Volume 28, Issue 3 (Summer 2022)                   Intern Med Today 2022, 28(3): 280-299 | Back to browse issues page

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Rezaei M. A Review of Recent Advances in Iron Oxide Nanoparticles as a Magnetic Agent in Cancer Diagnosis and Treatment. Intern Med Today 2022; 28 (3) :280-299
URL: http://imtj.gmu.ac.ir/article-1-3895-en.html
Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. , masood.rezaei69@gmail.com
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Nanotechnology is a science with great potential that has played a vital role in the development of useful materials in many fields, including medicine in recent years. According to the recommendation of the European :union: Commission, particles with sizes ranging from 1 to 100 nm (including nanoparticle coating) are considered nanoparticles [1]. The shape and size of nanoparticles are crucial parameters in their synthesis and applications because nanoparticles increase the reactivity and ion transport in the environment due to their high surface-to-volume ratio, which is the result of their very small size. Also, physical properties, such as shape, composition, charge, and solubility can especially change their behavior [2].
Recent nanotechnology studies in biomedical and pharmaceutical sciences have led to significant improvements in common drug delivery systems. Nanoparticles can be classified into four basic material categories: Carbon-based materials (containing carbon), inorganic materials (metallic and oxide nanoparticles), organic-based materials (made of organic materials excluding carbon), and composite materials (combination with larger materials or bulky materials) [3]. Mineral nanoparticles include transition metals and metal oxides (silver, iron, titanium), alkaline earth metals (calcium, magnesium), and non-metals (selenium, silicates), which have been used in various fields. Iron oxide nanoparticles (IONPs) are inorganic nanoparticles composed of ferromagnetic materials. The magnetization of IONPs has shown significant advantages, such as low production cost, environmental safety, stability, and high compatibility [4]. On the other hand, the most common biomedical applications include magnetic separation, targeted drug delivery, magnetic resonance imaging (MRI), hyperthermia by fluid containing magnetic nanoparticles, etc. Another use of IONPs, which has received a lot of attention in therapeutic and diagnostic nanomedicine, is the use of hyperthermia and also the ability to improve the effect of chemotherapy drugs in the conditions of combined treatment [5].
Due to the increasing growth of studies on the application of IONPS in the field of treatment and diagnosis and the need to integrate the findings and applications of these nanoparticles, this review article examines the characteristics and recent biomedical applications of IONPs in cancer diagnosis and treatment.
Stabilization and functionalization of iron oxide nanoparticles (IONPS)
The application of IONPs in biomedical sciences depends on three factors, morphology, size, and surface characteristics. During the synthesis, the morphology of IONPs can be affected by several factors, such as the presence of surfactants, concentration of reactants, reaction temperature, or time [6]. Morphology can also affect circulation time, cellular uptake, and biodistribution. Some studies have focused on the shape of nanoparticles for anticancer drug delivery. However, the effect of morphology on the biodistribution of IONPs has not been extensively studied. The size of nanoparticles determines their average circulation time in the bloodstream, for example, particles with a diameter of less than 10 nm are removed from the circulation through clearance by the kidneys, while particles with a diameter of larger than 200 nm are concentrated in the spleen or absorbed by the body’s phagocytic cells. Nanoparticles with sizes between 10 and 200 nm are ideal for biomedical applications because they have a longer circulation time, which increases the effect of permeability and persistence in tumor tissues. In this way, IONPs with a diameter of less than 2 nm are not suitable for medical use because they may cause toxic effects that can damage intracellular organelles [6, 7].
The high surface-to-volume ratio of nanoparticles is related to their colloidal stability. Also, high zeta potential (negative or positive) indicates their good dispersion and low accumulation. Uncoated iron oxide nanoparticles, due to their high specific surface area and strong inherent magnetic dipole interactions, tend to accumulate, which makes them easily removed from circulation by the reticuloendothelial system [8]. On the other hand, the surface charge of nanoparticles determines their distribution in the body. Neutral charges minimally interact with plasma proteins and help to increase circulation time in the body. Anionic IONPs can effectively interact with cells and enter the cell through endocytosis [9]. On the other hand, the cell membrane has a small negative charge and cell attraction is possible through electrostatic forces [5] that make it possible for IONPs with a positive surface to be absorbed faster. Hence, the charge and stability of IONPs in biomedical applications can be modified through surface coating. For example, particles coated with hydrophilic polymers (polyethylene glycol) can escape from circulating reticuloendothelial cells and macrophages and provide a better therapeutic effect [10]. 
Table 1 presents the advantages and disadvantages of IONPs synthesis methods.

As shown, the co-precipitation synthesis method has been used mostly in biological applications.
The magnetic property of IONPs causes instability, aggregation, and ultimately the formation of large particles. The accumulation of nanoparticles increases the content of iron ions and causes toxicity in cells [2]. In addition, IONPs are easily oxidized by ambient oxygen, which significantly reduces their magnetic properties. Based on this, the development of bioactive coatings on IONPs is necessary to improve their performance in biomedical applications [11, 12]. In the core-shell nanosystem, IONPs represent the core and the shell is the surface coating for functionalizing the nanoparticles. For biomedical applications, core-shell nanosystems can be connected to different types of drugs and drug delivery can be done by different methods, such as absorption, dispersion in the polymer matrix, encapsulation in the core, and covalent binding to the surface of nanoparticles [13, 14]. Also, these nanosystems can be functionalized by natural compounds that show potential activity for cancer diagnosis and treatment. There are two types of functional coatings for IONPs, organic and inorganic coatings (Figure 1).

Table 2 summarizes the advantages of organic and inorganic coatings in IONPs.

Organic coatings
Organic coatings increase the dispersity and biocompatibility of IONPs and have been used to target specific drugs in biological applications. Organic coatings can be classified into three groups, small molecules and surfactants, macromolecules, and polymers, and biomolecules [15].
Small molecules and surfactants
Surfactants improve the stability, dispersion, and biocompatibility of IONPs. They can also be used as coatings, and according to their nature, they are divided into three subgroups, oil-soluble, water-soluble, and amphiphilic surfactants. Oil-soluble surfactants contain hydrophobic groups and are used in oily solutions, which increases stability and prevents the accumulation of nanoparticles. During the synthesis of IONPs, surfactants, such as oleic acid are used, which can improve the stability of nanoparticles. Nanoparticles coated with this type of material can be used in various applications as MRI contrast agents and drug carriers in special drug delivery systems [7, 15]. Water-soluble surfactants convert hydrophobic nanoparticles into hydrophilic ones. Silanes are the most widely used coatings in IONPs, which increase dispersion, stability, and solubility in water [16]. In addition, silanes can be linked with metal ions, polymers, biomolecules, or other biological compounds [12].
Polymers, such as polyethylene glycol (PEG), polyvinyl alcohol, polymethyl methacrylate, and polylactic acid are the most studied coatings. Polymers create electrostatic repulsive forces and spatial effects and prevent the accumulation of particles [10]. Also, coatings have been made with smart polymers that respond to specific stimuli, such as pH, temperature, light, etc. However, the presence of polymers can affect the magnetic properties of IONPs in some cases. These characteristics can be related to changes in particle size distribution and particle interactions [15]. Natural polymers (dextran, chitosan, gelatin, and starch) are widely used in the synthesis of nanoparticles for cancer treatment. These compounds act as stabilizers during the synthesis process to increase the stability, biocompatibility, and biodegradability of nanoparticles. Avazzadeh et al. functionalized iron oxide nanoparticles with dextran-spermine and used them to treat breast cancer using hyperthermia. The results confirmed the ability of nanoparticles to target cancer cells and heat them to the hyperthermic range, while more than 63% of cancer cells were killed within a 20-minute treatment period [17]. Also, Nguyen used gelatin to coat IONPs, these nanoparticles were synthesized by the co-precipitation method and functionalized with paclitaxel. The results showed that paclitaxel loaded in Fe3O4@GEL nanoparticles can be used as a stable drug delivery system with dual therapeutic effects (hyperthermia combined with chemotherapy) for cancer treatment [18]. 
Biological molecules 
IONPs functionalized with biological molecules (enzymes, antibodies, proteins, polypeptides, etc.) are highly biocompatible. IONPs used in biological applications are functionalized with surfactants or functional groups, such as carboxyl or hydroxyl [15]. Unnikrishnan et al. synthesized INOPs coated with galactoxyl glucan attached to folic acid by hydroxyl functional groups to make these nanoparticles more stable in the tumor environment [13]. Also, IONPs can be functionalized through green synthesis [5]. Wu et al. used glucose in the co-precipitation method and obtained IONPs with an average size of 20 nm, which were used in targeted hyperthermia to kill cancer cells [19]. Another compound that has recently been used for green synthesis and coating IONPs with sizes of 15 to 30 nm is the nano cellulose from aloe vera, which has also shown antibacterial activity [20].
Mineral coatings
Minerals have many properties, such as high electron density and optical absorption (Au and Ag), photoluminescence, phosphorescence (metal oxides such as Y2O3), and magnetic moment (cobalt or manganese nanoparticles). In biological applications, mineral coatings are used to bind biological compounds on the surface of IONPs and increase their antioxidant properties [15, 21].
Silica coatings provide high dispersion, stability, and protection of IONPs in an acidic environment [19]. The silica coating is formed by alkaline hydrolysis with tetra orthosilicate (TEOS) in the presence of IONPs. Moorthy et al. synthesized IONPs via a salothermal method and functionalized the particles with TEOS and aminopolyglycidol, which are used for magnetic hyperthermia and bio-drug delivery [22]. Another reported method for silica coating includes the synthesis of IONPs by the salothermal method and their functionalization with TEOS, which has been tested in laboratory conditions as a binding agent for ibuprofen with the purpose of drug delivery [23].
Carbon coatings prevent oxidation and corrosion of the magnetic core. In addition, the hydrophilic carbon coating improves the dispersion and stability of nanoparticles. Song et al. synthesized IONPs by co-precipitation method and functionalized them with graphene oxide, lactoferrin, and doxorubicin hydrochloride. The results showed that these nanoparticles are highly efficient for the targeted delivery of anticancer drugs to brain tumors [24]. In addition, Cui et al. functionalized IONPs with graphene oxide, oleic acid, folic acid, and chitosan, these nanoparticles were non-toxic to A549 cells and showed excellent biocompatibility [25].
Metal nanoparticles have been used in catalysis, MRI contrast agents, medicine, and cancer diagnosis. These materials can be combined with IONPs that show various properties [19]. Some of the coatings used are gold, silver, copper, platinum, palladium, etc. In addition, these structures can be modified with different charges or functional groups on the surface of IONPs and improve the stability and compatibility of nanoparticles [15]. León Félix et al. showed that IONPs functionalized with poly (ethyleneimine) and gold have very low cytotoxicity. They presented interesting multifunctional nanoplatforms for the bimodal application of light and magnetic hyperthermia [26].
Metal oxides and sulfides
Metal oxides (zinc oxide [ZnO], tin dioxide [SnO], titanium dioxide [TiO2], zirconium dioxide [ZrO2], and tungsten oxide [WO3]) improve stability and increase heat production by IONPs in hyperthermia treatment. In addition, IONPs can be coated with metal sulfides (zinc sulfide [ZnS], cadmium sulfide [CdS], lead sulfide [PbS], and bi sulfide [Bi2S3]) and improve their magnetic and fluorescent properties. For example, Xu et al. synthesized IONPs functionalized with silica and cadmium sulfide/zinc sulfide (CdSe/ZnS). These particles were successfully used to induce apoptosis in pancreatic cancer cells using radiofrequency electromagnetic radiation [27].
Applications of iron oxide nanoparticles (IONPs)
The most common biomedical applications of IONPs include targeted drug delivery and hyperthermia by fluids containing magnetic nanoparticles. Figure 2 shows the cancer diagnostic and therapeutic applications of functionalized IONPs.

Table 3 summarizes some of the biological applications of IONPs using natural plant compounds.

In the following, we will examine these applications.
Functionalized IONPs can be loaded with various drugs, and by intravenous injection into humans and accumulation in the desired area (cancer cells or tumor), the efficiency in the treatment of cancer cells without damaging the cell’s healthy neighbors increases [28]. In Ghosh et al.’s study, IONPs were synthesized by the co-precipitation method, and citric acid was used to connect it with diosgenin present in Dioscorea bulbifera. These nanoparticles prevented the proliferation of breast cancer cells by inducing apoptosis to a greater extent compared to uncoated IONPs. Also, the incorporation of diosgenin into IONPs prevented the aggregation and growth of particles and thus increased the stability of nanoparticles [29]. Pham et al synthesized IONPs by microemulsion method using chitosan and curcumin as a coating. The maximum inhibition of A549 cells was reported at a concentration of 73.03 μg/mL. In addition, curcumin adsorbed to IONPs released up to 70% of the drug after 2800 minutes, which can be a good drug carrier for cancer treatment [30]. Brahui et al. synthesized IONPs by the co-precipitation method and functionalized them with chitosan and phytic acid (a natural component of grains and seeds). The results indicated the prevention of the proliferation of cancer cells in the large intestine without causing damage to the normal fibroblast cells. In addition, the results showed that the percentage of drug release from the nanocomposite reached 93% in 56 hours in the environment with pH 4.8 and 86% in 127 hours with pH 7.4. These results show better anticancer activity compared to pure phytic acid [31]. On the other hand, Nosrati et al. synthesized IONPs by co-precipitation method coated with bovine serum albumin and curcumin and showed, after 72 hours, high cellular compatibility (≤90%) of nanoparticles with a concentration of 15-950 μM in HFF-2. In addition, the IC50 values of these nanoparticles at 72 hours and 96 hours were reported at 915 and 275 μM, respectively, against free curcumin (730 and 300 μM). Hence, IONPS coated with bovine serum albumin and curcumin showed less cytotoxicity against MCF7 cells [32].
In another study, IONPs were functionalized by polyphenol compounds from Vitis vinifera and produced high cytotoxic effects against L20B cells at concentrations of 10 and 5 mg/L, which inhibited 70.8 and 5.8, respectively. The growth of cells was 57.0%. In addition, these nanoparticles had anti-inflammatory and antioxidant activity [33]. In another study, iron oxide nanoparticles with folic acid conjugated with DOX were used to treat a type of lymphoma cancer cells. The results showed that the decrease in tumor size in mice that received nanoparticles containing 5 μg of DOX drug was greater than in mice that did not receive DOX (P<0.05) [13]. Another application was recently presented by Sandhya et al., where IONPs were synthesized via green synthesis using B. flabellifer seed coat extract. These nanoparticles showed high cell compatibility (<80%) with NIH 3T3 cells at concentrations of 50-500 μg/mL. This type of synthesis increased the biocompatibility of nanoparticles and their therapeutic properties. In addition, these nanoparticles showed significant antimicrobial and antioxidant activity [34]. Farani et al. investigated the ability of iron oxide nanoparticles coated with hyperbranched polyglycerol (HPG@Fe3O4) and iron oxide nanoparticles coated with hyperbranched branched polyglycerol and with functional groups of folic acid (FA@HPG@Fe3O4) in loading the drug curcumin. The results showed that the ability to load curcumin by HPG@Fe3O4 and FA@HPG@Fe3O4 nanoparticles is 82% and 88%, respectively. Also, the ability of FA@HPG@Fe3O4 nanoparticles to enter HeLa cells and L929 fibroblasts of treated mice was more than other nanoparticles [35].
Hyperthermia treatment
Magnetic hyperthermia involves the generation of heat by applying an alternating or external magnetic field to magnetic nanoparticles. If we expose a ferromagnetic material (such as iron) to an external magnetic field, the magnetic fields of the material align with the direction of this field. By removing the magnetic field, a part of this orientation remains unchanged and the material becomes magnetized indefinitely. This phenomenon is called magnetic hysteresis. Hysteresis depends on the strength of the applied magnetic field. Also, the size and nature of magnetic nanoparticles affect the hyperthermic properties. In ferromagnetic or ferrimagnetic materials from many fields, heat generation occurs through magnetic field losses by hysteresis [36]. Balivada et al. investigated the thermal effect caused by IONPs and reported an increase in temperature of 11°C to 12°C in C57/BL6 mice. In addition, by increasing the concentration of IONPs (5-25 μg/mL), they showed that the number of viable tumor cells decreased [37]. Other studies have shown the effectiveness of magnetic hyperthermia as an alternative treatment for cancer. In the early work of Yanase et al., cationic liposomes based on magnetic properties were used to treat brain gliomas in F344 rats. In this study, the tumor volume was reduced by more than eleven times [38].
Drug delivery can be combined with the hyperthermia technique, which is the best way to reduce temperature. Temperature-sensitive drug formulations have been widely investigated in oncology. In addition, hyperthermia can be combined with the release of active plant substances. Nam et al. used IONPs coated with folate and curcumin. In addition to showing good biodistribution in mice bearing sarcoma-180 solid tumors, these nanoparticles showed good biodistribution. At a concentration of 0.3 mg/mL, they were able to reach a temperature of 42°C in 10 minutes for treating hyperthermia. The results of this study indicated that the synthesized nanoparticles are promising for the use of hyperthermia in cancer treatment [39]. In another study, IONPs were synthesized and coated using the green method and polyphenols extracted from cinnamon and vanilla. These nanoparticles were used in vitro to apply the hyperthermia technique and caused an 88% reduction of BV-2 cells after 30 minutes [40]. On the other hand, epigallocatechin gallate is a phytochemical that has a strong anticancer effect and has been used in the salothermal method for the synthesis of IONPs. These nanoparticles have been effective for hyperthermia treatment, drug delivery, and precise MRI in tumor-bearing mice. In addition, the results showed that the main organs, such as the heart, liver, spleen, lung, and kidney did not show significant toxicity in all experimental groups compared to the control group [41].
Toxicity of iron oxide nanoparticles (IONPs)    
Iron ions play various roles in biological processes, such as DNA synthesis, oxygen transport, mitochondrial respiration, and metabolic functions at the level of the central nervous system. In contrast, the toxicity of IONPs involves the production of reactive oxygen species (ROS) that affect macromolecules and cellular organelles. This process occurs as follows superscriptions react with H2O2 and produce ROS. Then, the high concentration of ROS causes a cascade of events and the release of more iron ions and harmful effects on the lysosomal membrane, lipid peroxidation, protein damage, breaking DNA chains, and destroying bases [42]. Also, high concentrations of iron ions increase apoptosis through mitochondria. On the other hand, the accumulation of iron due to protein agglomeration, such as Aβ and α-synuclein can increase the probability of developing neurodegenerative diseases [42, 43]. However, the toxicity of IONPs depends on the size, concentration, surface charge, and functional groups in their coating [2]. As mentioned earlier, the combination of phytochemicals from plants in the synthesis of IONPs can improve the solubility and stability of nanoparticles. Also, the toxicity caused by functional nanoparticles is higher in cancer cells compared to healthy cells. However, the cellular toxicity of nanoparticles is the main reason for limiting their biological application [1, 44].
 In a study, the biological toxicity of IONPs was investigated in tumor mice, and hematoxylin-eosin staining of organs, such as the heart, liver, spleen, lungs, kidneys, and tumor showed no significant toxicity in all test groups compared to the control group [41]. In another study, the use of IONPs functionalized with curcumin showed a lower hemolytic activity compared to IONPs without curcumin, which can be caused by the negative charge of their surface [45]. Ruan et al. synthesized two types of iron oxide nanoparticles with different agents (on their surface) to enter the nanoparticles into mitochondria and lysosomes. The results of the MTT assay showed that iron oxide nanoparticles with mitochondrial entry factor cause toxicity in MCF-7 cells by depolarizing the mitochondrial membrane. They stated that mitochondria are one of the cell organelles that can be damaged if iron oxide nanoparticles enter the cell [46].
Synthesis and functionalization of Fe3O4 nanoparticles is a promising first step in low-cost synthesis routes based on environmental friendliness. According to studies, iron oxide nanoparticles have a high potential as a factor in the treatment and diagnosis of cancer. These nanoparticles can not only be used as drug carriers in the treatment of cancer but they can also be directed to a specific area of the body through an external magnetic field and have various applications in the fields related to biology. The wide variety of functionalized Fe3O4 nanoparticles helps develop targeted functionalization and synthesis methods. Despite some common methods for the synthesis of iron oxide nanoparticles, the methods used for their preparation still need to be improved to achieve better control over their desired physicochemical and biological properties. Therefore, functionalization of IONPs is the critical step to prevent toxic effects in biomedical applications because magnetic saturation, size, shape, surface charge, colloidal stability, drug loading capacity, and drug release behavior are the characteristics that should be considered when selecting iron oxide nanoparticles for their applications in cancer diagnosis and treatment. Also, the integration of natural compounds from plants in the synthesis of IONPs improves their biocompatibility and promises a wide potential in cancer diagnosis and treatment. Regardless of the recent work that has shown excellent results in the synthesis of environmentally friendly iron oxide nanoparticles, future research on IONPs functionalized with phytochemicals should focus on their toxicity and degradability in vivo.

Ethical Considerations
Compliance with ethical guidelines

This research is a review article with no human or animal sample.

This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Conflicts of interest
The authors declared no conflict of interest.

The authors express their gratitude to all those who improved the present article with their constructive suggestions

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Type of Study: Review | Subject: Basic Medical Science
Received: 2022/05/14 | Accepted: 2022/06/22 | Published: 2022/07/1

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