Nano-Sized Iron Sulfide: Structure, Synthesis, Properties, and Biomedical Applications

Introduction

With the development of nanotechnology (Li et al., 2019), nanomaterials have become a major resource for the development of novel therapeutic medicines and technologies designed to improve human health and the quality of life (Zhang and Webster, 2009; Esmaeili et al., 2020; Wang et al., 2020). In particular, due to their multiple functionality and excellent biocompatibility, iron-based nanomaterials are frequently used in the biomedical field, such as bioseparation, biosensors, magnetic resonance imaging (MRI), tumor hyperthermia, and drug delivery (Chen and Gu, 2017). In addition, recent studies have revealed that these nanomaterials have intrinsic enzyme-like properties (Gao et al., 2007; Xie et al., 2012; Xu et al., 2018), an important form of nanozyme representing a new generation of artificial enzyme (Wei and Wang, 2013; Dong et al., 2019; Liang and Yan, 2019). Currently, the majority of iron-based nanomaterials are iron oxide which possess excellent supraparamagnetic properties, with catalytic activity mimicking that of oxido-reductases, including peroxidase, catalase, superoxide dismutase, and oxidase (Gao et al., 2007; Liang and Yan, 2019). However, iron sulfide nanomaterials have not been comprehensively studied or used in the biomedical fields. Since O and S are congeneric elements, iron sulfide demonstrates similar physiochemical properties as iron oxide (Fu et al., 2019). In addition, the phases of iron sulfide in nature include mackinawite (FeS), pyrrhotite (Fe_1−xS), pyrite (FeS₂), and greigite (Fe₃S₄), etc., which exhibit more variability than iron oxide containing only Fe₂O₃ and Fe₃O₄. The band gap in iron sulfide is smaller than that of iron oxide, leading to the former having more appropriate electron transfer and conductivity (Wadia et al., 2009; Jin et al., 2017; Zhang et al., 2018). Importantly, iron-sulfur clusters are important cofactors in many enzymes which serve as active centers for electron transfer in catalytic processes and respiratory chain reactions (Qi and Cowan, 2011). Therefore, it is anticipated that iron sulfide nanomaterials will display multiple functionalities and they have great potential in biomedical applications. Herein, we will summarize the types, synthesis and properties of iron sulfide nanomaterials and emphasize their applications in biomedical and medical fields. This will provide a comprehensive understanding of iron sulfide nanomaterials and illustrate their considerable potential as novel multifunctional biomaterials in biomedical applications.

Type and Structure of Iron Sulfide

Solid phases of iron sulfides principally comprise FeS (mackinawite), Fe_1−xS (pyrrhotite), FeS_2p (pyrite), FeS_2m (marcasite), Fe₃S₄ (greigite), and Fe₉S₁₁ (smythite). The content of iron within a biomaterial therefore influences its phase, shape, and physical and chemical properties. FeS naturally has a tetragonal structure, with each iron atom coordinated to four sulfurs. For Fe_1−xS, a monoclinic hexagonal is present. FeS_2p forms stable iron (II) disulfides with cubic structures. FeS_2m differs from FeS_2p as an orthorhombic metastable iron (II) disulfide, whilst Fe₃S₄ is a cubic metastable Fe (II) Fe (III) sulfide. Hexagonal Fe₉S₁₁ is related to the Fe_1−xS phase (Rickard and Luther, 2007).

Reported crystal structures of iron sulfide are displayed in Figure 1 (Fleet, 1971; Argueta-Figueroa et al., 2017). FeS possesses a tetragonal layered structure in which the iron atoms are linked through tetrahedral coordination to four equidistant sulfur atoms. A single iron atom is coordinated to four equidistant sulfur atoms. The distance of Fe-Fe is 2.5967 Å. In addition, Fe-Fe bonding is substantial in FeS. To assess the effects of van der Waals forces resulting from the S atoms, sheets including Fe are stacked along the C-axis. The spacing of these layers is 5 Å. The structure of Fe₂S₂ is closed to FeS. The structure of FeS₂ is similar to that of NaCl in which S²⁻ is located at the center of a cube. The cubic structure has a low symmetry. In addition, FeS₂ exhibits chirality through absorbed organic molecules. Fe₃S₄ has an inverse spinel structure in which 8 Fe atoms are located at the tetrahedral A-sites and 16 Fe atoms are located at the B-sites of the octahedron. The unit cell of Fe₃S₄ is 9.876 Å. In addition, the cubic structure of Fe₃S₄ forms a closely packed array of S molecules linked by smaller Fe units (Figure 1D). It has been established that the Fe₇S₈ structure is a hexagonal supercell (Fleet, 1971). The viable distribution of vacancy sites ideal for the base structure of NiAs was observed to describe the structure of Fe₉S₁₀ (Elliot, 2010).

FIGURE 1

Figure 1. Crystal structure of iron sulfide. (A) FeS. (B) FeS₂. (C) Fe₂S₂. (D) Fe₃S₄. Reproduced with permission from Rickard and Luther (2007). Copyright 2007, American Chemical Society.

Synthesis of Nano-Sized Iron Sulfides

Nano-sized iron sulfide encompasses a range of iron and sulfur compounds. Firstly, the range of chemical and biological methods for their production are discussed. In addition, the most reported synthesized methods for creating different phases of iron sulfide are presented in Table 1.

TABLE 1

Table 1. Appearances, sizes and lattice spaces of iron sulfide.

Hydrothermal Synthesis

Thermal decomposition is the most commonly-used hydrothermal reaction for iron sulfide production. The typical solvothermal synthesis method of nFeS firstly involves the dissolution of FeCl₃·6H₂O in 40 mL of ethylene glycol. NaOAc and organosulfur compounds (allyl methyl sulfide, diallyl sulfide, diallyl trisulfide, diallyl disulfide, cysteine, cystine, glutathione (GSH), or methionine) are then added under continuous and vigorous stirring. The system was then sonicated for 10 min and transferred to a Teflon-lined stainless steel autoclave. The mixture was reacted at 200°C for 12 h and precipitates washed three times with ethanol and water. Finally, the products were dried at 60°C for 3 h (Xu et al., 2018). For FeS₂, the single source molecular precursor Fe³⁺ diethyl dithiophosphate forms an aqueous solution through the reaction of FeCl₃ and (C₂H₅O)₂P(S)SNH₄, with hexadecyltrimethylammonium bromide (CTAB) added as a surfactant and reacted with a single precursor [(C₂H₅O)₂P(S)S]₃Fe (Wadia et al., 2009). For FeS, FeCl₃·6H₂O was dissolved in ultrapure water with ethanolamine and thiourea added to the solution. After stirring for 25 min, the mixture was added to a Teflon lined autoclave and reacted at 180°C for 12 h. The synthesis of Fe₃S₄ differs from that of FeS. FeCl₃·6H₂O, ethylene glycol, thiourea and H₂O₂ were mixed and reacted at 180°C for 18 h in the presence of the capping agent polyvinyl pyrrolidone (PVP) to prevent excessive growth and aggregation of the nanoparticles (NPs) (Moore et al., 2019). Fe_1−xS single crystals were then synthesized through a hydrothermal method by the addition of K_0.8Fe_1.6S₂ crystals, Fe powder, NaOH, and thiourea in deionized water, which was reacted at 120°C for 3–4 days (Guo et al., 2017). Ionic liquids that form extended hydrogen bond systems were then used to form higher structures in the base of the hydrothermal process, as reported by Zheng and colleagues when changing the structure of Fe₃S₄ (Ma et al., 2010). Generally speaking, the product obtained by the hydrothermal method has better dispersibility and controllability, but iron oxide impurities can also appear during the synthesis of iron sulfide. Meanwhile, multiphase iron sulfide appears to occur easily, as assessed by X-ray diffraction (XRD) patterns for hydrothermally-synthesized samples.

Microwave Production

The principal advantages of microwave-assisted methods, compared with conventional heating include its reduced reaction time, smaller particle size distribution, and higher purity. Ethylene glycol is a solvent suitable for microwave-assisted methods owing to its relatively high dipole moment. For FeS₂ microspherolites, FeSO₄·7H₂O, PVP-K30 and S powder in ethylene glycol can be reacted by microwave in an N₂ atmosphere (Li M. et al., 2011). Although this emerging technique may be more desirable it should be noted that the aggregation phenomenon does not appear to be improved.

Co-precipitation

Chemical co-precipitation does not introduce impurities. The operation is performed under mild conditions and is typically synthesized using Fe₃S₄ methods, in which iron (II) sulfate heptahydrate and sodium sulfide are dissolved in ultrapure deionized water. The solution was then added dropwise to acetic acid to adjust the pH to 3.0, followed by stirring for several minutes. The reaction was prepared under an N₂ atmosphere (Chang et al., 2011). In addition, green synthesis was achieved in a continuous stirred-tank reactor (Simeonidis et al., 2016). As previously reported, the conditions of synthesis required by co-precipitation are harsher than those of other methods, and the products obtained may show poor homogeneity.

High Temperature Chemical Synthesis

Chemical synthesis methods using high temperatures have been reported for FeS₂. Briefly, iron (II) acetylacetonate (Fe(acac)₂), trioctylphosphine oxide (TOPO) and oleyamine (OLA) were mixed and degassed at 110°C for 1 h under a vacuum. The mixture was then rapidly heated to 220°C for 1 h under vigorous magnetic stirring in the presence of nitrogen. Sulfur was then quickly injected into the solution, which was heated to 220°C for 1 h. Once the solution cooled, ethanol was added to the precipitate to develop the FeS₂ nanoplates (Bi et al., 2011). Synthesis methods for Fe_1−xS and Fe₃S₄ have also been reported. The rapid injection method has been used to reduce the size of Fe₃S₄ (Beal et al., 2012). This method of synthesis is highly sensitive to the experimental conditions.

Sonochemical Synthesis

As a convenient and stable synthetic method, Bala and colleagues described specific FeS' sonochemical synthesis. Firstly, sodium sulfide was dissolved in double distilled water. FeSO₄·7H₂O was then independently dissolved in a solution of double distilled water and polyethylene glycol (1:1). The sodium sulfide solution contained a drop of Triton-X surfactant which was added dropwise to the above solution while being continuously sonicated for 30 min. PVP was then added and the system was mixed via ultrasound for a further 30 min (Ahuja et al., 2019).

Other Chemical Methods

Some unusual synthetic chemical methods have been reported. The low temperature synthesis of FeS₂ nanoparticles was described in 2014 (Srivastava et al., 2014a). Briefly, FeCl₃ and sodium polysulfide (Na₂S_x) were mixed in pH 5.6 acetate buffer in an anaerobic environment. The black solution then was reacted in a 90–100°C oil bath for 4 h to produce a grayish FeS₂ product. Flux methods were then used to synthesize 1D Fe₇S₈. The reaction was conducted within a furnace at 750–850°C (Kong et al., 2005). FeS can also be created in a biological system (Mei and Ma, 2013).

Biomineralization

The bio-synthesis of iron sulfide using microorganisms is superior for biomedical applications (Li X. et al., 2011). When microorganisms interact with target ions, they are transported into microbial cells to form NPs in the presence of specific enzymes. In addition to the advantages of green synthesis, biological methods improve the biocompatibility of iron sulfide. The particles generated have higher catalytic reactivity and a greater surface area. Previous studies have reported that FeS₂, Fe₃S₄, and FeS NPs can be produced by microorganisms. For the biomineralization of Fe₃S₄ and FeS₂, a magnetotactic bacterium has been described (Mann et al., 1990). In 1995, FeS materials were produced by sulfate-reducing bacteria grown on iron containing substrates (Watson et al., 1995). Bazylinski and colleagues also reported the formation of Fe₃S₄ using non-cultured magnetotactic bacteria (Lefèvre et al., 2010). Sulfate-reducing bacteria were able to produce Fe_1−xS as reported by Charnock and colleagues (Watson et al., 2000). NPs were subsequently formed at the surface by the microorganisms and as such, the porous structure of the iron sulfide NPs failed to prevent normal metabolism. These studies verified the utility of this method for efficient NP production. Chemical biomineralization methods have also been used to synthesize FeS₂ and FeS Quantum dots (QDs) (Jin et al., 2018; Yang et al., 2020).

Iron Sulfide Modifications

Bare nanocrystal cores have an unstable structure that is prone to photochemical degradation. However, those that are unmodified display higher toxicity. As such, biocompatible moieties are essential as they serve as caps for nanomaterials, including polyethylene glycol (PEG), silica, lactose, citrate, and dextran (Simeonidis et al., 2016; Mofokeng et al., 2017). Previous studies have reported the synthesis, characterization, cytotoxicity and biodistribution of FeS/PEG nanoplates in vivo (Yang et al., 2015). An adsorption-reduction method was used to load silver onto the surface of 3-aminopropyltriethoxysilanemodified 3-aminopropyl triethoxysilane (APTES)-modified Fe₃S₄ particles, achieving the preparation of magnetic composite nanoparticles of Fe₃S₄/Ag (He et al., 2013). However, modifications also led to adverse effects. For example, the modification of CTAB inhibited the growth of nano Fe₃S₄ (Simeonidis et al., 2016).

Characterization of Iron Sulfide

Detailed characterization is required to confirm the synthesis of iron sulfide. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) can be used to image surface morphology. These represent the most direct and commonly-used methods to assess the microstructure, size, and dispersion of the materials. Differences in the synthetic methods have presented variations in TEM/SEM imaging, including within the same phase. For FeS, nanoplates, spherical nanoparticles, and pomegranate flower-like shapes have been reported. FeS₂ exists as large particles, cubic nanocrystals, monodisperse microspherolites, spherical and hexagonal nanoribbons, and nanorods. Typical images of iron sulfide are shown in Figure 2. Table 1 reports the most common morphology and size of FeS, FeS₂, Fe₃S₄, and Fe₇S₈. Lattice spaces are measured to judge the crystallinity of the materials. The reported lattice spaces of the iron sulfides are summarized in Table 1. The composition, content, and structure of a substance can be analyzed, measured, and inferred using Ultraviolet-visible (UV-Vis) spectrometry and the absorption of UV and visible light. According to previous studies, the UV absorption peaks of FeS are 285 nm and 500 nm (Table 2). Information on the composition of the materials and the structure and/or morphology of the atoms or molecules inside the materials can be obtained by XRD analysis. XRD is the most direct indicator of whether a crystal is pure and so represents a convenient system to analyze synthesized materials. JCPDS cards are used to contrast and analyze unknown crystals. JCPDS cards of FeS (JCPDS card No. 15-0037 and 75-0602), FeS₂ (JCPDS card No. 03-065-1211, 89-3057, 65-3321, and 42-130), Fe₃S₄ (JCPDS card No. 16-0713, 89-1998, and 16-0073) and Fe₇S₈ (JCPDS card No. 25-0411 and 76-2308) are listed in Table 2. For iron sulfide nanomaterials, the X-ray photoelectron spectroscopy (XPS) of Fe and S are essential. FeS materials are presented in Table 2 (Fe 2p: 2p_3/2 (711.4 eV), 2p_1/2 (724.9 eV), S 2p: 2p_3/2 (161.1 eV), 2p_1/2 (166.0 eV)), FeS₂ (Fe 2p: 2p_3/2 (707.0 eV), 2p_1/2 (720.0 eV), S 2p 2p_3/2 (162.3 eV), 2p_1/2 (163.5 eV)), Fe₃S₄ (Fe 2p: 2p_3/2 (711.0 eV), S 2p: 2p_3/2 (161.0 eV), 2p_1/2 (162.5 eV)), Fe₇S₈ (Fe 2p: 2p_3/2 (709.9 eV), (711.6 eV), S 2p: 2p_3/2 (163.5 eV), 2p_1/2 (164.7 eV)). Fourier transform infrared (FTIR) spectroscopy can be used to detect functional groups in a complex mixture and so is therefore essential to the characterization of modified iron sulfide. Previous studies have provided FTIR spectra, showing successful modifications by APTES on the surface of the Fe₃S₄ nanoparticles (He et al., 2013). Fe₇S₈/N-C nanohybrids were prepared for FeMOF and FeMOF-S and analyzed by FTIR (Jin et al., 2019). In addition, energy dispersive spectroscopy (EDS) (Paolella et al., 2011; Ding et al., 2016; Guo et al., 2016), dynamic light scattering (DLS) (He et al., 2013; Ding et al., 2016), Raman spectroscopy (Gan et al., 2016; Guo et al., 2016), selected area electron diffraction (SAED) (Kar and Chaudhuri, 2004), X-ray absorption fine structure (XAFS) (Feng et al., 2013), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) (Jin et al., 2019), nitrogen adsorption–desorption isotherms and pore size distribution (Guo et al., 2016) analysis of iron sulfide have been reported as characterization systems.

FIGURE 2

Figure 2. Representative images of nano-sized iron sulfide. (A) TEM image of the spherical FeS. Reproduced with permission from Dai et al. (2009). Copyright 2009, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) TEM and HRTEM of FeS₂ nanodots. Reproduced with permission from Jin et al. (2018). Copyright 2017, American Chemical Society. (C) TEM images of platelet-like Fe₃S₄. Reproduced with permission from Paolella et al. (2011). Copyright 2011, American Chemical Society. (D) SEM and HRTEM of Fe₇S₈ nanowires. Reproduced with permission from Yao et al. (2013). Copyright 2013, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

TABLE 2

Table 2. UV-VIS, XPS and XRD of iron sulfide.

Characteristics of Nano-Sized Iron Sulfides

In addition to both the physical and chemical properties, characteristics include the structure, solubility, stability, reactivity, magnetic properties, and photothermal properties of the products.

Solubility

The major forms of nano-sized iron sulfides are solid precipitates which have poor solubility in water. However, Rickard et al. revealed that sedimental FeS can dissolve at c (S²⁻) ≤ 10^−5.7 M to form Fe²⁺. The solubility can be increased in an alkaline as opposed to neutral environment (Rickard, 2006). FeS does not dissolve in HCl, meaning it cannot be removed with HCl (Rickard and Luther, 2007). According to previous studies, the K_sp of FeS₂ was 10^−16.4 at 25°C. The solubility products of various iron sulfides were assessed and resulted in consensus values for the pKs (FeS: 3.6 ± 0.2; FeS₂ 16.4 ± 1.2; Fe₃S₄ 4.4 ± 0.1; Fe₇S₈ 5.1 ± 0.1). This improved our understanding of the solubility of iron sulfide in both synthetic and natural water at room temperature (Davison, 1991).

Stability

FeS is stable within the P-T range of the Martian core (Kavner et al., 2001). Understanding the relationship between the stability of iron sulfide and its chemical environment is of key importance. Once iron sulfide is formed, its structure is reversible. Studies have examined the stability of FeS₂ in different temperatures and the concentrations of absorbed water on the surface. Temperature has little effect on the morphology of FeS₂ under low absorbed water concentrations. However, at above 90 K, the conversion from an octahedral structure to a cubic shape is promoted. At higher concentrations of water, the dependence on temperature is more apparent (Barnard and Russo, 2009). The latter study established that functions of the surface ligands affect the stability of FeS₂ (FeS₂ nanorods synthesized in laboratory) (Barand and Russo, 2009). The stability of FeS contributed to low energy excitation from Fe d to S-Sσ^*p (Zhang et al., 2018). Fe₃S₄ was observed at 200°C for 30 h then it transformed to FeS₂ over time (Gao et al., 2015).

Reactivity

Iron sulfide is highly reactive to N₂ and H₂S. This reaction occurs at room temperature and the adsorption of N₂ is dependent on the surface FeS and on the electronic state of N₂. A decrease in absorbed N₂ and H₂S could be explained by the formation of ammonia (Kasting, 1993). The reactivity of Fe₇S₈ is similar to FeS (Niño et al., 2018). The presence of both Au¹⁺ and Au atoms has been observed on the surface of FeS₂. Au deposition increased at higher pH and temperatures. The reactivity of Au¹⁺ sulfides with FeS₂ have also been investigated (Scaini et al., 1998). The reactivity of FeS₂ using gaseous H₂O and O²⁻ was similarly reported. Gaseous H₂O leads to the formation of iron hydroxides on FeS₂. A sequence of different exposures also leads to the formation of a range of products (${\text{SO}}_4^{2-}$, Fe(OH)₃) (Usher et al., 2005). Recently, FeS₂ was shown to be a potential nanomaterial for prebiotic chemistry due to its highly reactive surface that drives amino acid adsorption (Ganbaatar et al., 2016). Among the most common probes, water molecules have been used to explore the reactivity of FeS₂ (De Leeuw et al., 2000). The different phases of iron sulfide display a wide range of reactivities to chlorinated solvents. Conditions including pH, sulfide concentrations, metal ions, and natural organic matter can affect the reaction kinetics of the degradation of chlorinated solvents (He et al., 2015). The interaction of FeS, Fe₃S₄ and CO₂ have also been reported. The charge transfer on FeS can also effectively activate CO₂, whilst Fe₃S₄ is unreactive to CO₂ (SantosCarballal et al., 2017).

Magnetic Properties

Nanomaterials with magnetic properties have numerous applications, including magnetocaloric therapies, as MRI agents, magnetic separation materials, and magnetic carriers. The discovery of their magnetic properties led to the identification of iron sulfide phases. The ferromagnetism of Fe₇S₈ can be explained by Fe³⁺ ions with excess sulfur (Yosida, 1951). The magnetic susceptibility χ of natural FeS₂ was found to be 64 × 10⁻⁶68 × 10⁻⁶ cm³ /moles between 4.2 and 380 K (Mohindar and Jagadeesh, 1979). Magnetic ordering in FeS was inferred and used to prove strong itinerant spin fluctuations. FeS can also be used as a superconductor (Kwon et al., 2011). Even when the structure of FeS is changed from troilite to the MnP-type under high pressure, the antiferromagnetic properties are preserved until the monoclinic structure is formed (Ono, 2007). The magnetic moment then disappears and yetragonal-phase FeS (Tc: 5K) was observed for the same structure as the superconductor FeSe (Tc: 8 K) (Kuhn et al., 2016). Fe₃S₄ displays high Mrs/χ, (Mrs/χ: the saturation isothermal remnant magnetization: magnetic susceptibility) and its MrsMs (hysteresis ratios) and Bcr/Bc are 0.5 and 1.5 (Ms: saturation magnetization; Bc: the coercive force; Bcr: the coercivity of remanence). Fe₃S₄ also displays unique high-temperature properties, with a clear drop in magnetization from 270 to 350°C (Roberts, 1995). Synthesized Fe₃S₄ contains various crystals from small superparamagnetic grains (non-remanence) to large multi-domain grains (Snowball, 1991). The magnetic hysteresis properties of Fe₇S₈ have also been studied (Menyeh and O'Reilly, 1997). The relationship between structure and magnetic properties has been reported within variable temperatures. Magnetic transitions occurred within the transformation of the structure (Powell et al., 2004). The magnetocaloric conversion ability of Fe₃S₄ nanoparticles has been measured under an alternating magnetic field (AMF). Meanwhile, the excellent physical and chemical properties provide magnetothermal thrombolytic ability in medical applications (Fu et al., 2019; Figure 3).

FIGURE 3

Figure 3. Magnetocaloric conversion performance (a–d) and photothermal property of iron sulfides. (a) Temperature change of the Fe₃S₄ nanoparticles in water at varied concentrations of Fe²⁺ (i.e., 0, 0.5, and 1.0 mg/mL) as a function of magnetic field action time. (b) Plot of temperature change over 300s vs. the concentration of Fe₃S₄ nanoparticles. Thermal imaging of (c) pure water and (d) Fe₃S₄ nanoparticles (1.0 mg/mL) under the action of an AMF for 5 min. Reproduced with permission from Fu et al. (2019). Copyright 2019, Frontiers in Materials. (e) Synthetic route and applications of FeS₂ nanodots in the base of its photothermal activity. (f) Scheme showing photothermal enhanced cellular uptake of FeS₂@BSA-Ce6 nanoparticles. Reproduced with permission from Jin et al. (2018). Copyright 2017, American Chemical Society.

Photothermal Properties

Photothermal therapy (PTT) has attracted considerable attention in recent years. The mechanism of PTT results mainly from photo-absorbing nanomaterials that generate heat through continuous laser irradiation, destroying cancer cells, but causing no damage to healthy tissue. It is therefore necessary to pay attention to the photothermal properties of iron sulfide. PEGylated FeS (FeS-PEG) nanoplates exhibit high near infrared (NIR) absorbance. Using Infrared (IR) thermal imaging, the temperature can reach 70°C within 5 min. Meanwhile, FeS-PEG displays stronger photothermal conversion efficiency than other known iron oxides (Yang et al., 2015). Ultrasmall FeS₂ nanodots have also been synthesized and have been shown to be useful for photodynamic therapy. Chlorin e6 (Ce6) was used to conjugate FeS₂ in the presence of the template bovine serum albumin (BSA). FeS₂@BSA-Ce6 nanodots (7 nm) demonstrated good results in in vivo photoacoustic (PA) imaging, MRI and enhanced cellular uptake (Jin et al., 2018; Figure 3).

Biomedical Applications

To-date, a variety of biomedical applications of iron sulfide (catalysts, antibacterial agents, cancer therapies, drug delivery systems, thrombolytic agents, biosensors, antifungal agents, seed improvers in phyto-applications) and their functional mechanisms have been summarized (Scheme 1).

SCHEME 1

Scheme 1. Schematic diagram of biomedical applications of nano-sized iron sulfide.

Enzyme-Like Catalysis

Iron sulfur clusters are critical cofactors in many enzymes and proteins which conduct redox reactions and regulate oxidative stress. Thus, nano-sized iron sulfides are expected to perform similar catalysis and act as nanozymes. Previous studies have shown that iron sulfide can effectively activate persulfate (PS) or peroxymonosulfate (PMS) to generate sulfate radicals (Xiao et al., 2020). Other common reactions involving iron sulfide are shown in section Sonochemical Synthesis. Since iron oxide nanoparticles were shown to possess intrinsic peroxidase activity in 2007 (Gao et al., 2007), it has been speculated that iron sulfide has similar properties. The catalytic processes of iron sulfide are shown in Figure 4. High catalytic activity, multi-enzymes activities, harsh environmental resistance, storage stability, and the intrinsic advantages of nanomaterials provide further possibilities for biomedicine development, meaning that good alternatives to natural enzymes exist. The enzymatic activity of iron sulfide has been intensely investigated. In 2010, FeS nanosheets were reported to possess peroxidase-like activity. FeS suspensions were shown to catalyze the oxidation of peroxidase substrates, 3, 3′, 5, 5′-Tetramethylbenzidine (TMB) to produce a blue product in the presence of H₂O₂ (Dai et al., 2009) (Figure 4). Fe₇S₈ nanowires' also possessing intrinsic peroxidase activity was also reported in 2013 for which catalytic behavior was observed. The apparent K_M of Fe₇S₈ with TMB as a substrate was 0.548 mM, almost six times lower than that of horseradish peroxidase (HRP). These results demonstrate that Fe₇S₈ has a higher affinity to TMB than to HRP (Yao et al., 2013). In 2015, magnetic Fe₃S₄ NPs was shown to possess peroxidase-like activity. Through investigating steady state kinetics, Fe₃S₄ was shown to possess a higher affinity for H₂O₂ than HRP. The reasons could be that Fe₃S₄ binds to and reacts with H₂O₂, following which nanozyme is released prior to reacting with the second substrate TMB (Ding et al., 2016). nFeS (Fe_1−xS and Fe₃S₄) (detailed description in section Hydrothermal Synthesis) have been shown to possess both peroxidase-like and catalase-like activity (Figure 4). nFeS is able to decompose H₂O₂ into free radicals and O₂, promoting the release of polysulfanes (Xu et al., 2018). FeS₂ has also been shown to possess amylase-like properties (Srivastava et al., 2014b).

FIGURE 4

Figure 4. Schematic diagram of catalysis of iron sulfide as a nanozyme. (A) The peroxidase-like activity of FeS. Images of the suspension of sheet-like FeS nanostructure (1), mixture of TMB and H₂O₂ after catalytic reaction by sheet-like FeS nanostructure (2), mixture of TMB and H₂O₂ after adding H₂SO₄ to quench the catalytic reaction by sheet-like FeS nanostructure (3). Reproduced with permission from Dai et al. (2009). Copyright 2009, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) The catalase-like activity of Cys-nFeS. The trend of KM and the ratio of Vmax/KM in the kinetics assay with varied cysteine. Reproduced with permission from Xu et al. (2018). Copyright 2018, Nature Publishing Group.

Antibacterial Alternatives

Schoonen et al. reported on the antibacterial action of FeS₂. Its mechanism was shown to be related to the formation of H₂O₂. The same group also reported how minerals can induce the formation of reactive oxygen species (Cohn et al., 2006; Schoonen et al., 2006). The rapid absorption of Fe²⁺ can influence bacterial metabolism. The oxidization of Fe²⁺ to Fe³⁺ leads to reactive oxygen species (ROS) production and biomolecular damage. As a result, iron sulfide can act as antimicrobial agents. Iron sulfides have been reported to be effective in bacterial infections. In 2013, He et al. reported on the bacteriostatic activity of Fe₃S₄/Ag against E. coli (86.2%) and S. aureus (90.6%). Meanwhile, Fe₃S₄ NPs without Ag have no effect (He et al., 2013). The Arenas-Arrocena group synthesized Fe_x−1S NPs and reported their antibacterial and cytotoxic activity in 2018. Antibacterial activity against S. aureus, E. coli and E. faecalis was observed (Argueta-Figueroa et al., 2018). In addition, Gao and coworkers discovered antibacterial inorganic iron polysulfides materials that were converted by organosulfur compounds in 2018. Inorganic nano-sulfides (nFeS, Fe_1−xS, and Fe₃S₄) have shown inhibition against Pseudomonas aeruginosa and Staphylococcus aureus. These studies also described new strategies to synthesize iron sulfide nanomaterials. Furthermore, the S. mutans biofilm-related infections could be prevented by nFeS (Xu et al., 2018) (Figure 5). The antibacterial properties of FeS₂-Bi₂O₃ against the pathogenic microorganisms Mycobacterium tuberculosis and Salmonella have also been measured (Manafi et al., 2019). Diksha et al. reported that FeS NPs could enhance intrabacterial ROS levels in bacteria by light irradiation in 2020. This was revealed as the primary antibacterial mechanism of FeS NPs (Agnihotri et al., 2020).

FIGURE 5

Figure 5. (A) Morphology of P. aeruginosa before (control) and after Cys-nFeS treatment. The red triangles indicate flagella. Scale bars: 1 μm. (B) Photographs of P. aeruginosa infected wounds treated with buffer (control), Cys-nFeS, H₂O₂, and Cys-nFeS + H₂O₂ at different times (five mice in each group). (C) Confocal 3D image of a S. mutans UA159 biofilm treated by Cys-nFeS. Scale bars: 100 μm. (D) SEM image of a S. mutans biofilm treated by Cys-nFeS. The red arrows indicate EPS. Left scale bars: 100 μm. Right scale bars: 3 μm. (E) Scheme of polysulfane release from nFeS. Reproduced with permission from Xu et al. (2018). Copyright 2018, Nature Publishing Group.

Cancer Therapy

Chen and colleagues reported that tumors in mice could disturb iron metabolism in the major organs. The chemical form of iron in the tumors was ferrous-sulfide-like iron and ferritin, highlighting the potential of iron sulfide for cancer treatment (Chen and Chen, 2017). Chang et al. synthesized Fe₃S₄ particles with magnetic properties through co-precipitation. The NPs were used for cancer hyperthermia providing a new avenue for multimodal anticancer therapies (Chang et al., 2011). In 2015, Yang et al. concluded that triangle nanoplates (FeS/PEG nanostructures) could be used as nanoagents for in vivo MRI-guided photothermal cancer treatment. High doses of FeS nanoplates were shown to be safe and effective in mice. This study highlighted the potential clinical use of FeS, for MRI in addition to PTT (Figure 6) (Yang et al., 2015). In 2018, Fe₃S₄ nanosheets were shown to possess high efficiencies for MRI guided photothermal and chemodynamic synergistic therapy, opening up a new direction for the design of inorganic iron sulfide for future clinical applications (Guan et al., 2018). Tiny nano-sized iron sulfide with simple biomineralization method has also been attention owing to its huge potential in vivo application especially in cancer therapy combined with its excellent photothermal and magnetic performance. FeS₂@BSA-Ce6 (detailed in section Biomineralization) exhibited good results whether in vivo multimodal imaging or in vivo combined therapy (Jin et al., 2018). Meanwhile, the latest literature proved 3 nm FeS@BSA QDs could be used as T1-weighted MRI contrast agents. Moreover, the ultrasmall QDs showed good results in photothermal therapy and they could be cleared via glomerular filtration into bladder after treatment (Yang et al., 2020). The use of iron chalcogenides has also been investigated. Cu₅FeS₄-PEG NPs were effective in dual-modal imaging and PTT (Zhao et al., 2016). In 2017, CuFeS₂ nanoplates were used for in vivo photothermal/photoacoustic imaging and cancer chemotherapy/PTT (Ding et al., 2017).

FIGURE 6

Figure 6. (A) In vivo fluorescence images of 4T1 tumor-bearing nude mice taken at different time points post iv injection of FeS₂@BSA-Ce6 nanodots (3.5 mg/kg Ce6 and 12 mg/kg FeS₂). (B) Photoacoustic images of tumors in mice taken at different time points post iv injection of FeS₂@BSA-Ce6 nanodots. (C) MR images of 4T1 tumor-bearing nude mice before and 8 h after iv injection of FeS₂@BSA-Ce6 nanodots. (3.5 mg/kg Ce6 and 12 mg/kg FeS₂). (D) IR thermal images of tumors in mice iv injected with FeS₂@BSA-Ce6 under 808 nm laser irradiation (0.8W/cm², 15 min). (E) Surface temperature changes of tumors monitored by the IR thermal camera during laser irradiation. (F) Representative immunofluorescence images of tumor slices after hypoxia staining. The cell nucleus, hypoxia areas, and blood vessels were stained with DAPI (blue), antipimonidazole antibody (green), and anti-CD31 antibody (red), respectively. Reproduced with permission from Jin et al. (2018). Copyright 2017, American Chemical Society.

Drug Delivery

Iron sulfide holds utility as a drug carrier. In previous studies, modified β-cyclodextrin (β-CD) and PEG Fe₃S₄ (GMNCs) were used as drug loading NPs. Both β-CD and PEG have been used to control the shape and size of GMNCs as surfactants. In addition, the biocompatibility of Fe₃S₄ is enhanced, with entrapment efficiencies of 58.7% for the modified delivery of the chemotherapeutic drug doxorubicin. Meanwhile, the enhanced chemotherapeutic treatment of mouse tumors was obtained through the intravenous injection of doxorubicin (Dox) loaded GMNCs (Feng et al., 2013; Figure 7).

FIGURE 7

Figure 7. (A) Schematical illustration of the greigite-containing magnetosome and the chemical synthesized magnetosome-like GMNCs. (B) Growth inhibition effect in murine S180 sarcoma model of the sample. The photos and weight ratios of tumor tissue from mice treated with normal saline (control group), GMNCs, Dox at low concentration, and GMNCs loading with Dox (without and with the guidance of external magnetic field), respectively. Reproduced with permission from Feng et al. (2013). Copyright 2013, Nature Publishing Group.

Thrombolytic Agents

In studies of vascular disease, the removal of thrombosis through non-invasive methods is challenging. However, studies regarding iron sulfide NPs as thrombolytic agents have been reported. Ge et al. first highlighted the utility of Fe₃S₄ NPs as thrombolytic agents with both photothermal and magnetothermal thrombolytic capability. Using Fe₃S₄ nanoparticles, celiac vein thrombosis could be prevented using magnetic hyperthermia combined PTT. Both in vivo and in vitro, Fe₃S₄ has demonstrated beneficial effects for the removal of thrombi (Figure 8), providing a novel hyperthermia strategy for the prevention of thrombosis (Fu et al., 2019).

FIGURE 8

Figure 8. (A) Thrombolytic capacity in vitro of Fe₃S₄ nanoparticles under the indicated conditions. Fe₃S₄ nanoparticles: 0.5 mg/mL; NIR: 808 nm, 0.33 W cm⁻²; AMF: 4.2 × 10⁹ A m⁻¹ s⁻¹. (B) T2-weighted MR imaging in vivo of a mouse with celiac vein thrombosis before (left) and after (right) an intravenous injection of a solution of the Fe₃S₄ nanoparticles followed by the simulation of AMF. Reproduced with permission from Fu et al. (2019). Copyright 2019, Frontiers in Materials.

Biosensors

Iron sulfides have been used as glucose sensors due to their intrinsic peroxidase-like activity (Dai et al., 2009). Glucose sensors can be developed using colorimetric methods in which cascade reactions form the core mechanism of glucose detection. TMB could be oxidized to oxTMB in the presence of glucose, GOx and iron sulfide. H₂O₂ produced by the decomposition of glucose in the presence of glucose oxidase can be used as a substrate for iron sulfide. Iron sulfide peroxidase-like mimics can oxidize TMB to oxTMB in the presence of H₂O₂. Fe₇S₈ nanowires also possess peroxidase activity. Using a linear range, glucose concentrations of 5 × 10⁻⁶ to 5 × 10⁻⁴ M could be detected (Yao et al., 2013). In 2016, Xian and colleagues used Fe₃S₄ magnetic nanoparticles (MNPs) to quantify glucose concentrations in human serum. A linear range was measured from 2 to 100 μM, and the limit of detection (LOD) was 0.16 μM (Ding et al., 2016). These studies highlighted the potential of as-prepared iron sulfide as both glucose sensors and artificial peroxidase nanozymes.

Antifungal Agents

In vitro antifungal FeS NPs exhibited significant anti-fungal activity against F. verticillioides at 18 μg ml⁻¹, with a higher efficiency than standard fungicides (carbendazim (median effective dose (ED50): 230 μg ml⁻¹). These were the first reports highlighting the antifungal activity of iron sulfide. The influence of FeS on both seed health and quality parameters of rice was also evaluated based on this antifungal activity. Iron sulfides were shown to be effective in iron deficient soils as an alternative to high dose organic fungicides (Ahuja et al., 2019).

Seed Improvements in Phyto-Applications

FeS₂ represents a photovoltaic material, which increases plant biomass in the seeds of chickpeas (Cicer arietinum). Meanwhile, the mechanism of functional FeS₂ is attributed to its amylase-like activity. In the presence of H₂O and FeS₂, starch in the seeds can be broken down to H₂O₂, which participates in the absorption of CO₂ and improves plant health. Spinach seeds treated with FeS₂ exhibited broader leaf morphologies, larger leaf numbers and an increased biomass (Srivastava et al., 2014b) (Figure 9). In later studies, seed priming with FeS₂ was reported as an innovative strategy (Das et al., 2016). FeS₂ also improved both seed yield and growth in the Brassica juncea field (Rawat et al., 2017).

FIGURE 9

Figure 9. Plant growth parameters: control vs. test (FeS₂). (a) Leaf area/Plant, showing significant increase in leaf area/test plants (52.4 ± 0.3) as compared to control (25.6 ± 0.2). (b) Leaf area index signifying total photosynthetic area available to plant and high values for test samples (1.5 ± 0.07) can be correlated with high biomass content of pro-fertilized spinach plants in comparison with (0.9 ± 0.02). (c) Comparative photograph of leaves showing larger leaf area in test plants as compared to control plants. Plant growth parameters: control vs. test (FeS₂). (d) Number of leaves/Plant: control: 13 ± 1.0; test: 19 ± 1.0. (e) Specific leaf area signifies leaf thickness and was found similar for both test and control samples. (f) Field photograph taken at day 50 (just before harvesting the crop) depicting that the test group plants have comparatively more foliage as compared to the control plants. (g) Proposed outline of the mechanism of action of FeS₂ on spinach seed in enhancing germination and plant growth. Reproduced with permission from Srivastava al. (2014). Copyright 2014, The Royal Society of Chemistry.

Conclusions

In summary, we have highlighted the most recent methods of nano-iron sulfide synthesis, including nano iron sulfide modifications and characterizations. Strikingly, nano-sized iron sulfides demonstrate versatile physiochemical properties, enzyme-like catalysis, high stability and biocompatibility, which facilitate their biomedical applications. A range of nano-iron sulfides have been assessed in catalysis, tumor therapy, antibacterials and antifungals, drug delivery, biosensors, thrombus removal and in plants. Their advantages include (1) high biocompatibility due to the key role of iron and sulfur in natural life; (2) the photothermal and magnetic properties of nano-sized iron sulfide; (3) their nanostructure and large surface area that can improve drug delivery; and (4) their enzyme-like properties as nanozymes, including their high reactivity to numerous chemical substances that can regulate hydrogen peroxide, ROS and various catalytic reactions to treat related diseases.

Although it has been shown that nano-sized iron sulfides represent great potential in numerous applications in biomedicine (Scheme 2), a number of issues remain to be addressed, including the synthesis of iron sulfide that is stable and in a single phase, with modifications to adapt to the biological environment. Studies have found that the modification of molecular CTAB inhibits the preparation of Fe₃S₄ NPs due to competitive inhibition with Na₂S under acidic conditions, resulting in the formation of non-magnetic iron sulfides and other byproducts. Citrate modified nanoparticles have not sufficient particle spacing due to aggregation effects (Simeonidis et al., 2016). In addition, the biomedical assessments of iron sulfides remain sparse, and their mechanisms of action under physiological conditions are poorly understood. The intrinsic enzyme-like properties of iron sulfide as nanozymes may provide a window to understand its biological effects and potential cytotoxicity in vivo. Taken together, nano-sized iron sulfides possess versatile physiochemical properties and enzyme-like properties, which describe a form of distinctive nanomaterials with great potential for use in biomedical applications.

SCHEME 2

Scheme 2. Schematic diagram of biomedical applications based on physiochemical properties of nano-sized iron sulfide.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by the National Key R&D Program of China (Grant No. 2018YFC1003500), as well as the National Natural Science Foundation of China (Grant Nos. 81930050, 81671810, and 31701236).

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