern due to an increasing pollution from industrial wastewater. Several sectors, including pulp, paper, textile, and plastics, use chemicals and dyes to produce their goods and need a lot of water as well. As a result, harmful substances including heavy metals and chemical compounds infiltrate water. The toxins have negative effects on both the terrestrial and aquatic environments. The use of magnetic IONPs coated with appropriate surfactants to remove pollutants from wastewater shows promise. Magnetic loaded adsorbent materials have gained special attention in water purification due to various advantages such as high separation efficiency, simple manipulation process, fast processing speed, economic and environmental friendly, able to handle concentrated feed, selectivity to particular guest molecules and easy specifically functional modifications.

Municipal wastewater frequently contains copper, which may be harmful to living beings. Techniques including ion extraction, coagulation, or adsorption have been used to remove it, however they have limitations because to their limited sensitivity and cross reactivity. Currently, surface modified IONPs afford an alternative in bioremediation processes for the removal of Cu (II), Cr (VI), Ni etc., from water by adsorption.

The most polluted industry in the world is textiles industry, since it requires a huge amount of two major components, chemicals and water. More than 1000 different chemicals have been used in textiles industry, mostly they are dyes and transfer agents. Natural and synthetic dyes are used in textiles industry for economical and efficiency reasons. It creates problems to the environment, due to the fact that many synthetic dyes are made to be very stable compounds that are resistant to degradation by light, chemicals, and biological processes. Certain synthetic colours used in commerce frequently contain unreportedly huge, complicated structures. Since dye wastewater contains several contaminants, including acid or caustic, dissolved solids, hazardous compounds including heavy metals, and colour, it can be one of industry’s biggest problems to discharge. Colour is one of them and is readily identifiable in wastewater since it is very apparent. Moreover, these coloured effluents pose serious environmental risks. Synthetic dyes are present in little amounts, but they are extremely visible and unwanted. The majority of synthetic dyes are also recalcitrant/stable, poisonous, non-degradable, extremely soluble in water, and even carcinogenic.

4.3 Corrosion inhibition on mild steel

Corrosion is the destructive attack to metal by chemical or electrochemical reaction problem in mild steel, since which is easily corroded in acidic medium. To guard against corrosive environments, mild steel was coated with a corrosion inhibitor. A corrosion inhibitor is a substance that prevents corrosion by creating a barrier coating of protection, which in turn halts the corrosive reaction. Paint is a substance that stops corrosive media like air and water from coming into direct contact with the metal surface. After curing, it produces a thin, homogenous coating that shields the base metal from corrosion caused by its surroundings. Various metal oxide materials have been used in the formulation of paints. Mixed metal oxides are synthesised from corresponding oxides and are used as pigments in paints which constitute the nanoformulated paints. Nanoformulated paint coatings are being carried out on mild steel plate and the coatings were tested in corrosion atmosphere. The most common corrosion inhibitors are costly, environmentally hazardous organic or inorganic compounds. Mechanistic knowledge of the mechanisms involved in corrosion and inhibition is required for optimal inhibitor selection. As a result, researchers are creating brand-new eco-friendly inhibitors based on natural ingredients and environmentally friendly biopolymers. The organic derivatives found in natural goods with plant origins, such as alkaloids, polysaccharides, pigments, organic acids, and amino acids, can be employed as corrosion inhibitors. Gums and other polysaccharides have been utilised as corrosion inhibitors for metals in salty, acidic, and alkaline conditions.

5. Nanotoxicology

Nanotoxicology is the study of the potentially detrimental effects of nanomaterials, in particular nanoparticles, on living creatures. Toxicology is the study of potentially hazardous effects of chemicals on living organisms. Understanding the link between the toxicity of NPs and their physical-chemical characteristics, such as size, shape, reactivity, and material composition, is the main goal of nanotoxicology. There are hundreds of commercially available products using nanotechnology currently on the market including cosmetics, sunscreens, textiles, sport items, veterinary medicines and so on.

The changes in nanoparticle size and structure play an important function on cell toxicity, with rod-shaped or nano-sized IONPs being more toxic than sphere-shaped and microsized particles, respectively. The surface charge of Iron Oxide Nanoparticles could affect cell cytotoxicity and genotoxicity. Absolutely charged IONPs were shown to be more toxic, since they suffer nonspecific interactions and adsorptive endocytosis with the negatively charged cell membrane, thereby increasing their intracellular accumulation and affecting cell membrane integrity.

Nanoparticles are emitted into the environment by primary sources such as natural phenomena, combustion processes or industrial activities during generation and handling of engineered NPs. As NPs are transported through the environment, they can be physically and chemically modified due to interactions with sunlight, water and other environmental substances. The rapid growth of nanotechnology industry and its ever increasing applications will inevitably increase the concentration of nanomaterials in the environment with potential human and environmental exposure as a consequence. The human body is exposed to NPs through four possible routes: inhalation of airborne NPs, ingestion of drinking water or food additives, dermal penetration by skin contact and injection of engineered nanomaterials.

5.1 Prevention of toxicity of IONPs

Studies have shown that iron oxide nanoparticles require a biocompatible coating to prevent agglomeration that may lead to toxicity in biological media. The clearance rate, cell toxicity, and cellular response to superparamagnetic iron oxide nanoparticles are significantly influenced by their dimension and surface properties. In general, macrophages are more likely to take up nanoparticles with sizes greater than 200 nm. On the other hand, extravasations and renal clearance both work quickly to eliminate tiny particles with sizes less than 10 nm. This suggests that the best likelihood for a particle to remain in circulation for a longer period of time is between 10 and 200 nm. Amphiphilic coatings are used to increase the circulation duration of superparamagnetic iron oxide nanoparticles from minutes to hours. This increases the targeting potential of a surface-modified contrast agent and prevents a harmful contact between the particles.

Several studies have revealed that the polymer coated nanoparticles barely affect the viability and functionality of cells. A biodegradable polymer coating was used to stabilise the magnetic nanoparticles that Gomez-Lopera et al. created. In their work they were synthesised colloidal nanoparticles that were highly responsive to magnetic field for drug delivery systems. Another study shows that dextran coated superparamagnetic nanoparticles labelled with a cationic peptide had no significant effect on cell viability or the biodistribution of human haematopoietic cells.

In summary, all studies have shown that iron oxide nanoparticles with biological coating very prominent and inevitable in reducing the toxicity to the cells which uptake them. Recently the nanotechnology has been moving towards to develop a new kind of materials without any harmfulness to the society by adopting green synthesis procedures [11, 12, 13, 14].

6. Conclusion

This article briefly presents the characteristics of nanosized metallic iron oxides, as well as their applications and toxicology. Metal oxides at nanoscale as iron oxides, haematite (α-Fe₂O₃) and maghemite (γ-Fe₂O₃) have been widely applied in various mankind applications since they are strongly dependent on the size of their particles and surface area. As a result of the reduction of particle size, there is an increase in atoms located on the surface and consequently an increase in the catalytic activity of nanoparticles iron oxidehematite and maghemite.