Synthesis techniques of iron oxide nanoparticles with its characteristic size.
Abstract
In recent years, functional Iron oxides nanoparticles and nano-composites have gained a special traction in the field of nano-biomedicine, owing to their multifunctional capabilities that includes the inherent magnetic resonance imaging, magnetic bioseparation, cargo delivery and magnetic hyperthermia behavior. Interestingly, there are various forms of iron oxides available, with each form having their own specific characteristics. The different polymorphic forms of iron oxides are obtained through various synthetic routes and are usually surface modified to prevent their oxidation. The chapter shall encompass the synthesis and surface modification of Iron oxides nanoparticles, physicochemical properties, and theranostic application of the magnetic iron oxide nanoparticles in cancer. Also, the future directions of Iron oxide nanoparticles and nano-composites towards the achievement of clinically realizable nanoformulation for cancer theranostic applications were highlighted.
Keywords
- iron oxide nanoparticles
- functionalised nanoparticles
- hyperthermia
- MRI contrasting ability
- tumor ablation
- tumor environment
- nano-carrier
- clinical translation
1. Introduction
Over the past few decades, nanomaterials have gained a special interest and are being investigated widely for various applications, owing to their unique characteristics [1]. Until now, several nanoparticulate systems have been studied to demonstrate their potential to detect, diagnose and treat cancer effectively with high degree of specificity and affinity to target cells, in comparison to the other onco-therapeutic approaches [1, 2, 3]. Iron oxides are being investigated widely in the field of nano-biomedicine, owing to their greater degree of variability and versatility [4]. The multifunctional capabilities of iron oxide nanoparticles including tumor labelling, magnetic bioseparation, biological entities detection, transfections,
In general, the magnetic behavior of nanomaterials is greatly influenced by various features, such as size, size distribution, shape, polymorphic form, surface modification and purity [11, 12, 13]. Iron oxide nanoparticles of various polymorphic forms are synthesized through various approaches, including co-precipitation [14, 15], sol-gel method [16], sol-gel cum reverse-micelle technique [16], thermal decomposition [17], sonochemical [18], microwave heating [19, 20], hydrothermal [21, 22, 23], microemulsion [24, 25, 26], green synthesis [27, 28], bacterial synthesis [29], laser pyrolysis [30], and electrochemical synthesis [31]. For effective practical applications, the nanoparticles and nano-composites must be readily aqueous dispersible, stable and biocompatible with fascinating magnetic properties and interactive surfaces. The particle characteristics of Iron oxides such as size, shape and surface charges serves as a determining factor in achieving biological distribution and elimination [32]. Multiple studies evidence that the particle characteristics play an important role in the toxicity, i.e. smaller particles showed increased toxicity than larger particles [33, 34, 35].
2. Synthesis and surface functionalization of iron oxides
In the last two decades, several synthetic approaches have been followed to synthesize iron oxide nanoparticles with controlled size and morphology, biocompatibility and monodisperse nature [32, 36]. The schematic depiction of commonly employed chemical approaches is shown in Figure 1.
Of many approaches, co-precipitation is widely used for the synthesis of iron oxide due to their process simplicity [37]. At the same time, it is necessary to consider several factors such as precursor salts used, ratio of Fe2+/Fe3+ ions, nature and type of surfactants used, reaction parameters (pH and ionic strength of media, reaction temperature, stirring rate, drop rate of salt/base solution) and chemical processes employed in the co-precipitation technique to achieve the iron oxide nanoparticles with desirable crystal structure and morphology, monodispersity, and attractive magnetic properties [32, 38]. Peternele et al. synthesized magnetite and maghemite nanoparticles by precipitating the mixture of chloride salts of Fe2+ and Fe3+ (1:2 ratio) using 1.5 M NaOH or 25% Ammonia under vigorous stirring. The sequences of addition of base strongly affect the formation of phase and size of the magnetite nanoparticles. Further, much smaller sized maghemite was obtained by oxidizing prepared magnetite nanoparticles due to the Ostwald ripening effect. The nanoparticles obtained using ammonia displayed uniform size and were monodisperse in nature [37]. Cui et al. synthesized magnetite, maghemite and hematite using a common epoxide precipitation route involving an ethanolic solution of ferrous chloride tetrahydrate and a gelation agent propylene oxide. Initially, the nucleation of magnetite was observed due to the oxidation of Fe(II) precursor. From this step, the magnetite solution can be transformed into Fe3O4, γ-Fe2O3 and α-Fe2O3 nanoparticles through centrifugation-followed by vacuum drying, sol-to-xerogel formation followed by oxidation at 150°C and, atmosphere controlled evaporation of sol at 150°C, respectively [39, 40]. In another study, Cui et al. synthesized nanoparticles of other polymorphic forms such as lepidocrocite and goethite just by regulating the pH of the obtained greenish precipitate comprising an ethanolic solution of ferrous chloride tetrahydrate and a gelation agent propylene oxide using ammonia, followed by air oxidation under room temperature [41].
In several studies, the microemulsion and reverse micellization has been employed for the preparation of iron oxide nanoparticles with controlled morphology, but at the same time the aggregation of nanoparticles are high and requires several washing, and stabilization [32]. For instance, Lee et al. synthesized magnetite nanoparticles by adding the hydro-ethanolic Fe (II, III) salt precursor solution into sodium dodecylbenzenesulfonate (SDBS) dispersed xylene solution under vigorous stirring for 12 h. Hydrazine was added to the solution maintained at 90°C, and the solution was refluxed for 5 h to obtain nanoparticles. The size of the nanoparticles can be tuned by modifying the relative amounts of precursor and the polar solvent-surfactant ratio [42]. In another study, Jung et al. applied the reverse micelle technique to synthesize uniform and monodisperse Fe3O4 nanoparticles for sensing and drug targeting applications. Herein, the precursor and surfactant immobilized in the organic phase were added to the aqueous phase comprising stabilizer and stirred for several hours to form stable reverse micelles of sub 3 nm size. The formation of large irregular and small worm-like nanoparticles was observed in the absence of stabilizer [43].
In order to achieve iron oxide nanoparticles with high-quality monodisperse nature, thermal decomposition approach has been used widely. However, this requires relatively higher temperature and involves complex operations. Hyeon et al. prepared maghemite nanocrystallites with a high degree of crystallinity and monodiperse nature by subjecting Iron pentacarbonyl-oleic acid complex to thermal decomposition. Initially, the complexation was carried out by transferring the Iron pentacarbonyl into a hot mixture containing oleic acid and octyl ether and maintained at 100°C for 1 h. The resulting mixture was cooled and treated with mild oxidant trimethylamine oxide. Following the addition of trimethylamine oxide, the solution was again heated to 130°C for 2 h under an inert (Ar) atmosphere. Further, the temperature was slowly increased to 300°C and refluxed for 1 h to obtain the maghemite nanocrystallites [44]. Later, Lassenberger et al. used a slightly modified thermal decomposition technique to synthesize the monodisperse oleic acid stabilized Iron oxide nanoparticles [45], which does not involve the use of mild oxidants. The particle size of nanocrystallites is directly linked to the concentration of the complexation agent and the heating rate employed in the synthesis process [44, 45]. Zhou et al. successfully synthesized various morphologies of monodisperse Fe3O4 nanoparticles by varying the ratio of Iron oleate/sodium oleate, reflux temperature, and heating rate [46]. The biggest problem with the nanoparticles obtained via thermal decomposition route is their limited solubility in aqueous environments. Thus, phase transformation is required to render them water soluble [45].
A simple hydrothermal process can be a better alternative for the preparation of monodisperse, dislocation-free, highly crystalline iron oxide nanoparticles, as it does not require high temperature. The use of surfactants in the hydrothermal process could limit the growth of nanoparticle size, while retaining the crystallinity and magnetic properties close to that of the iron oxides prepared without surfactants and bulk iron oxides [6, 32]. Ozel et al. synthesized Iron oxides of varying crystallinity and size ranging from 12 to 49 nm by varying the reaction temperature (60–180°C) and reaction time (1–48 h) [47]. Further, Torres-Gomez et al. reported the synthesis of various γ-Fe2O3 nanostructures such as quasi-spherical, octahedral and truncated cubes by varying the reaction temperature from 120 to 160°C [22]. Ellipsoid 3D superstructures, plate-like nanostructures and irregular structures of α-Fe2O3 were obtained by employing varying proportions of Fe3+ precursor, surfactants and solvent under varying temperatures [48]. Xu et al. used urea to synthesize template-free rod-like β-FeOOH structures by varying the reaction temperature and time [49]. Also, urea in combination with ammonia was added to ferric chloride solution and autoclaved at 150°C for 6 h to obtain β-Fe2O3 [50]. Various reports highlight that depending on the type of the reducing agent and surfactants used in the hydrothermal process, different iron oxide phases and nanostructures such as spherical, polyhedral, nanocubes, octahedral, truncated cubes, hollow spheres, nanorods etc. [6, 22, 23, 32, 47, 49, 51, 52] can be obtained.
Sonochemical technique is a competitive alternative, to prepare ultrafine, monodispersive iron oxide nanoparticles with unusual properties. Usually, iron oxides prepared through this route are amorphous and possess low magnetization with speromagnetic behavior below magnetic transition temperature [6]. Hassanjani-Roshan et al. demonstrated the effect of ultrasonic power and reaction temperature on the particle characteristics such as crystalline/amorphous behavior and particle size of α-Fe2O3. The particle can be transformed into a highly crystalline form by subjecting them to higher temperature, following the sonochemical synthesis [53]. A cube-like Fe3O4 nanoparticle with different particle sizes ranging from 20 to 58 nm was obtained by varying the molar concentration of the precursor and the reducing agent [54]. According to the LaMer model, the local supersaturation should be higher to achieve the smaller particles. Ludtke-Buzug et al. state that the maximum local supersaturation is higher at lower ultrasound frequency [55].
Recently, green chemistry and biological methods are being used for the preparation of iron oxide nanoparticles owing to their safety, low cost, non-toxic and eco friendliness approach. However, the consistency of synthetic process is highly influenced by the source of the green and biological reducing agents [40]. The microbial-mediated approach demands a lengthy incubation time for the synthesis of iron oxide nanoparticles [56]. Whilst, the plant-mediated environment-friendly approach requires less time and can be used for the synthesis of various iron oxide nanostructures like spherical, needles, cubical, dendrites, cylindrical, and so on [56] with appreciable biological activities. Many studies utilize plant extracts with mild reducing capability along with bases like sodium hydroxide [57, 58], sodium carbonate [59], glycine [60] to synthesize stabilized iron oxide nanoparticles, as this can avoid the use of environmentally-toxic stabilizing agents. Few studies reported the successful synthesis of Iron oxide nanostructures using the extracts like grape berry ferment [61], flower extract of
Nanoparticle type | Precursor | Precipitating agent | Process and conditions | Size | Ref. |
---|---|---|---|---|---|
Fe3O4 | FeCl2·4H2O, FeCl3·6H2O | 1.5 M NaOH | Addition of precursor solution into alkali, a. stirring under air for 30 min b. N2 bubbling (100 mL/min) for 30 min c. kept under magnetic field for 24 h | 9.82 nm 6.31 nm 7.21 nm | [37] |
Fe3O4 | FeCl2·4H2O, FeCl3·6H2O | 25% NH4OH | Addition of alkali into precursor solution a. stirring under air for 30 min b. N2 bubbling (100 mL/min) for 30 min c. kept under magnetic field for 24 h | 11.22 nm 5.05 nm 5.41 nm | [37] |
γ-Fe2O3 | FeCl2·4H2O, FeCl3·6H2O | 1.5 M NaOH | Addition of precursor solution into alkali, adjusted to pH 3.5 using HCl a. stirring under air for 1 h at 95°C b. O2 flux (100 mL/min) for 1 h at 95°C c. Oxidation at 250°C for 3 h | 7.21 nm 7.21 nm 7.21 nm | [37] |
γ-Fe2O3 | FeCl2·4H2O, FeCl3·6H2O | 25% NH4OH | Addition of alkali into precursor solution, adjusted to pH 3.5 using HCl a. stirring under air for 1 h at 95°C b. O2 flux (100 mL/min) for 1 h at 95°C c. Oxidation at 250°C for 3 h | 6.31 nm 5.41 nm 5.41 nm | [37] |
Fe3O4 | FeCl2·4H2O | Propylene oxide | 78°C for 30 min, centrifugation and vacuum drying | 7.5 nm | [40] |
γ-Fe2O3 | FeCl2·4H2O | Propylene oxide | 78°C for 30 min, xerogel formation (100°C), followed by oxidation at 150°C | 8.6 nm | [40] |
α-Fe2O3 | FeCl2·4H2O | Propylene oxide | 78°C for 30 min, atmosphere controlled evaporation at 150°C | 18.4 nm | [40] |
γ-FeOOH | FeCl2·4H2O | Propylene oxide | 60°C for 30 min, pH 6.5, air oxidation for 5 h | 40–80 nm | [41] |
α-FeOOH | FeCl2·4H2O | Propylene oxide Ammonia | 60°C for 30 min, pH 8 to 8.5, air oxidation for 20 h | 20–90 nm | [41] |
Fe3O4 | FeCl2·4H2O | Propylene oxide Ammonia | 60°C for 30 min, pH ≥9, air oxidation for 2 h | 25–50 nm | [41] |
Fe3O4 | Fe(SO4)·7H2O, Fe(NO3)3·9H2O | NaOH | Primary nucleation was carried out by adding NaOH solution into precursor solution at 60°C under stirring and after 10 min HCl was added to the precipitate and stirred for 1 h | 7.8 nm | [11] |
Fe3O4 | Fe(III) stearate | hydrazine | Organic phase—precursor, olyelamine and xylene; aqueous phase—F127 in water; reverse micelles solution heated to 90°C, hydrazine addition and stirring for 3 h | 2.8 nm | [43] |
Fe3O4 | Fe(III) oleate | hydrazine | Organic phase—precursor, olyelamine and xylene; aqueous phase—F127 in water; reverse micelles solution heated to 90°C, hydrazine addition and stirring for 3 h | 7 nm | [43] |
Fe3O4 | Fe(III) acetylacetonate Oleic acid | hydrazine | Organic phase—precursor, olyelamine and xylene; aqueous phase—F127 in water; reverse micelles solution heated to 90°C, hydrazine addition and stirring for 3 h | <2 nm | [43] |
Fe3O4 | FeCl2·4H2O, Fe(NO3)3·9H2O | hydrazine | Organic phase—SDBS, xylene; aqueous phase-ethanol, precursor salts in water; reverse micelles solution heated to 90°C, hydrazine addition and refluxed for 5 h | 2–10 nm | [42] |
γ-Fe2O3 | Fe(CO)5 | Trimethalamine oxide | Complexation—precursor, octylether, oleic acid; maintained at 100°C for 1 h; treated with trimethyloxide; heated to 130°C under Ar atmosphere; refluxed at 300°C | 4–16 nm | [44] |
Iron oxide | Fe(CO)5 | — | Complexation—precursor, dioctylether, oleic acid; raised to 100°C, N2 atmosphere, and held for 10 min; refluxed at 290°C for 1 h | 3–10 nm | [45] |
Fe3O4 | Iron oleate | Isopropanol | Precursor, sodium oleate (different concentration), oleic acid dissolved in 1-octadecene or tri-n-octylamine; refluxed at 300 to 360°C (with varying heating rate from 5 to 15°C/min) for 2 to 6 h | Diverse morphology and size | [46] |
Iron oxide | FeCl3·6H2O, FeCl2·4H2O | Ammonia | The primary nanoparticles prepared by adding ammonia into precursor solution were grown in an autoclave at 60°C (12 h), 100°C (12 h, 72 h), 150°C (12 h, 24 h), 180°C (1 h, 12 h, 24 h, 48 h) | 12–49 nm | [47] |
γ-Fe2O3 | FeCl3·6H2O | Hydrazine | The primary nanoparticles prepared by adding hydrazine into precursor/PEG8000 solution were grown in an autoclave at 120°C, 140°C, 160°C for 4 h | Diverse morphology and size | [Torrez] |
α-Fe2O3 | FeCl3·6H2O | Ammonium hydroxide | The solution containing different precursor, solvent and additives was autoclaved at 160°C/180°C for 10–12 h | Diverse morphology and size | [48] |
β-FeOOH rods | FeCl3·6H2O | Urea | 70–110°C for 8 h | 0.4–2.3 μm | [49] |
β-Fe2O3 | FeCl3·6H2O | Urea, Ammonia | pH 9.66, 150°C for 8 h | 50–90 nm | [50] |
α-Fe2O3 | FeCl3·6H2O | NaOH | The precursor solution was added dropwise into NaOH solution and subjected to varying sonication power (1, 3, 5, 7, 9 W) and reaction temperature for 30 min; annealed for 1 h | Amorphous/ crystalline particles | [53] |
Fe2O3 rods | Fe(SO4)·7H2O | Leaf extract/NaOH | To the precursor solution, a mixture of | 10–20 nm | [57] |
Fe2O3 | FeCl3·6H2O | Leaf extract | To the Bauhinia tomentosa leaf extract, the precursor solution was added; precipitate obtained was air-dried | 70 nm | [27] |
Iron oxide | FeSO4·7H2O | Henna extract/ NaOH | Henna extract was added to precursor solution maintained at 60 °C for 30 min; NaOH is added to form Iron oxides | 150–200 nm | [58] |
Iron oxide | FeCl3·6H2O | Leaf extract/Na2CO3 | One part of precursor solution was mixed with leaf extract of | 9 ± 4 nm | [59] |
Fe3O4 | FeCl2·4H2O, FeCl3·6H2O | Plant extract/glycine | Hot precursor solution was added to whole plant extract of | 10–30 nm | [60] |
Fe-O | FeCl3·6H2O | Flower extract | Precursor solution was added dropwise into flower extract of | 10–40 nm | [61] |
γ-Fe2O3 | Fe(NO3)3·9H2O | Grape berry ferment | The pH of the precursor solution was adjusted from 2.7 to 1.5 using grape berry ferment; transferred to autoclave and kept at 200°C for 24 h; iron oxide precipitate was obtained | 6–18 nm | [62] |
Avoiding agglomeration while retaining the stability is the most crucial challenge every magnetic material undergoes. In last two decades, considerable efforts have been devoted for the passivation of iron oxide nanoparticle surface using organic and inorganic materials, to avoid agglomeration, and to have improved solubility, stability and biocompatibility. The surface functionalization of iron oxide nanoparticles could be achieved by coating the iron oxide core with shell material (or) by dispersing the iron oxide core over the shell material (or) through chemical interaction of iron oxides with shell material (or) through bioconjugation reactions (or) by coating a shell-core structure with shell material. The shell materials could be organic or inorganic materials with functional properties. The commonly employed functional materials in the passivation of iron oxide surface include organic small molecules (drugs, fatty acids, polyol, dyes, vitamins, cyclodextrins), surfactants (dextran, polyvinyl alcohol), biological molecules (proteins, nucleic acids, antibody, cells, enzymes, microbes), silanes (
3. Physicochemical properties of iron oxides
3.1 Crystallographic properties and polymorphism
Iron (III) oxides exhibit distinct physical properties due to its polymorphic forms that has same molecular formula but with different crystallographic structures. Iron (III) oxides occur in various polymorphic forms such as α-Fe2O3, β-Fe2O3, γ-Fe2O3, ε-Fe2O3, and ζ-Fe2O3. The polymorphic forms are characterized by crystal structure as: (i) rhombohedrally-centric hexagonal α-Fe2O3 (R
3.2 Magnetic properties
Magnetic properties of the nanomaterials play a key role in MRI contrasting ability, magnetically-induced heating, externally-targeted drug delivery and bio-sensing applications. The γ-Fe2O3 polymorph exhibits ferrimagnetic and superparamagnetic behavior with a curie temperature of 928 K [16, 76], whilst, the ferromagnetic ε-Fe2O3 possess highest coercivity [76, 84] with a curie temperature close to 500 K [85]. Interestingly, the magnetic order of ε-Fe2O3 nanoparticles does not get vanished even at 500 K and this different ferromagnetic state persists up to 850 K [86]. A weak ferromagnetic behavior was reported in α-Fe2O3 phase with a Morin transition at ∼269 K, i.e., a transition of antiferromagnetic state from weak ferromagnetic state [76] and a curie temperature of 950 K [16]. The paramagnetic β-Fe2O3 becomes magnetically ordered below the Neel temperature (∼110 K) and exhibit antiferromagnetic state. Similarly, the recently identified ζ-Fe2O3 exhibited an antiferromagnetic nature below Neel transition temperature of ∼69 K [76]. A paramagnetic transition of amorphous Fe2O3 at temperatures above the Neel temperature of 80 K was concluded based on the interpretation on Mössbauer data [84]. In some cases, non-ideal magnetic behavior could be observed in iron oxides due to wide range of blocking temperatures, aroused from wide range of particle size distribution [6]. Wustite (FeO) is generally stable above 560°C and possess antiferromagnetic nature with a Neel temperature of about 200 K [79]. Among all Iron (III) oxyhydroxide, δ-FeOOH is the only polymorphic form which showed significant magnetization at room temperature with ferrimagnetic behavior (Tc—450 K) [87] and significant relaxation properties [88]. The smaller crystals of Feroxyhites (δ-FeOOH) showed speromagnetic behavior between 80 K and 300 K [87]. β-FeOOH is usually paramagnetic at room temperatures and below Neel temperature they exhibit antiferromagnetic property [89]. The bulk α-FeOOH and γ-FeOOH displayed a Neel transition at 252 K and 53 K respectively [90]. The magnetic property of Ferrihydrite is size dependant, which displayed antiferromagnetic behavior below 4 nm, and above 4 nm ferrimagnetic behavior was observed [91]. The magnetic properties of iron oxide nanoparticles are greatly influenced by the oxidation and aggregation. The oxidation of iron oxide nanoparticles could lead to the loss of magnetic properties. In contrast the aggregation of particles may lead to mutual magnetisation that is usually aroused by the interaction of magnetic field of one nanoparticle with the neighboring nanoparticle [32].
3.3 Chemical properties
Iron oxide nanoparticles are highly prone for oxidation, particularly in the atmospheric air, and hence require a thin and non-interactive protective coating that has minimal effect on its characteristic physical properties, especially its magnetic properties [32]. Many studies also concluded that the naked iron oxide nanoparticles tend to agglomerate owing to their high surface energy, surface area-to-volume ratio, magnetic interactions and van der Waals forces [32, 92]. The agglomeration of the particles not only increases the particle size, but also enhances strong magnetic dipole-dipole attractions, that make the particles ferromagnetic. In general, the hydrophobic character and the huge surface area-to-volume ratio render the iron oxide nanoparticles toxic, insisting the need for the modification of particle surface, to make them hydrophilic and biocompatible [32].
4. Theranostic applications of magnetic iron oxide nanoparticles in cancer
4.1 Tumor imaging
Among various imaging modalities, magnetic resonance imaging acquires a rapid image of
4.2 Cancer labelling and sorting
Cell labelling and sorting is a key technique in the field of oncology and stem cell research. Usually, cells are labeled using ferro or superpara or paramagnetic materials in the process of
The magnetic behavior of iron oxides allows the isolation of specific cells from the biological suspensions like blood, apart from its diagnostic ability. In non-invasive magnetic-activated cell sorting, the antibody-bound iron oxides bind specifically to the specific antigens present on the surface of target cells. The bound fraction can be separated from the unbound fraction by applying a magnetic field. For instance, circulating tumor cells are captured, and analyzed for staging cancer, selection of therapy and monitoring treatment [106]. Mi et al. developed a low cytotoxic Herceptin-functionalised conjugated oligomer-based Iron oxide-silica nanoparticle system for magnetic-activated sorting and fluorescence-activated detection of circulating tumor cells at its metastatic stage [107]. Du et al. bioengineered D-tyrosine phosphate decorated iron oxides that can be dephosphorylated to tyrosine coated iron oxides by the overexpressed alkaline phosphatases in the surface of cancer cells. The tyrosine-coated iron oxides upon dephosphorylation have been attached to the tumor cells and captured using a small magnet [108].
4.3 Cancer immunotherapy
Immunotherapy is a robust strategy to eliminate cancer cells. For effective cancer immunotherapy, the immune system must be activated against tumor antigens. The immunotherapeutic approaches include cell-based immunotherapy, monoclonal antibodies (mAb) for checkpoint blockade and cancer vaccines. In cell-based immunotherapy, the migration, expansion, and depletion of immune cells are tracked to understand the complex cellular and molecular mechanism involved in the immune system [100]. The schematic representation of various applications of iron oxide nanoparticles is depicted in Figure 2.
4.3.1 Cell-based immunotherapy
The T cells have the ability to differentiate into various forms based on the interaction of specific tumor antigens on the antigen-presenting cells. Real-time T-cell trafficking using MRI can improve the T cell-based immunotherapies by achieving better localization [109]. For instance, the three-dimensional MRI visualization of
Macrophages eliminate foreign particles and cellular wastes by secreting cytokines and initiating phagocytosis. Reprogramming or polarizing the tumor-associated macrophages (TAM) in the tumor environment shall overcome the difficulty of penetration of M1 macrophages from the outside environment. Iron oxides on their own activate the macrophages through metabolic degradation. In a study, the response to CD47 monoclonal antibodies by tumor-associated macrophages (TAM) has been monitored using ferumoxytol-enhanced MRI. The study showed that phagocytosis of TAM had been activated due to the inhibition of the interaction between SIRPα and CD47 by CD47 mAb [112]. In another study, 3-methyladenine was incorporated into hollow iron oxide nanoparticles to promote the immune response by reprograming the TAM into M1-type macrophages. The nanoparticle system upregulates the NF-κB p65 while inhibiting the expression of P13Kγ to promote an immune response. The mouse model revealed a synergistic effect of polarization of macrophages by 3-methyladenine and iron oxide nanoparticles [113]. An artificial reprogramming of macrophages was reported in a study using hyaluronic acid-coated iron oxide nanoparticles. In this study, the iron oxide nanoparticles and macrophages from RAW 264.7 mouse were incubated together and injected into 4 T1 tumor-bearing mice. The results indicated the capability of these artificially programmed macrophages in polarization of TAM and enhanced tumor effect [114].
Dendritic cells play a key role in activating cytotoxic T lymphocytes and regulating adaptive immune response by presenting the tumor antigens into the draining lymph nodes. The immune response is highly dependant on the migration of activated dendritic cells to lymph nodes [103, 115]. The incorporation of iron oxides into a dendritic cell does not impair the viability of cells [103] and demonstrate the tracking of dendritic cells with MRI [100]. The antigens are loaded into immature dendritic cells, as the phagocytic ability is higher than the mature dendritic cells. The internalization of iron oxides takes place via endocytosis for the particles ranging from 20 to 200 nm [100]. Iron oxide nanoparticles bound to oval albumin showed increased expression of TNFα, IL-6, and IFN-γ in murine dendritic cells. Further the assessment of immunotherapeutic capability in mice revealed a dramatic reduction in the tumor [116, 117]. De Vries et al. reported the enhanced accuracy of magnetic resonance tracking of iron oxides-loaded dendritic cells over scintigraphic imaging. Herein, the iron oxide nanoparticles are phagocytized into the autologous
4.3.2 Cancer vaccines
Cancer vaccines play a crucial role in presenting the tumor antigens to activate specific T cells against the tumor cells. Recently, biomimetic nano vaccines encompassing tumor cell membranes with tumor antigens are used for targeting the immune or tumor cells. The vaccination capacity can be increased by introducing iron oxides with intrinsic magnetic properties. For instance, Zhang et al. developed a biomimetic magnetosome to expand and stimulate antigen-specific cytotoxic T-cell and to track and effectively guide them into tumor tissues [118]. Further, Wang et al., demonstrated antitumor activity and immunogenic cell death with low systemic toxicity using Ce6-loaded magnetic/mesoporous organosilica nanoparticles concealed with cancer cells [119]. In another study, Long CM et al. developed magneto-vaccination using iron oxide labeled GM-CSF secreting cells mixed with tumor to stimulate the immune system by inducing the T cell tumor targeting factors proliferation [120].
4.3.3 Checkpoint blockade
The immune checkpoint is the molecular interactions between cancer cells and immune cells. The ability of tumor cells to evade the surveillance of the immune system is the common problem associated with the T cell-mediated approach, as many healthy cells like certain tumor cells encompass inhibitory checkpoint programmed cell death protein 1 ligand 1 (PD-L1) that can inactivate the T cells by binding to the inhibitory checkpoint PD1 protein expressed on T cell surface [100]. The immune response shall be enhanced by targeting inhibitory checkpoint molecules such as proteins and antibodies. Under physiological conditions, the checkpoint inhibitory molecules are highly prone to degradation and hence required to be encapsulated into a robust delivery system. In a study, the immunoswitch design was demonstrated using antibodies-loaded dextran-coated iron oxide nanoparticles for the inhibition of immune checkpoints. The antibodies against PD-L1 and 4-1BB were used to stimulate T cells. In this study, the tumor-bearing mice (C57BL/6) was initially treated with adoptively transferred T cells, followed by the administration of antibodies-loaded dextran-coated iron oxide nanoparticles or free individual antibodies. The results suggest the targeting of multiple checkpoints, as targeting only one checkpoint did not result in size reduction of tumors. Also, highlights the multifunctional utility of iron oxides for checkpoint inhibition [121]. In another study, the Iron oxide-coated folic acid-functionalised-disulphide-polyethylene glycol-conjugated polyethylenimine nanoparticles were developed for the delivery of siRNA to inhibit PD-L1 protein. The nanoparticles exhibited higher transfection ability, MRI contrasting ability, and the high cellular uptake downregulate the PD-L1, which in turn affected the T-cells cytokine-secretion level [122]. The schematic representation of immune checkpoint regulation using immunoswitch nanoparticles is shown in Figure 3.
4.4 Tumor ablation therapy
In tumor ablation therapy, the use of non-contact magnetic heating (above 42°C) has gained a special attention and are being utilized in clinical practice in few hospitals as an adjuvant therapy. The magnetic heating is achieved through hysteresis loss and relaxation losses under varying alternating magnetic field and radio frequencies. The efficiency of magnetic heating is directly linked to the size, shape and concentration of the magnetic nanoparticles, the strength and frequency of alternating magnetic field and cooling rate in biological tissues. The major obstacle in the use of Iron oxides for non-contact heating of tumor tissues is their low heating power. Magnetite and maghemite nanoparticles are widely employed for magnetic hyperthermia applications due to their well-established biocompatibility. However, these nanoparticles possess relatively low coercivity and require high applied frequency, usually ranging from 400 kHz to 900 kHz, to effectively heat the media in which it is dispersed. In contrast, studies indicate that ε-Fe2O3 nanoparticles exhibit hyperthermia potential at low applied frequency of about 20 kHz to 100 kHz. Though many magnetic materials reported to have high heating power, their concern over safety has limited their use in clinical practice, and encourages the optimisation of structural features of iron oxide nanoparticles for enhanced clinical hyperthermia potential [123].
Kolosnjaj-Tabi et al. demonstrated a mild hyperthermia efficacy of PEG-coated iron oxide nanocubes in a magnetic field of 23.8 kA/m and 111 kHz until the particle resides in the interstitial extracellular location. The hyperthermia efficiency of the nanoparticles was lost after cellular internalization and capture in the liver and spleen. However, the hyperthermia effect destabilize the tumor stroma to enhance the drug penetration [124]. The cancer theranostic agents are widely employed for the effective control of tumor owing to their potential diagnostic cum treatment approach. The magnetic hyperthermia efficiency and MRI T2 contrasting ability of iron oxide nanoparticles were demonstrated using the fourth-generation dendrimer coated iron oxides [125]. Hayashi et al., developed iron oxide nanoclusters for combined MRI cum hyperthermia, as the individual iron oxides (<10 nm) are prone to leakage from capillaries. In this study, the surface of Iron oxide nanoclusters is modified with polyethylene glycol and folic acid to enhance their accumulation within the tumor environment of mice, following the intravenous administration. The mice that underwent local heating for 20 minutes reduced the tumor volume to about 1/10th of the control mice, indicating the hyperthermia efficiency of the iron oxide nanoclusters [126]. Lin et al. developed a multifunctional pegylated albumin nanocomplex comprising Iron oxide and a hydrophobic dye (IR780). The photothermal effect and MR imaging of nanocomplex were demonstrated on a cancer colon model and tumor-bearing mice, respectively [127]. The combined photothermal effect (NIR-induced) and cancer imaging (MRI and fluorescence) were demonstrated using a novel dumbbell-like Gold-Iron oxide nanoparticle by Kirui et al. [128]. A similar kind of bimodal cancer imaging with a photothermal effect was reported in hyaluronan-targeted iron oxides to bring out the photothermal efficiency and cell staining potential of the iron oxides apart from its MRI contrasting ability [129]. Espinosa et al. demonstrated a complete tumor regression using the dual-mode hyperthermia and photothermal therapeutic potential of iron oxide nanocubes [130].
4.5 Drug delivery applications
The successful delivery of therapeutic agents into the tumor environment with minimal toxicity to surrounding tissues is the biggest challenge, as it is often limited by tumor heterogeneity, dense fibrotic stromal barriers and various vascular barriers including abnormal tumor blood vessels, tumor cells proliferating nests, normal blood vessels, positive intratumoural pressure [131, 132]. Iron oxide nanocarrier systems are often believed to overcome these biological barriers by altering the pharmacokinetics and tissue distribution profile via enhanced permeability and retention effect [9]. However, for clinical success, EPR effect may not be sufficiently enough as it offers only certain level of tumor targeting and non-specific biodistribution. Thus, the logical choice for tumor therapy shall be actively tumor-targeted iron-oxide nano-carrier system, which can be minimally toxic to normal tissues while having enhanced bioavailability, intracellular bio-distribution, and potent cyto-toxic effects against the tumor cells. [131, 132]. Recently, the tumor-targeted iron oxide nanoparticles are used to monitor the accumulation of drugs in the tumor site, while simultaneously estimating the drug level in the tumor tissues. The detection of MRI signal changes of drug loaded iron oxides can provide a track over drug delivery, estimated drug levels in tissue and therapeutic response
Li et al. developed the iron oxide nanoclusters with photothermal mediated synergistic chemotherapy and chemodynamic therapy. In this study, the core iron oxides were surface modified using the paclitaxel-loaded human serum albumin and conjugated to the Arg-Gly-Asp peptides for tumor specific targeting [133]. Several studies indicate that insufficient penetration through BBB reduces the efficiency in treating glioblastoma multiforme. Norouzi developed pH-sensitive doxorubicin-loaded Iron oxide nanoparticles stabilized with trimethoxysilylpropyl-ethylenediamine triacetic acid to demonstrate their uptake in brain-derived using mouse model. The cellular uptake of nanoparticles was increased by 2.8 folds and provided an enhanced anti-tumor effect than free doxorubicin. Further, the study indicated that the penetration of nanoparticles into the brain was augmented due to the combination of cadherin binding peptide and external alternating magnetic field [134]. Hussein-Al-Ali et al. developed iron oxide/chlorambucil/chitosan nanocomposite with a particle size of about 15 nm. Controlled release of drug chlorambucil from the nanocomposite with significant anti-tumor effects on leukemia cancer cell lines was observed [135].
5. Concluding remarks and future directions of iron oxides
Since several decades, many studies have been conducted to evaluate the potential use of functionalised iron oxide nanoparticles for the delivery of anticancer drugs, yet there are several obstacles that need to be overcome for increased adoption of these nano-carrier systems into clinical practice. The various challenges that needs to be considered while developing the newer targeted iron oxide nanoparticles includes the synthesis of conjugated iron oxide nanoparticles without inducing a change in the chemical and magnetic properties, the high drug loading efficiency, regulation of circulation time [113], specificity and selectivity of towards tumor tissues, and controlled release of drug with the tumor region. The other challenges that are least explored in the development of iron oxide nanocarrier systems includes tumor uptake, biodistribution and bioelimination. The biological distribution is highly dependent on the nanoparticles size, morphology and surface characteristics, as these properties can strongly influence the particle interaction with serum proteins and cells [32]. The major obstacle in achieving the effective tumor therapy is the tumor heterogeneity resulted from the genetic mutations. This emphasis the need for personalized medicine involving both imaging and targeted drug delivery simultaneously, signifying the concept ‘we observe what we treat’. The potent MRI capability of the iron oxide nanoparticles shall allow the visualization of events such as delivery of drug and other cargo molecules, efficacy of the undergoing treatment, gene expression and metastasis, bioelimination of iron oxides. Though, iron oxides exhibit many distinctive properties, the long-term fate of iron oxides, PK/PD studies, toxicology studies and the toxicity criteria are yet to be clearly defined. Recently, there is an intense focus on the development of multifunctional tumor-targeted drug-loaded iron oxide nano-carrier systems, as it can offer many benefits such as, tumor-specific targeting, MRI contrasting ability (track and monitor the accumulation of the nano-carrier system), combined hyperthermia and chemotherapy to tumor cells and stimulus-induced drug release (control over the drug release at the tumor-specific site). Until today, there are numerous studies reported to have such multifunctional properties in
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