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REVIEW ARTICLE Table of Contents  
Ahead of print publication
Fundamentals of superparamagnetic iron oxide nanoparticles: Recent update

1 Department of Pharmaceutics, Sanjivani Institute of Pharmaceutical Education and Research, Kopargaon, India
2 Department of Pharmaceutics, Sanjivani Institute of Pharmaceutical Education and Research, Kopargaon; Department of Pharmaceutics, School of Pharmaceutical Sciences, Sandip University, Nashik, Maharashtra, India

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Date of Submission25-Feb-2022
Date of Decision11-Sep-2022
Date of Acceptance12-Sep-2022
Date of Web Publication05-Jan-2023


The medical sciences have mirrored the rapid growth of nanotechnology in recent years. Superparamagnetic iron oxide nanoparticles (IONPs) are a good example. Owing to its unique features, for example, superparamagnetism, higher surface area, surface-to-volume fraction, facile uncoupling methods, and IONPs have recently received a great deal of focus. Magnetic nanoparticles (NPs) with appropriate Surface chemistry have been created utilizing a range of physical and chemical methods. The IONPs employed in bioscience, health aid, environmental rehabilitation, and other domains were examined. The surface stabilization of IONPs with different stabilizers is explained in this review. This review discusses the necessary characterization of IONPs using multiple qualitative and quantitative methodologies in biological activity, which is beneficial owing to biodegradability and biocompatibility, simplicity of production, and magnetic behavior. This review covers practically all methods of IONP synthesis, size, and morphology, as well as their latest applications in many domains. With the present significance of Fe NPs, the current review aims to provide best of the information on the production, characterization, and uses of these NPs.

Keywords: Applications, characterization, metabolism, superparamagnetic iron oxide nanoparticles, surface modification, synthesis, toxicity

How to cite this URL:
Nehe AD, Kulkarni AD. Fundamentals of superparamagnetic iron oxide nanoparticles: Recent update. J Microsc Ultrastruct [Epub ahead of print] [cited 2023 Feb 8]. Available from: https://www.jmau.org/preprintarticle.asp?id=362486

  Introduction Top

Nanoparticles (NPs) are on the cutting edge of nanotechnology's expeditious growth. Nanomaterials are required and preferable for a vast array of applications due to their quirky size-dependent properties. Because Fe is the conspicuous current metallic component inside the Earth's core, it acts as the core of the current development. Concerning a set of elements such as Au, Co, Ni, and Pt, FeO is frequently disregarded. The chemical reaction between Fe and O2 produces iron oxides (compounds), of which there are 16 known. In nature, rust is an example of iron (III) oxide.

FeO is common, widely used for its low cost, and plays a vital part in a variety of situations in a range of biological and geological processes. Iron ores in catalysts, thermite, long-lasting dyes (colored concretes, paints, and coatings), and hemoglobin are only a few examples.[1] Iron oxide NPs (IONPs) are employed in several applications and hold a crucial influence on the biological process. Many NPs satisfy the criteria for improved biological development. Ferromagnetic materials, electrostatics, gas sensing, storing power, cancer therapy, magnetic storage, and medicinal therapies are just a few of the uses for FeO NPs. Hematite (FeO) is one of the prevalent minerals, naturally occurring, and ecologically friendly NPs. It is vital to the biological systems of iron in the environment. FeO crystallites include hematite, maghemite, goethite, and magnetite. The n-type semiconductor behavior of hematite is considered to be more stable. For biological applications, scientists are now concentrating their efforts on stable hematite FeO2. −Fe2O3 (hematite) iron oxide was chosen as a distinctive NP due to its minimal cost and nonpoisonous character.[2]

Superparamagnetic iron oxide NPs (SPIONs) are colloidal carriers made up of tiny crystals of FeO (generally characterized as magnetite Fe3O4 or maghemite γ-Fe2O3) that have modified surfaces to achieve water stability of colloidal particles. SPIONs can be changed using a biocompatible, hydrophilic polymer (e.g. poly (ethylene glycol)), coating them, with polysaccharides, or organic acids (e.g. citric acid). SPIONs are characterized by their nanosize (usually 10–100 nm) and are sensitive to a magnetic field. They provide a wide range of uses since they may be linked with several compounds. A popular strategy is to attach anticancer antibodies to the surfaces of SPIONs and then inject the derived, targeted materials into the circulatory system. They might be combined with other materials to either monitor tumor cells (because magnetic resonance imaging [MRI] can identify them) or eliminate them (through letting go of drugs or by magnetic hyperthermia).[3] Processes in tissues with an intact blood–brain barrier are thus protected from contact with this classic contrast medium, and changes in the tissue will only be seen if they are accompanied by a change in the circulatory. This approach may be used to identify malignancy and physiological functioning alterations in the brain, such as schizophrenic activities.[4] Other biological applications have been found, including tissue repair, cell labeling, and magnetoreception. Apart from these applications, using IONPs as carriers to deliver therapeutic compounds has become a popular study topic in the last few years. Using the magnetic and biological properties of iron oxide nanosystems to bind or load drugs has shown to be a successful technique for improving treatment effectiveness. By conjugating pharmaceuticals to FeO NPs, most of their unfavorable properties (low solubility, high toxicity, nonspecific distribution, and short circulatory half-lives) may be rectified.[5] Many types of iron oxides (such as porous spheres, nanorods, and nanocubes) may be made using very similar synthetic techniques by modifying the precursor iron salts is all it takes. These cutting-edge techniques are simple to use, cost-effective and give a long-term form control. In contrast to synthesis, iron oxide surface modification is important (to provide better compatibility with bio-systems, correct functionalization, and molecular conjugation).

The modification on the surface is an important postsynthesis step for manufacturing biocompatible and stable iron NPs because it inhibits chemical erosion caused by destabilization. Other alterations may be applied to IONPs, leading to the addition of physical and chemical properties.[1] Sizes (inert core) of <100 nm and precise size distributions are frequently required in biomedical applications. The coating that promotes the stability and stealth of NPs in the biological medium must be carefully chosen. Moreover, the coating can be changed such as drug release is been controlled by a stimulus (such as a change in pH, temperature, or redox state). Finally, a combination of the above-mentioned properties can optimize medication release, for example, drug delivery combined with heat can synergistically provide optimal performance.[5] Yet, other changes had unintended consequences, such as expanding the size of the complex when MIONPs were replaced with PEI, making it impossible for the cell to endocytose it. Perhaps some MIONPs that have been functionalized and released into the environment can adsorb hazardous substances (such as phenols and benzenes), forming combinations that are harmful to the environment and our systems once they have vaporized. MIONP's surface modification strategies must be perfected as soon as feasible. A simple figure is explained in [Figure 1]. We highlighted the chemical synthetic techniques and external surface-engineered modified approaches of MIONPs, applying fields, and barriers fronted by MIONPs or functional MIONPs in this work to improve the utilization and applications of MIONPs or functional MIONPs.[6] Furthermore, the preparatory methods for IONPs are listed in [Table 1].
Figure 1: Multifaceted SPIONs with a NP core, coatings, and targeting moieties are depicted graphically. NP: Nanoparticle, SPIONs: Super paramagnetic iron oxide NPs

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Table 1: Various methods to fabricate iron oxide nanoparticles

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  Synthesis of Magnetic Nanoparticles: Brief Techniques Top

Deposition of gas-phase

The significant contact of vapor-phase atomic metals with ligands is required for gas-phase synthesis. It necessitates product stability with the circumstances of the reaction at high temperatures, which limits this approach. Supersaturation of metal with its ligands vapors over low temperatures, typically over 35 the ranges between 4 and 272K, may usually improve product stability (cytochemistry). A unique vacuum apparatus is required, in which an energy source vaporizes an objective form of the appropriate zero-valent metal, which is then transported to a 2nd compartment where it combines with a donor ligand in the gas phase before condensing in a frigid environment or freezing finger. The end product of the mechanism for the metal chelates synthesized directly in the gas medium may differ depending on the type of metal to be vaporized or the type of ligand that is to be distributed.[30] A category of bottom-up approaches for creating versatile NPs from each atom or molecule is known as gas-phase synthesis. The sprayed atomic vapor is cooled with inert gas and then condensed in the gas phase, also magnetron-sputtering has been widely employed to manufacture single and multi-component NPs. Due to the quick kinetics and nonequilibrium systems occurring, magnetron-sputter gas-phase condensation is given special attention, as it allows for the flexible synthesis of growth complex, advanced NPs. [Figure 2] specifies the ADME process of the SPIONs in the human body. Clustering, shell coating, mass filter, and deposition are the four phases of NP production.
Figure 2: SPIONs' bio-kinetics and in vivo destinies are influenced by their physicochemical characteristics. The ADME process of SPIONs from the body all show these modifications. Another element controlled by diverse physicochemical properties of nanoparticles is the protein corona, which can alter the aiming abilities of SPIONs in imaging applications. The protein corona can impact not only the toxicity, absorption, targeting, and circulation time of SPIONs, but also their relativity as MR imaging contrast agents. SPIONs: Super paramagnetic iron oxide NPs, ADME: Absorption, Distribution, Metabolism, Excretion

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Electron-beam lithography

Scanning electron microscopes with field-emission guns (FEG-SEM), both electron-beam printing and SEM investigations were carried out in (Leo 1500 series equipped with the nanometer pattern generation system, from JC Nabity Lithography systems). The FEG-SEM was tuned to 20-kV acceleration and 426 pA beam current during electron-beam lithography. The diameter of the electron beam is ≤2 nm when these parameters are fulfilled. Each of a range of initial Au (I)-thiolate film widths was subjected to a dose-matrix experiment. The single-pass aspect of the electron beam was used in some situations to make isolated lines resistant. In other circumstances, the electron beam was swept across the sample to reveal finite regions (closed polygons of different forms, such as triangles, lines of definite width, or rectangles). Depending on the units used to define the dosage as the sample has received, these circumstances may be identified. Linear doses (in nC/cm) or surface doses (in mC/cm2) are mentioned. Using an “in-lens” detector, FE-SEM measurements were conducted in the scanning electron fashion.[31]

Ultrasound-assisted method

Ultrasound is used to aid the synthesis process and make it more efficient. Cavitation is a fundamental element in ultrasonic-aided material production. Cavitation is known as the production, expansion, and interfacial fall of bubbles in a liquid, which results in severe circumstances inside the falling bubble and is the source of most sonochemical processes. The major benefit of ultrasonography is that it reduces reaction time when compared to conventional synthesis techniques. The acoustic cavitational effect is responsible for the decrease in reaction time. The creation of nonaggregated NPs in a short period and with a greater yield is facilitated by the generation of bubbles caused by cavitation during ultrasonication. As a result, this ultrasound-assist photosynthesis of IONPs is thought to be a viable synthesis method.[32]


Coprecipitation, also known as the multi-component cationic technique, entails Fe21 salt, Fe31 salt (typically chloride, nitrate, or sulfate), and excessive precipitator (e.g. NaOH or ammonia water). It is one of the most widely utilized ways of producing large amounts of MIONPs quickly.[6]

In the existence of a moderate oxidant, the reaction of Fe (II) salt to a base in an aqueous solution produces circular NP with a diameter of 35–100 nm. The presence of cation's oppositely charged elements, as well as the solution's pH, are all influencing factors of the medium and dimensions of the particles. Changes in pH and ionic strength are important in determining particle mean size (from 15 to 2 nm). Due to the huge ratio of surface-area, to volume and to minimize surface charge, NPs frequently agglomerate.[1]

Protein coating on the surface can also help to stabilize the surface.[33] The factors of this approach show how base (ammonia, CH3 NH2, and NaOH), pH, additional cations (N (CH3) 4+, K+, CH3 NH3+, Li+, Na+, and NH4+), and the Fe3+/Fe2+ ratio affect the result from this reaction as well as the polydispersity and dimension of the generated NPs. It is feasible to get particles with sizes varying from 16.5 nm to 4.1 nm after modifying the researched factors.[34] The factors of this approach show how base (ammonia, CH3 NH2, and NaOH), pH, additional cations (N (CH3) 4+, K+, CH3 NH3+, Li+, Na+, and NH4+), and the Fe3+/Fe2+ ratio affect the yield of this reaction as well as the size and polydispersity of the generated NPs. It is feasible to get particles varies in size from 16.5 to 4.1 nm after modifying the researched factors.

Sol-gel method

The process of sol-gel comprises a series of metallic oxides by condensation and hydrolysis of substrates in a colloidal dispersion. If the hydrolysis rate is low, fine particles will result, and vice-versa. Furthermore, the item is highly related to the concentration of solvent, pH, reaction temperature, and other factors.[6] To create a 3D metal oxide system, the obtained “solution” from nanoparticulate is dehydrated or “gelled,” either through solvent extraction or a chemical synthetic reaction. Although H2O is utilized as the solvent, the substrates can be determined using an acid or base. Basic catalysis results in the formation of a colloidal gel, whereas a polymer gel is produced by acid treatment.[35] The synthesis is carried out at an ambient temperature, although the ultimate crystalline state requires a heating process. The following chemical steps depicts the sol gel reaction process for the production of magnetite NPs from an aqueous iron (III) solution.

Disproportionation: Fe3+ +H2O Fe (OH)x3-x

Oxidation: Fe (OH)x3-x

Magnetite scarcity: Fe3O4 (pH 9.1, 60°C)[36]

The magnetic directional forces generated externally are too modest to withstand the thermal mobility of (SPIONs) when MIONPs size is lower than a specific value. There will be no residue magnetization after the external magnetic influence is removed since the magnetization of NPs reaches zero.[37] The sol-gel process overcomes some of the drawbacks of the co-precipitation method (such as significant agglomerate, a large range of PSD, and MIONPs with irregular shapes) while still achieving higher quality MIONPs. Yet, in this approach, the particulate size and shape of the resulting products could not be managed and the appropriate solvent concentrations and reactivity time must be improved significantly.[1]

Hydrothermal process

The hydrothermal processes are carried out in an aqueous phase in a reactor or autoclave under a >2000 psi pressure and a temperature of >200°C. The supersaturation of the media is caused by the hydrolysis of metal alkali and the limited oxides' solubility in water.[38] Fe31 (source of iron), aqueous phase (reactive phase), ethylene glycol (reactive solvent), ammonium acetate, ammonium bicarbonate, and sodium citrate are combined and transported to stainless steel (SS) autoclave with a polytetrafluoroethylene liner in the hydrothermal synthesis technique. The produced MIONPs show great crystallinity, purity, dispersibility, and controlled shape after they have been heated and purified by recrystallization at 200°C for 8–24 h.[39]

Precursor, temperature, and time have all been studied concerning the form of NPs of various sizes. Particle size is increased by increasing the concentrations of the precursors; however, residence time has a bigger influence over concentration. Monodispersed particles often have short residence times.[40]

In different experiments, the consequence of varying the preceding (e.g. ferric nitrate) concentration (while keeping all the additional factors remain constant) is investigated, and the (transmission electron microscope [TEM]) images of particulate acquired show that they are spherical, with an average particle size of radius 15.64.0 nm. In other investigations, a few bigger polyhedral particles with a mean particle size of 27.47.0 nm were also discovered (change in concentration of precursor). Moreover, the particles were predominantly rhombic, with some smaller spherical particles thrown in for good measure.[41] Moreover, in comparison to the co-precipitation approach, the hydrothermal method necessitates specific equipment, has a greater cost of production, and has a major oxidation problem in the reactive process, making it difficult to apply to commercial MIONP production.[1]

Thermal decomposition method

Thermal breakdown of precursors of organometallic elements in organic solvents combined with surfactant masking agents in an inert atmosphere provides a diverse foundation for the production of oxide-based NPs, together with magnetic NPs. Thermal breakdown techniques were used to limit the size, polydispersity, and form of the nanomaterials.[42] In the thermal breakdown approach, reacting precursors such as iron acetylacetonate, Fe(CO)5, and/or iron oleate are introduced into a mixture consisting of surfactants at greater temperatures. MIONPs of different sizes are created by varying the reactive temperature and duration.[43] The most frequent way to acquire magnetic NPs is by thermal breakdown syntheses. Recent research has discovered that the thermal breakdown methods may begin with the development of a nonmagnetic Wü site phase, with the magnetic magnetite/maghemite phases forming later owing to oxidation after changes in atmospheric oxygen.[44],[45] Whenever the reflux solvents are present, they are allowed to heat at various boiling temperatures, such as 320°C (1-octadecene), 360°C (eicosane), or 380°C (docosane), and sustained for 30 min, Chen et al. (2012) found that the dimensions of the particles of MIONPs were 12.6 nm, 17.3 nm, and 21.7 nm, respectively. MIONPs consisting of diameters 12.6 and 17.3 nm had a sphere-like shape, but MIONPs with a diameter of 21.7 nm had a cuboidal structure. As a result of the temperature dependency seen during the formation and development of narrow-size distribution NPs, MIONP formation was aided by a reaction temperature of more than 320°C. According to Chen et al. (2012), various iron-containing chemicals have different effects on MIONP synthesis. Iron pentacarbonyl was found to be particularly useful for producing MIONPs of a compact design (10 nm), while iron oxy-hydroxide with Fe oleate was frequently utilized to create larger MIONPs (10–30 nm). As a result, for the manufacture of MIONPs using the high-temperature decomposition technique, the reflux solvent, reflux temperature, and organic ingredients are critical factors. However, the majority of the synthesized MIONPs are hydrophobic, limiting their applicability, and investigators must enhance the approach to create water-soluble MIONPs.[46]

Sonolysis method

The sonolysis method focuses on ultrasonic technology which is used in this procedure (US) energy to create bubbles inside a liquid, resulting in localized heat exceeding Five thousand (K) in <1 s, accompanied by free radical formation. Sonolysis creates amorphous magnetite particles in the cavitation bubbles, unlike the other heat-driven processes that produce crystalline particulates.[47] Due to enhanced floccules of the particles, Drozdov et al. (2016) found that magnetite generated through sonolysis had limited stability, specifically in hydrosols.[48]

Ultrasonic irradiation primarily generates cavitation in an aqueous phase, where microbubbles develop, expand, and burst. Cavitation may produce temperature as high as around 5000°C and high pressures as 1800 KPa, allowing for a wide range of chemical reactions. Crystal NPs are formed through thermal induction, whereas amorphous NPs are formed by ultrasonic induction. Pinkas et al. (2008) investigated the sonochemical production of yttrium IONPs with a size of 3 nm. (SEM) and (TEM) analysis of spherical agglomerates revealed that they were immersed in an acetate matrix.[49] Stabilizers (such as oleic acid) might be employed to prevent agglomeration of sonolysis-formed particles, however owing to potential toxic effects and lower organic solution solubility in biofluids, their usage in biomedicine is constrained.[50]

Microemulsion method

The microemulsion is a kind of isotropic dispersion of 2 immiscible liquids that are thermodynamically stable that consist of nanosized domains and are stabilized by the presence of one liquid in the other by a surface-active molecular interface coating. The confining action of the surfactant molecules prevents particle nucleation, growth, and aggregation. Co-precipitation takes place in small droplets of water (”water pools”) coated with the help of surfactant molecules uniformly dispersed in an oil phase in this process.[51] Particle formation, nucleation, and clumping are all represented by nanocavities.[52] The fundamental benefit of this method is the variety of NPs according to surfactant, nature, physiological circumstances, and other factors.[53] Nanoemulsions containing iron source and NaOH are combined to make magnetite NPs, which are then lysed and rinsed with ethanol after removing the surfactant with acetone.[1] The choice of the surfactant (and cosurfactant) is based on the physicochemical features of the system since there are various dissolved elements in the water and oil phases. Surfactants of several types, including cationic, anionic, and nonionic, can be used. The primary drawbacks of this technology are the negative impact of remaining surfactants on characteristics and the difficulty of scaling up operations.[54]

Polyols method

The polyols approach is an important technique for producing distinct NPs with precise form and size.[55] Nonagglomerated metal particulates of metal with a desirable form as well as size are generated by regulating the precipitating kinetics. Responsive media, heterogeneous nucleation, and heterogeneous nucleation determine the average size of metal particles. The synthesis processes are unaffected by the homogeneous particle size that results. FeOH in an organic medium can produce 100 nm Fe NPs.[56] Due to their high dielectric constants, the solvents utilized, such as polyols and poly (ethylene glycol) (PEG), have fascinating features. Such solvents may dissolve inorganic substances and have a broad working temperature range (from 25°C to B.P.) because of their comparatively higher boiling points.[57] The development, form, size, and yield of the particles are affected by the kind of polyols, salt ratio, concentration, and other physiological circumstances. The reduction potential of the polyol is shown to influence the production and size of Fe particles.

Chemical vapor deposition

For synthesizing SPIONs, chemical vapor deposition (CVD) has been documented; however, there are fewer reports available. Tristao et al. demonstrated that by reducing − Fe2O3 in the presence of N and CH4, CVD may be used to make carbon-based SPIONs.[58] Mantovan et al. (2012) recently employed the CVD approach to manufacturing a Fe3O4-based thin coating with compounds as a precursor and found that the stoichiometric ratio was improved when compared to the beginning precursor.[59],[60] However, CVD pulses can control the thickness of Fe3O4, but this technology is not ideal for producing IONPs. Other publications state that postsynthesis techniques such as scraping powder off materials and dispersing it in a liquid using the sonochemical process or surface functionalization are required to tune the Fe particles into their NPs.

Green synthetic approach of iron oxide nanoparticles form phytoconstituents

Green nanotechnology has started to use natural resources for NP synthesis in recent years by altering the biological system through a green-chemistry approach that reduces environmental toxicity.[61] For NP synthesis, an environmentally friendly innovative approach is used to reduce waste and eliminate the use of harmful chemicals. The major process of reduction or oxidation happens in green nanomaterial production, which is a form of bottom-up technique. Microbial and phytoconstituents are used to stabilize the surface of NPs throughout the manufacturing process.[62] The principal phytochemicals responsible for the quick bio-reduction of metal ions into NPs include terpenoids, flavones, ketones, aldehydes, amides, and carboxylic acids. The electron shuttle enzymatic metal reduction process is most likely involved in the reduction of iron ions.

  Iron Oxide Nanoparticles Surface Modification Top

The integral destabilization of magnetic IONPs in the size range is unpreventable, manifesting in two means: (1) lack of dispersibility, in which tiny NPs tend to clump together to agglomerate and result in the formation of larger particles to minimize surface potential; and (2) in the case of bare IONPs, there is a depletion of magnetism., especially Fe3O4 and − Fe2O3 NPs, in which they are quickly oxidized because of their great chemical reactivity, the air is a good choice.[63] A particle is a compound hetero version substance that consists of an internal magnetic core with a defined “core” size and altering external coating. The hydrodynamic diameter of the particles or their aggregates differs from the magnetic core size, usually. For targeting reasons, both factors are critical. The first is in charge of the magnetic responsiveness' nonhomogeneous field of magnetization, while the second is pivotal for cell targeting (hydrodynamic forces) and couplings. The surface properties of NPs are a key element that not only impacts the biodistribution and biocompatibility of such magnetic substances but also plays a crucial role in cell attachment to bioelements.[64] Because the vast majority of biological mediums are virtually unbiased/neutral aqueous solutions, water-dispersible NPs are required.

During the previous decade, two kinds of FeO (magnetite [Fe3O4] and maghemite [γ-Fe2O3]) have mostly been exploited in biological applications. Due to its biocompatibility, magnetite is the more promising of the two. The cubic inverse spinel form of magnetite belongs to the spinel group. The usual formula for magnetite is A(B)2O4. The A metal in magnetite (Fe3O4) is Fe2+, while the B metal is Fe3+. Maghemite (Fe2O3 or − Fe2O3) is a spinel ferrite that is ferrimagnetic and also has the same structure as magnetite. A number of NPs may be circulated in a polymeric matrix to create pellets, or coating substances may be adsorbed out on the NP surfaces to produce a core-shell structure. The particles in the former are regular and range in size from 20 to 200 nm, and they may be dispersed in appropriate solvents to create homogeneous suspension. Magnetic pellets, when distributed in proper solvents, have a singularity mix of fluidity with the capacity to react with a field of magnetization because of their composition. Based on the pressure employed, high-pressure homogenization can decrease the effect on the bead's range in size from micrometers to between 10 and 100 nm.[65] Colloidal suspensions of magnetic particles are known as ferrofluids (Fe3O4 or Fe2O3) that produce polarizable streams that stay liquid even in the greatest magnetic fields and are a tool that can be utilized in a number of ways.

Owing to their nature, magnetic fluids own a distinctive blend of fluidity and the ability to interrelate within the magnetic field.[66] The remaining magnetic particles are attached, causing mutual magnetization, and enhanced aggregation qualities. However, while selecting coating materials for NPs, caution should be exercised. NP coatings can be made up of a variety of materials, including inorganic and polymeric ones. There are two types of polymeric coating materials: synthetic and natural. Synthetic polymeric materials include poly (ethylene-co-vinyl acetate), poly (vinyl pyrrolidone), poly (lactic-co-glycolic acid), PEG, poly (vinyl alcohol) (PVA), and others[67],[68] chitosan, dextran, gelatin, pullulan, and other natural polymer systems are used. Surfactants such as sodium oleate, dodecyl amine, and sodium carboxymethylcellulose are commonly employed to improve dispersibility in aqueous media.[69],[70]

Polymeric stabilizers for surface modification

Magnetic NPs with polymeric coatings have a lot of potential in a variety of disciplines. The deposition of the number of inorganic particles in a matrix of cross-linked polymers or gel network usually resists coagulation, resulting in monodisperse particles.[71] The process is based on the iron salt precipitation directly within the orifice of the seed of porous polystyrene. The particles produced have particle sizes that are large (between 2.8 and 4.5 mm) and high magnetic isolation. Enclosing deposited IONPs upon differently charged polystyrene-core/poly (N-isopropyl acrylamide) shells yielded hydrophilic thermosensitive latexes. N-isopropyl acrylamide, N-N0 methylene bisacrylamide acrylamide, itaconic acid, and other water-soluble monomers were used in the encapsulation. Thermal sensitivity was seen in the resulting particles.[72] Lee et al. (1996) used PVA to modify the surface of NPs by precipitating Fe salts in an aqueous PVA solution to generate a dispersed phase that is in a stable form. The particle's crystallinity reduced as the PVA content increased, while the shape and size of the particle remained nearly similar. Self-assembling of ligand-equilibrated NPs with sizes as small as a few nanometers into 2D and 3D ordered patterns has recently been described.[73] PVA with outstanding film-forming, emulsifying, and adhesion capabilities. PVA coating on particle surfaces reduces particle aggregation, resulting in monodisperse particles.[74] The crystallization of the particles dropped as the PVA concentration increased, but the shape and particle size remained nearly similar, according to Lee et al. Due to its low durability and agglomeration properties, atactic PVA NPs have exhibited shortcomings as a drug delivery medium. To make a gel, PVA can be cross-linked chemically.[75] Magnetic materials are included in polymer composites to create these gels. In the polymeric substance, well-dispersed particles can be precipitated. Prior, though, and after the cross-linking procedure, in situ precipitation can be done.

Due to its hydrophilicity and lack of antigenic and immunogenic characteristics, PEG is commonly employed as a covering material for NPs. The tight adhesion of PEG molecules over the interface of a specific carrier of the drug not only increases the steric stability in vivo against the particles of macromolecule interactions (e.g. opsonins) as well as cells that allows for extended blood circulation and reduced RES absorption.[76] Dextran is a biodegradable and biocompatible polymer that may be taken orally or intravenously. It increases blood circulation by stabilizing the colloidal solution. Berry et al. (2003) investigated the effects of dextran-derived MNPs on skin fibroblasts.[77] Despite the fact that both the dextran-derivatized and uncoated particles are uncoated, they are swallowed up by the cell, and the derived particles cause unique modifications in the cell's entire morphology and actions from the basic particles, according to the findings. The particle's size and surface, according to scientists, are critical aspects of particle application. The periodate approach was used to mimic the MNPs coated with dextran binding to each other (hydrodynamic diameter of 70 nm) to mouse endothelial cells in culture.[78]

Nonpolymeric organic stabilizers for surface modification

Gedanken et al. (1999) investigated the accumulation of alkane sulfonic and alkane phosphonic acids on the interfaces of amorphous Fe2O3NPs to stabilize the colloidal dispersion and postulated possibly two types of bonding strategies for the ions of phosphonate on Fe3+, namely, atoms of phosphonate group binds in the quantity of 1–2 oxygen atoms of over the surface.[79] To stabilize magnetite NPs in organic solvents, Sahoo et al. (2001) used oleic acid, lauric acid, dodecyl phosphonic acid, hexadecyl phosphonic acid, di-hexadecyl phosphonic acid, and other surface derivatization agents such as lauric acid, oleic acid, hexadecyl phosphonic acid, dodecylphosphonic, and dihex. This twist is required for good stabilization because stearic acid (CH3(CH2) 16CO2H) cannot stabilize ferrofluid suspensions because of double bond absence in its C18 (stearic) terminal. Magnetite surface derivatization with lauric acid, oleic acid, hexadecyl phosphonic acid, dodecyl phosphonic acid, and di-hexadecyl phosphonic acid to stable NPs in organic solvents was reported by Sahoo et al.[80]

The ferrofluids, which are commonly dispersed in hexadecane (HD: C16H34) as the carrier medium, can be balanced by a variety of long-chain surfactants, the most well-known of which is oleic acid (CH3(CH2) 7CH14CH (CH2) 7CO2H), which has a cis-double-bond in the center with C18 (oleic) tail, forming such twists have been proposed as essential for good stabilization, and stearic acid (CH3(CH2) 16CO2H) cannot stabilize ferrofluid suspensions because it lacks an its C18 (stearic) tail has a double-bond.[81],[82] The existence of a silanol group at the surface that could actively react with silane and alcohol pairing agents to create dispersions that are stable not only in nonaqueous but also give the best possible substrate for the purpose of covalent bonding targeting ligands is an upper hand on the property of having a surface-enhanced in silica. Tartaj et al. (2001) recently used the pyrolysis approach to create a silica-coated submicronic magnetic spherical aerosol. The synthesis of silica-coated IONPs was also done using a w/o microemulsion approach. As a result, the particles' magnetic sensitivity is significantly larger than that of any composite material made so far using MNPs enclosed in inorganic matrices, as well as the extensive chemistry and facile the silica's functionalization of external surfaces that make them ideal materials for use as magnetic carriers.[83] A surface force balance (SFB) was used to measure the forces among oleic acid layers-acid-across HD medium like surfactants or between layers of stearic-acid like surfactants, as well as the force path length of wettability and patterns between stearic-tailed and oleic-tailed surfactant layers of the ferrofluid suspensions (SFB).[84]

The fabrication of iron/gold (Fe/Au) elemental-shell NPs is of specific importance because of potential applications in sensors, drug administration, and bio-detection. Lin et al. (2001) used a reversal micelle technique to produce core-shell-designed Fe/Au NPs. The Au shell was supposed to preserve the Fe core while also adding biological functionality. Other research has revealed that the Fe/Au NPs cannot be made by the reverse micelle technique of reduction. The most essential concerns are the chemistries' states of the key constituents and whether the oxide forms after or during the synthesis process.[85] Transferrin, lactoferrin, elastin, albumin, folic acid, and other targeting proteins are among the coatings used to stabilize ferrofluids utilized for NPs which are shown in [Table 2].
Table 2: Nanoparticles coating with selected polymers/molecules to stabilize ferrofluids

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  Metabolism of SPIONS Top

Many endocytic macromolecules' final breakdown mechanism is thought to be blended with lysosomes via endosomes, both early and late.[95] The metabolic reactions of SPIONs in cells require lysosomes. NPs are thought to dissolve as a result of a combination of the low pH microenvironment of endosomes/lysosomes and chelating compounds for intracellular iron (such as dicarboxylic acids, phosphates, and nucleotides).[96],[97] Arbab et al. (2005) used TEM at several time periods after incubation SPIONs with cells to examine the SPION metabolism in cells as a one-of-a-kind process. SPION's adhered to the cell membrane after 1 h of incubation and intracellular uptake was seen after 3 h of incubation. By 72 h, only a few endosomes bearing Fe-PLL complexes had fused with distinct vacuoles. The existence of NPs in intracellular lysosomes was discovered on day 5 by the researcher. Certain unique coating materials have been shown in some investigations to keep water out from accessing the SPIONs core. It is characterized by the comparatively slow decay of SPIONs into the body, resulting in an increase in the blood half-life. In RAW264.7 cells, Gu et al. (2011) hypothesized three plausible routes for the metabolism and excretion of the absorbed SPIONs. The incorporated SPIONs are first disseminated to daughter cells during cell mitosis. Second, the embedded SPIONs reach the lysosome, where they are destroyed at a lower pH, releasing free iron entering the pool of iron metabolism. Third, exocytosis may allow RAW264.7 cells to entirely eliminate SPIONs.[98]

An additional study found that SPIONs administration activated IRE-dependent regulatory mechanisms in M2 macrophages, causing decreased iron absorption and adequate iron transport.[99] In biological systems, the secure approach to eliminating SPIONs is through the kidneys, which can limit intracellular breakdown and ROS generation. The kidneys exhibit a strong absorption of sub-5SIO-Fl NPs 2 h following the injection, according to Ledda et al. (2020) who studied the metabolism of SPIONs in living organisms. Furthermore, 1 week following the injection, the level of iron in the kidneys reduced considerably. They pointed out that for Fe NPs <5.5 nm in diameter, the kidney is frequently the primary metabolic route.[100] In contrast, the time it takes for SPIONs to be entirely eliminated in organisms is unknown. Mesenchymal progenitor cells were tagged with SPIONs and transplanted into rat Achilles tendon lesions, and the cells that had been transplanted were followed in vivo utilizing bioluminescence assessment and MRI for a long time. These cells stayed and lived for a minimum of 4 weeks following implantation, according to the findings.[101] It is worth mentioning, that the time interval of 4 or 7 weeks is still quite short in terms of long-term monitoring effectiveness. The long-term impacts of SPIONs and the body's metabolic cycle must be verified over a lengthy period.

  Characterization Top

Morphologies, chemical properties, and functional group distribution patterns are utilized to get a better knowledge of surface attributes.[102] Fourier transform infrared spectroscopy (IR), X-ray diffraction (XRD) analysis, SEM, TEM, X-ray photoelectron spectroscopy, atomic force microscopy, vibrating sample magnetometry (VSM), and thermal gravimetric analysis are some of the fundamental techniques used to study magnetic NPs.[103] Ion–particle sensor, thermodynamic, NP tracking analysis, tilted laser microscopy, zeta-potential measurements, isopycnic centrifugation, hydrophobic interaction chromatography, field-flow fractionation, electrophoresis, and turbidimetry are some of the other characterization techniques. XRD is used to determine the crystalline type and shape of a substance of iron composite NPs. The form and size of the particles, as well as the existence of an iron core, were all verified using a TEM. The vibrating sample magnetometer creates a hysteresis loop (VSM) which is used to evaluate the magnetic flux density and coercivity of the NPs. Thermogravimetry/differential thermal analysis and IR can be used to assess the surface coating on particles. The above-listed techniques are shortly explained in [Table 3] with a characterization assessment of the physicochemical properties of NPs.
Table 3: Characterization techniques for iron oxide nanoparticles

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  Applications of Super Paramagnetic Iron Oxide Nanoparticles Top

MIONPs have earned a lot of curiosity from academics to the biomedical sector. IONPs were originally utilized in biology and thereafter in healthcare for biological product magnetic separation and cells, as well as magnetic guiding of particulate systems for site-oriented drug administration, due to their strong magnetic characteristics.[104],[105] Magnetic particle surface chemistry, size, and charge all have an impact on NP biodistribution. Magnetic transporters and particles have been used in clinical applications for decades, thanks to their significance in diagnostics and therapy techniques.[106] Because of its unique qualities, including superparamagnetic behavior, biocompatibility, and transferable electrons, MIONPs have a wide range of bio applications, which include the transfer of genes, targeted medication administration, magnetic hyperthermia, and so on. Magnetic NPs have sparked a lot of attention as a material for labeling in the biological sciences and other significant scientific domains. In [Table 4], several well-known fields with potential uses for magnetic NMs are summarized.
Table 4: Applications of iron oxide nanoparticles in various fields

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Antimicrobial activity of FeO nanoparticles

There are a plethora of nanomaterials on the market right now that can be used as a particular element in bio-analytical instruments. One of the most common infectious illnesses is a bacterial infection. Moghadamtousi et al. (2014) performed thorough research investigations.[132] Antimicrobial investigations rely heavily on variances in antibacterial, antifungal, and antiviral drugs with a variety of physical and structural forms. Isolates do change in the physical and structural changes of antimicrobial, antifungal, and antiviral isolates. As a result of the emergence of microorganisms that are resistant to a variety of antibiotics, there is still a focus on finding novel antibacterial agents, according to developments antibacterial agents are being researched. In many circumstances, the change in a material's property in the nano range plays a significant role in this sector. It is evident because the sensitivity and detection limit has been improved to the point where single molecules can be detected. At the same time, diverse combinations of nanomaterials, depending on their unique properties, might improve the efficiency of microbial applications.

The impact of iron oxide on anticancer research

In the vast field of nanotechnology, the expanding contemporary world also presents new societal challenges, such as air contagion, and plays a critical role in human health difficulties. New inventions and increased focus on particular IONPs are the results of social requirements. IONPs and their uses have been employed in a variety of biological applications. Anticancer, antitumor, bone marrow cell, and cell-binding uses are among them. When their sizes are decreased to a few 10–100 of nanometers, IONPs display ubiquitous and distinctive physicochemical and chemical characteristics. SPIONs are tiny, synthetic α-Fe2O3 (hematite), γ-Fe2O3 (maghemite), or Fe3O4 (magnetite) particles having a core diameter of 10–20 nm, according to Malekigorji et al.[133]

Many variables influence the behavior of IONPs, including coating, targeting molecules, total particle size, delivery route, doping, coating, surfactant, transport origin, and biomarkers. Kumar et al. (2014)[134] have developed a new delivery technique based on NPs that can convey intracellular delivery of therapeutic cargos without the use of a cell transduction or penetration domain. They employed Fe NPs to deliver NuBCP-9, a BCL-2 BH3 region-targeting oncopeptide. Citric acid/2-bromo-2-methylpropanoic acid-coated superparamagnetic IONPs were used to immobilize and deliver the NuBCP-9 peptide to cancer cells without causing any unintended side effects. NuBCP-9-superparamagnetic IONPs successfully enter cancer cells and attach to their intracellular target protein BCL-2, according to their findings. Furthermore, when cancer cells were treated with NuBCP9-SPIONs at varied time frames, considerable suppression of proliferation and significant triggering of cell death were detected.

  Toxicity of Magnetic Iron Oxide Nanoparticles Top

The generation of excessive reactive oxygen species (ROS), such as hydroxyl radicals, superoxide anion, and nonradical hydrogen peroxide, causes the majority of intracellular and in vivo nanotoxicity caused by magnetic IONPs. Cells when are exposed to NPs at high concentrations, ROS with strong reactivity to chemicals are produced. The enhanced chemical reactivity of NPs can result in the growth of the formation of ROS.[62],[135]

High quantities of ROS can harm cells by peroxidizing lipids, damaging DNA, regulating gene transcription, changing proteins, and causing physiological dysfunction and cell death. The most often afflicted genes/proteins are involved in oxidative stress, DNA damage, infection, and immune system harm.[136]

In reaction to IONPs, there are four basic causes of oxidative stress:[137],[138] (1) direct formation of ROS from the NP surface; (2) formation of ROS via iron molecule leaching; (3) modification of mitochondrial and other cellular activities; and (4) stimulation of cell signaling pathways NP-induced oxidative stress appears to alter cell signaling in a multistage process, with low levels of oxidative stress increasing transcription of defense genes and antioxidant enzyme production to battle ROS. Pro-inflammatory cytokine production and extremely increased amounts of oxidative stress are linked to the initiation of apoptotic pathways if damage continues.

In vitro toxicity of magnetic iron oxide nanoparticles

An essential study topic, i.e. in vitro cytotoxicity testing in the evaluation of magnetic IONPs safety since it is noncomplicated, affordable, and easy to regulate the uniformity of experimental settings. In vitro assay for viable cells, multiplication, and division (1) mitochondrial biogenesis MTT assay, the lactate dehydrogenase (LDH) assay of membrane stability, and immunochemistry indicators for apoptosis/necrosis; (2) microscopic study of intracellular localization (atomic force microscopy and electron microscopy); (3) hemolytic in vitro studies; and (4) analysis of gene expression and mutagenicity are the most commonly used techniques to evaluate toxicity. These in vitro approaches are highly useful for determining the predicted biocompatibility of novel IONPs in the early stages of development.[139],[140] However, because NPs might interfere with the interpretation of the results or interfere with the experiment materials, those in vitro tests listed above should be done with caution. NPs, for example, can able to connect LDH and prevent its release into the extracellular media, disrupting LDH tests, whereas NP-induced ROS can disrupt MTT experiments, affecting mitochondrial enzyme function. Furthermore, because 2D-cell cultures may not fully simulate the functions of 3D tissues with complex cell-to-cell and cell-to-matrix interactions, they may not correctly reflect the true toxic effects of FeO NPs.[141] To improve our awareness of IONP-induced cytotoxicity, the techniques and variables should be more consistent. Thus, in vitro systems are primarily utilized to determine certain properties of IONPs that may be employed as toxicity indicators, as well as to build a toxicity rating for mechanistic research.

In general, toxicity concerns with magnetic IONPs are concentration-dependent, and a bigger quantity of IONPs will increase the chance of any adverse consequences.[142]

The number of IONPs cultured as well as the incorporated NP count over time must be linked in cytotoxicity studies.

In vivo toxicity of magnetic iron oxide nanoparticles

Magnetic FeO NPs interact with biological systems in a complex and dynamic way in vivo.[136] When IONPs invade the body, they can be absorbed through interactions with biotic elements such as proteins and cells, and then distributed to other organs, where they can either stay in the same nanostructure or be digested.[107],[143] A systematic and comprehensive assessable analysis of IONP materia medica (i.e. absorption, distribution, metabolism, and excretion) can lead to betterment in the biocompatible design of IONPs, a better comprehension of NP nonspecificity toward tissues, and cell types, and basic distribution and elimination analyses that serve as the foundation for understanding their activity and potential toxicity. Blood compatibility is a requirement for most NPs to function in vivo.[91],[144]

Agglomeration can be triggered by a lack of blood compatibility, hence the blood contact qualities of IONPs should always be assessed before clinical studies to ensure their safety. Several conventional and readily accessible clinical tests may be used to assess the coagulation characteristics of IONPs (i.e. prothrombin time, activated clotting time, activated partial thromboplastin time, and time of thrombin). After injection, the IONPs surfaces are quickly coated by a specific set of blood plasma proteins. Size of NPs, charge on surface, shape, and stability are some of the key elements that influence how IONPs interact with proteins. Protein adsorption has a significant impact on the fate and biodistribution of IONPs throughout the body. Adsorption of human serum albumin, for example, has been shown to lengthen blood circulation time.[145] Magnetic IONPs may be dispersed throughout the body, including organs, tissues, and cells. Iron oxide particles with large size (more than 200 nm) are trapped by mechanically filtering the spleen, whereas iron oxide particles with smaller size (10 nm) are quickly eliminated through renal clearing and exudation.[146]

The ultimate biodistribution of IONPs is typically 80%–90% in the liver, 5%–8% in the spleen, and 1%–2% in the bone marrow. These all organs have a lot of macrophages in them, which is part of RES. The RES system, also known as the system of mononuclear phagocytes is an immune system component that comprises monocytes and macrophages that are in charge of the absorption and processing of foreign chemicals and particles.[147] IONPs are typically found in endosomes/lysosomes after cellular absorption, where they break down into the free iron form, which is progressively transferred into the cytoplasm and ultimately adds to the entire cellular iron pool. How IONPs would interact with iron metabolism physiologically following the iron liberated from NP disintegration is one of the biologically safe concerns about IONPs. Excess intracellular iron can oxidize and destroy a cell's components such as protein and nucleic acid. In tagged cells, ferritin in the form of up-regulation and transferrin in the form of down-regulation receptors may protect cells against cytotoxicity caused by increased intracellular iron concentrations.[148] Stabilizing compounds and/or biological molecules are often coated on functional IONPs. Although conventional radiolabeling of molecules on the surface is simple, the PK data obtained with this approach can be deceptive. Multi-indicator approaches, such as multimodality imaging (PET-MRI), would offer a comprehensive view of metabolic processes. More efficient association between IONPs characteristics and in vitro cytotoxicity and metabolism data will be possible if the in vivo distribution resolution is increased to the molecular level.[149]

  Conclusion Top

When compared to other materials, NPs possess distinct chemical, physical, and biological features. As a result, scientific discipline has piqued their attention. Magnetic NPs like SPIONs, for example, are among them because of their multimodal functions, one of the most potential candidates. The iron oxide's property in the nanorange demonstrates significant efficacy in biological applications, as this review study demonstrates. It guides the enhancement of iron oxide properties by the addition of adsorbate and surfactants, which might be helpful assistance in certain target-based biological applications. SPIONs, on the other hand, continue to be effective, dependable, and diverse instruments in cancer development theranostics. Such particles can also be used as medicine delivery and therapeutic agents that target-oriented sites. In this study, regularly utilized targeting methods are shown, with the expectation that additional breakthroughs in the biomedical area will be made in the future. Furthermore, iron NP biocompatibility is connected to toxicity and degradability capacity, and this scenario changes when the surface is changed with other molecules, which affects biodistribution and bioaccumulation. The advancement of theranostic nanomedicine would benefit greatly from the effective creation of multipurpose NPs.

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Correspondence Address:
Abhijeet Dattatraya Kulkarni,
Department of Pharmaceutics, School of Pharmaceutical Sciences, Sandip University, Nashik - 422 213, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmau.jmau_17_22


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