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Iron oxide nanoparticles areiron oxide particles with diameters between about 1 and 100nanometers. The two main forms are composed ofmagnetite (Fe3O4) and its oxidized formmaghemite (γ-Fe2O3). They have attracted extensive interest due to theirsuperparamagnetic properties and their potential applications in many fields (althoughcobalt andnickel are also highly magnetic materials, they are toxic and easily oxidized) includingmolecular imaging.[1]
Applications of iron oxide nanoparticles includeterabitmagnetic storage devices,catalysis,sensors,superparamagnetic relaxometry, high-sensitivity biomolecularmagnetic resonance imaging,magnetic particle imaging,magnetic fluid hyperthermia, separation of biomolecules, and targeted drug and gene delivery for medical diagnosis and therapeutics. These applications require coating of the nanoparticles by agents such as long-chainfatty acids,alkyl-substituted amines, anddiols.[citation needed] They have been used in formulations for supplementation.[2]
Magnetite has aninverse spinel structure with oxygen forming a face-centeredcubic crystal system. In magnetite, all tetrahedral sites are occupied byFe3+
and octahedral sites are occupied by bothFe3+
andFe2+
. Maghemite differs from magnetite in that all or most of the iron is in the trivalent state (Fe3+
) and by the presence ofcationvacancies in the octahedral sites. Maghemite has a cubicunit cell in which each cell contains 32 oxygen ions, 211⁄3Fe3+
ions and 22⁄3 vacancies. The cations are distributed randomly over the 8 tetrahedral and 16 octahedral sites.[3][4]
Due to its 4unpaired electrons in3d shell, an iron atom has a strongmagnetic moment. IonsFe2+
have also 4 unpaired electrons in 3d shell andFe3+
have 5 unpaired electrons in 3d shell. Therefore, when crystals are formed from iron atoms or ionsFe2+
andFe3+
they can be inferromagnetic,antiferromagnetic, orferrimagnetic states.
In theparamagnetic state, the individual atomic magnetic moments are randomly oriented, and the substance has a zero net magnetic moment if there is nomagnetic field. These materials have a relativemagnetic permeability greater than one and are attracted to magnetic fields. The magnetic moment drops to zero when the applied field is removed. But in a ferromagnetic material, all the atomic moments are aligned even without an external field. A ferrimagnetic material is similar to a ferromagnet but has two different types of atoms with opposing magnetic moments. The material has a magnetic moment because the opposing moments have different strengths. If they have the same magnitude, the crystal is antiferromagnetic and possesses no net magnetic moment.[5]
When an external magnetic field is applied to a ferromagnetic material, themagnetization (M) increases with the strength of the magnetic field (H) until it approachessaturation. Over some range of fields the magnetization hashysteresis because there is more than one stable magnetic state for each field. Therefore, aremanent magnetization will be present even after removing the external magnetic field.[5]
Asingle domain magnetic material (e. g. magnetic nanoparticles) that has no hysteresis loop is said to besuperparamagnetic. The ordering of magnetic moments in ferromagnetic, antiferromagnetic, and ferrimagnetic materials decreases with increasing temperature. Ferromagnetic and ferrimagnetic materials become disordered and lose their magnetization beyond theCurie temperature and antiferromagnetic materials lose their magnetization beyond theNéel temperature.Magnetite is ferrimagnetic at room temperature and has a Curie temperature of 850K.Maghemite is ferrimagnetic at room temperature, unstable at high temperatures, and loses itssusceptibility with time. (Its Curie temperature is hard to determine). Both magnetite and maghemite nanoparticles are superparamagnetic at room temperature.[5]This superparamagnetic behavior of iron oxide nanoparticles can be attributed to their size. When the size gets small enough (<10 nm),thermal fluctuations can change the direction of magnetization of the entire crystal. A material with many such crystals behaves like aparamagnet, except that the moments of entire crystals are fluctuating instead of individual atoms.[5]
Furthermore, the unique superparamagnetic behavior of iron oxide nanoparticles allows them to be manipulated magnetically from a distance. In the latter sections, external manipulation will be discussed in regards to biomedical applications of iron oxide nanoparticles. Forces are required to manipulate the path of iron oxide particles. A spatially uniform magnetic field can result in a torque on the magnetic particle, but cannot cause particle translation; therefore, the magnetic field must be a gradient to cause translational motion. The force on a point-like magnetic dipole momentm due to a magnetic fieldB is given by the equation:
In biological applications, iron oxide nanoparticles will be translate through some kind of fluid, possibly bodily fluid,[6] in which case the aforementioned equation can be modified to:[7]
Based on these equations, there will be the greatest force in the direction of the largest positive slope of the energy density scalar field.
Another important consideration is the force acting against the magnetic force. As iron oxide nanoparticles translate toward the magnetic field source, they experience Stokes' drag force in the opposite direction. The drag force is expressed below.
In this equation, η is the fluid viscosity, R is the hydrodynamic radius of the particle, and 𝑣 is the velocity of the particle.[8]
The preparation method has a large effect on shape, size distribution, andsurface chemistry of the particles. It also determines to a great extent the distribution and type of structural defects or impurities in the particles. All these factors affect magnetic behavior. Recently, many attempts have been made to develop processes and techniques that would yield "monodispersecolloids" consisting of nanoparticles uniform in size and shape.
By far the most employed method iscoprecipitation. This method can be further divided into two types.In the first,ferrous hydroxidesuspensions are partially oxidized with different oxidizing agents. For example, spherical magnetite particles of narrow size distribution with mean diameters between 30 and 100 nm can be obtained from aFe(II) salt, a base and a mild oxidant (nitrate ions).[9] The other method consists in ageing stoichiometric mixtures of ferrous and ferric hydroxides in aqueous media, yielding spherical magnetite particles homogeneous in size.[10] In the second type, the following chemical reaction occurs:
Optimum conditions for this reaction arepH between 8 and 14,Fe3+
/Fe2+
ratio of 2:1 and a non-oxidizing environment. Being highly susceptibile to oxidation, magnetite (Fe3O4) is transformed to maghemite (γFe2O3) in the presence of oxygen:[3]
The size and shape of the nanoparticles can be controlled by adjusting pH,ionic strength, temperature, nature of thesalts (perchlorates,chlorides,sulfates, and nitrates), or theFe(II)/Fe(III) concentration ratio.[3]
Amicroemulsion is a stableisotropicdispersion of 2immiscible liquids consisting of nanosized domains of one or both liquids in the other stabilized by aninterfacial film of surface-active molecules. Microemulsions may be categorized further as oil-in-water (o/w) or water-in-oil (w/o), depending on the dispersed and continuous phases.[4]Water-in-oil is more popular for synthesizing many kinds of nanoparticles. The water and oil are mixed with an amphiphillicsurfactant. The surfactant lowers the surface tension between water and oil, making the solution transparent. The water nanodroplets act as nanoreactors for synthesizing nanoparticles. The shape of the water pool is spherical. The size of the nanoparticles will depend on size of the water pool to a great extent. Thus, the size of the spherical nanoparticles can be tailored and tuned by changing the size of the water pool.[11]
The decomposition of iron precursors in the presence of hot organic surfactants results in samples with good size control, narrow size distribution (5-12 nm) and goodcrystallinity; and the nanoparticles are easily dispersed. For biomedical applications like magnetic resonance imaging, magnetic cell separation or magnetorelaxometry, where particle size plays a crucial role, magnetic nanoparticles produced by this method are very useful. Viable iron precursors includeFe(Cup)
3,Fe(CO)
5, orFe(acac)
3 in organic solvents with surfactant molecules. A combination of Xylenes and Sodium Dodecylbenezensulfonate as a surfactant are used to create nanoreactors for which well dispersed iron(II) and iron (III) salts can react.[3]
Magnetite and maghemite are preferred inbiomedicine because they arebiocompatible and potentially non-toxic to humans[citation needed]. Iron oxide is easily degradable and therefore useful for in vivo applications[citation needed]. Results from exposure of a humanmesotheliumcell line and amurinefibroblast cell line to seven industrially important nanoparticles showed a nanoparticle specificcytotoxic mechanism for uncoated iron oxide.[12] Solubility was found to strongly influence the cytotoxic response.Labelling cells (e.g.stem cells,dendritic cells) with iron oxide nanoparticles is an interesting new tool to monitor such labelled cells in real time bymagnetic resonance tomography.[13][14] Some forms of Iron oxide nanoparticle have been found to be toxic and cause transcriptional reprogramming.[15][16]
Iron oxide nanoparticles are used in cancer magnetic nanotherapy that is based on the magneto-spin effects infree-radical reactions and semiconductor material ability to generateoxygen radicals, furthermore, controloxidative stress in biological media under inhomogeneouselectromagnetic radiation. The magnetic nanotherapy is remotely controlled by externalelectromagnetic field reactive oxygen species (ROS) andreactive nitrogen species (RNS)-mediated localtoxicity in thetumor duringchemotherapy with antitumor magnetic complex and lesser side effects in normal tissues. Magnetic complexes with magnetic memory that consist of iron oxide nanoparticles loaded with antitumor drug have additional advantages over conventional antitumor drugs due to their ability to be remotely controlled whiletargeting with a constant magnetic field and further strengthening of their antitumor activity by moderateinductive hyperthermia (below 40 °C). The combined influence of inhomogeneous constant magnetic and electromagnetic fields during nanotherapy has initiatedsplitting of electron energy levels in magnetic complex and unpairedelectron transfer from iron oxide nanoparticles to anticancer drug andtumor cells. In particular, anthracycline antitumor antibiotic doxorubicin, the native state of which isdiamagnetic, acquires the magnetic properties of paramagnetic substances. Electromagnetic radiation at thehyperfine splitting frequency can increase the time that radical pairs are in thetriplet state and hence the probability ofdissociation and so the concentration offree radicals. Free radicals in cancer cells induce changes inmechanochemicaltumor heterogeneity by modifying bonds which influence the spatial arrangement of molecules in cell structures. The translation of the magnetic force exerted on the tumor and its microenvironment by magnetic nanoparticles into biochemical signaling pathways is known as the magneto-mechanochemical effect. This leads to the formation of regions with different biomechanical and biochemical properties within the tumor.The reactivity of magnetic particles depends on theirspin state. The experimental data was received about correlation between the frequency of electromagnetic field radiation with magnetic properties and quantity paramagnetic centres of complex. It is possible to control thekinetics of malignant tumor. Cancer cells are then particularly vulnerable to an oxidative assault and induction of high levels of oxidative stress locally in tumor tissue, that has the potential to destroy or arrest the growth of cancer cells and can be thought as therapeutic strategy against cancer. Multifunctional magnetic complexes with magnetic memory can combine cancer magnetic nanotherapy, tumor targeting andmedical imaging functionalities in theranostics approach for personalized cancer medicine.[17][18][19][20][21]
Yet, the use of inhomogeneous stationarymagnetic fields to target iron oxide magnetic nanoparticles can result in enhanced tumor growth.Magnetic force transmission through magnetic nanoparticles to the tumor due to the action of the inhomogeneous stationary magnetic field reflectsmechanical stimuli converting iron-induced reactive oxygen species generation to the modulation of biochemical signals.[22]
Iron oxidenanoparticles may also be used in magnetic hyperthermia as acancer treatment method. In this method, theferrofluid which contains iron oxide is injected to the tumor and then heated up by an alternating high frequency magnetic field. The temperature distribution produced by this heat generation may help to destroy cancerous cells inside the tumor.[23][24][25]
The use of superparamagnetic iron oxide (SPIO) can also be used as a tracer in sentinel node biopsy instead of radioisotope.[26]
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