Synthesis of Cu_0.5Zn_0.5-xNi_xFe₂O₄ nanoparticles as heating agents for possible cancer treatment

1 Introduction

Magnetic materials are an important group of engineered systems that are widely used for different applications (Ram et al., 2021). Among them, magnetic spinel ferrites have attracted lots of attention because of their unique properties (Soufi et al., 2021; Amiri et al., 2019; Tolani et al., 2019; Bielan et al., 2021). The general formula of this magnetic group is MFe₂O₄ (Wang et al., 2008). M is a divalent metal ion, although a mixture of different divalent metal ions is also possible. Spinel ferrites can be utilized in many applications, including magnetic resonance imaging (MRI) contrast agents, magnetic fluids for information storage, magnetic recording media, photocatalysts, hyperthermia agents for cancer therapy, magnetically guided drug delivery, pigments, sensors, etc. (Qin et al., 2021; Akhlaghi and Najafpour-Darzi, 2021; Kim et al., 2009; Sukmarani et al., 2020; Abdel Maksoud et al., 2022; Harada et al., 2020; Talaei et al., 2021; Hassanzadeh-Tabrizi, 2021). Magnetic properties of these materials originate from their structure. A unit cell of 32 oxygen ions with a closely packed oxygen arrangement. Apart from oxygen, there are vacancies in the lattice, which include tetrahedral sublattice (A) and octahedral sublattice (B) sites. Metal ions are placed in A or B sites. Only 8 of the 64 tetrahedral positions and 16 of the 32 octahedral sites in the unit cell are occupied by metal ions (Azimi-Fouladi et al., 2023).

It was reported that two important factors control the magnetic properties of spinel ferrites. First, their composition has the most important effect. In other words, based on which metal ions go to which place (A or B sites) in the spinel ferrite unit cell, they can reveal different magnetic behavior (Narang and Pubby, 2021; Jasrotia et al., 2020; Akhtar and Khan, 2018; Hassanzadeh-Tabrizi et al., 2016). Therefore, one way to manipulate and adjust magnetic parameters is to change their composition and make mixed spinel ferrites with different kinds of metal ions and dopants. In addition, without changing the crystal structure, the physical properties of spinel ferrites can be effectively adjusted by adjusting their chemical composition and replacing the divalent cations and/or trivalent iron cations with appropriate metal ion dopants. For example, It was reported that minor substitutes of iron ions with rare earth elements affect the magnetic and electrical properties of ferrites, creating good magnetic properties (Kadam et al., 2023; Shitole et al., 2023; Shitole et al., 2023; Khan and M.J. ur Rehman, K. Mahmood, I. Ali, M.N. Akhtar, G. Murtaza, I. Shakir, M.F. Warsi, , 2015; Akhtar et al., 2020). However, the ionic size of dopants must be similar to that of host cations to form well-defined solid solutions without any indications of a secondary phase. The important parameters for achieving desired physical qualities are the dopant ionic sizes and their nature (non-magnetic or magnetic), the dopant ions' valence state, the dopant ions' preferred crystallographic location (tetrahedral or octahedral site), and the quantity of substitution (Paswan et al., 2024). In recent years, mixed spinel ferrites when different cations and Fe occupy both A and B-positions have attracted lots of attention due to exceptional and controllable magnetic properties (Almessiere et al., 2019; Suryawanshi et al., 2023; Suryawanshi et al., 2023). Among mixed spinel ferrites, CuZnNiFe₂O₄ is a significant magnetic system due to its exceptional features, including low sintering temperature, large electrical resistivity and high permeability, which is usually needed in technical applications such as multilayer chip inductors. In addition, copper and zinc ions in this spinel are useful for the body in low concentrations. It has been demonstrated that lack of Zn²⁺ and Cu²⁺ in bone tissue results in thinning, which in turn reduces osteogenesis (O’Neill et al., 2018; Bejarano et al., 2017; Marie, 2010). Radovanovic et al. (Radovanović et al., 2014) prepared Cu²⁺ substituted hydroxyapatite for biomedical applications and reported that low concentration of copper ions liberation caused appropriate antibacterial activity against various types of bacteria without showing any cytotoxicity. The antibacterial effects of zinc ions also have been proven (Sukhodub, 2015; Elaaraj et al., 2022). The medical use for spinel ferrite systems has been extensively investigated and researchers have shown that these magnetic materials can be effectively utilized in this field (Manohar et al., 2024; Manohar et al., 2024; Manohar et al., 2023; Manohar et al., 2023; Manohar et al., 2023; Manohar et al., 2023).

The second strategy is the synthesis process of spinel ferries which affects size, morphology and textural properties (Thakur et al., 2020; Tatarchuk et al., 2017; López and Antuch, 2020; Kudr et al., 2017). It is known that these parameters also have paramount effects on the final properties of the products. Different methods of synthesis have been utilized to produce nano spinel ferrites. For instance, sol–gel (Hakeem et al., 2021), co-precipitation (Ajeesha et al., 2022), hydrothermal (Hamza and A. ur Rehman, I. Ali, M. Asif, M. Ahmad, , 2022); solvothermal (Abd Zaid et al., 2023); Pechini approach (Motavallian et al., 2018), polyacrylamide gel (Wang et al., 2016), and mechanical milling (Modi et al., 2013, 1049) are the most common fabrication methods reported in the literature. Each of these techniques has its disadvantages. Some of them take a long time and consume high energy to produce nanoparticles. In addition, toxic, expensive and hazardous solvents are used in some methods. Among these methods, sol–gel combustion has many advantages. In this method, the reactions can be completed quickly in only minutes. This method produced high processing temperatures (up to 4000 °C) which facilitates the reaction to the final product. Additionally, it creates high-purity, homogeneous material with nano-particle sizes and enables excellent stoichiometric control (Akhtar and Khan, 2018; Raut et al., 2014; Sutka and Mezinskis, 2012; Borhan et al., 2023; Idrees et al., 2022). It seems that it is an appropriate method for the synthesis of ceramic oxide materials with complex structures. Strong variations in the degree of spinel inversion are frequently seen for ferrite nanoparticles based on the method of synthesis (Andersen et al., 2019; Andersen et al., 2018; Yang et al., 2009; Carta et al., 2010; Carta et al., 2009). In other words, the synthesis method has a significant impact on the magnetization and, consequently, the spin disorder of ferrite nanoparticles. As mentioned before, with control of spinel ferrite composition and the method of synthesis, it is possible to manipulate the magnetic material for a special purpose. For example, in medical use as hyperthermia agents, a superparamagnetic behavior is desirable, whereas as permanent magnets a high remnant magnetization is more favorable.

Because magnetic ferrites can convert electromagnetic energy into heat and can raise localized temperature through the use of an external oscillating magnetic field, the concept of designing and implementing ferrite-based hyperthermia has attracted lots of attention in recent years for curing cancerous tumors and bone cancer. When tumors are removed from bone tissue, these ferrites can be used to fill in the bone deficiencies. When exposed to an external magnetic field, these magnetic nanomaterials can produce heat, which is necessary to kill cancerous cells in the implanted location (Nandhini and Shobana, 2022; Peiravi et al., 2022).

To the best of our knowledge, there is no report on the application of Cu_0.5Zn_0.5-xNi_xFe₂O₄ for magnetic hyperthermia treatment. In addition, most of the works on the ZnCuNiFe₂O₄ system have been on the replacement of copper with nickel ions (Vatsalya et al., 2021; Rahman and Ahmed, 2005; Houshiar and Jamilpanah, 2018; Ramakrishna et al., 2017; Molaahmadi et al., 2016; Krishnaveni et al., 2006; Rezlescu et al., 2000; Venkatesh et al., 2015; Venkatesh et al., 2020). However, there are not many studies on the replacement of nickel with zinc ions with a constant amount of copper in the structure of CuZnNiFe₂O₄. Therefore, in the present study, Zn_0.5Cu_0.5Fe₂O₄ nanoparticles were synthesized via a sol–gel combustion method with a fixed copper ions content of 0.5. Then, the effect of nickel substitution on the magnetic properties of the Cu_0.5Zn_0.5-xNi_xFe₂O₄ mixed spinel ferrite was investigated. The hyperthermia potential of Cu_0.5Zn_0.5-xNi_xFe₂O₄ mixed spinel ferrites was also assessed in vitro. The results showed that the produced nanoparticles have a high potential to be used as heating agents for cancer treatment via magnetic hyperthermia.

2 Experimental procedure

2.1

2.1 Materials and methods

Ni(NO₃)₂·6H₂O, Fe(NO₃)₃·9H₂O, Cu(NO₃)₂.6H₂O, Zn(NO₃)₂.6H₂O and citric acid (C₆H₈O₇) were utilized as raw materials for synthesizing Cu_0.5Zn_0.5-xNi_xFe₂O₄ mixed spinel ferrites nanoparticles. The x value varied from 0.1 to 0.5. The molar ratio of metal salts to citric acid was 1, according to the literature (Hassanzadeh-Tabrizi et al., 2016). All the metal salts and citric acid were obtained from Sigma Aldrich company. Sol-gel combustion method was used to synthesize nanoparticles. The synthesis procedure was schematically illustrated in Fig. 1. For this aim, the metal salts were dissolved in deionized water and the pH was adjusted to 7 by the addition of ammonium hydroxide solution. For instance, for the synthesis of Cu_0.5Zn_0.5-xNi_xFe₂O₄ nanoparticles with x = 0.1, 0.2 mmol iron nitrate, 0.04 mmol zinc nitrate, 0.01 mmol nickel nitrate, and 0.05 mmol copper nitrate were dissolved in deionized water and stirred for 1 h using a magnetic stirrer to obtain a homogeneous solution. After adjusting the pH to 7, 0.3 mmol of citric acid was added. The solution was heated at 100 °C till the water evaporated. A self-combustion reaction happened and a dark powder was obtained. The powder was calcined at 400 and 700 °C for 2 h.

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Fig. 1

Schematic illustration of synthesis procedure.

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3 Results and discussion

Fig. 2 shows the TG and DTA curves of the dried Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ samples. Three distinguished weight losses were observed in the TG curve. The first weight loss between 50 °C to 250 °C (about 5 %) is due to the removal of absorbed and structural water. The second weight loss at around 300 °C (about 30 %) could be attributed to the thermal decomposition of metal salts in the mixture. The last weight loss (about 60 %) between 450 °C to 550 °C accompanied by an immense exothermic peak in DTA is due to the self-combustion of the mixture and removal of remaining volatile components. The total weight loss of the sample was about 90 %.

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Fig. 2

TG and DTA curves of the dried Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ sample.

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For a better understanding of the chemical bonds and the functional groups in the mixture, FTIR analysis was taken from the Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ samples before and after heat treatment at 700 °C (Fig. 3) . As can be seen, the spectrum of the dried sample is relatively complex in comparison with that of the calcined one. Some absorption peaks between 900 cm⁻¹ and 1100 cm⁻¹ are related to the organic bonds (Kloprogge et al., 2004; Xia et al., 2005; Vonach et al., 1998). These organic peaks may be related to citric acid. Also, the bands for stretching vibration of [COO]^- and C = O in the metal citrate complex should appear at 1400 cm⁻¹ and 1717 cm⁻¹, respectively (Mercadelli et al., 2008) but they are covered with the peaks of nitrates and water. The broad absorption peaks at around 3200 cm⁻¹ and 1640 cm⁻¹ could be attributed to the stretching and bending vibrations of O-H groups (Hassanzadeh-Tabrizi and Taheri-Nassaj, 2013) that show the existence of water in the as-prepared samples. The peak at 1640 cm⁻¹ disappears after calcination, whereas the one at 3200 cm⁻¹ with small intensity still exists which probably is due to water absorption from the atmosphere. The absorption peaks at around 840 cm⁻¹ and 1359 cm⁻¹ are pertinent to nitrate groups (Kloprogge et al., 2004; Mercadelli et al., 2008). These nitrate groups originate from nitride metal salts used as raw materials. After calcination, nitrate groups and organic groups were decomposed and these peaks disappeared from the FTIR results. In the as-prepared sample, the peak at around 560 cm⁻¹ is related to the metal–oxygen bond (Monisha et al., 2021). After calcination, two peaks related to metal–oxygen were observed at around 556 cm⁻¹ and 410 cm⁻¹, confirming the formation of the spinel structure. As it is known, there are tetrahedral and octahedral sites in the structure of spinel ferrites, which are occupied by divalent and trivalent ions (Rathod et al., 2017). It was reported that the formation of spinel structure is accompanied by two bands in FTIR results. One peak at around 530 cm⁻¹ corresponds to the vibrations of tetrahedral sites and another band around 430 cm⁻¹ reveals vibrations of octahedral sites (Jain and Gulati, 2023).

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Fig. 3

FTIR spectra of the dried and calcined Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ samples at 700 °C.

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Fig. 4 displays XRD patterns of Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ sample calcined at different temperatures. As-prepared sample shows the peaks related the ceramic oxides like Fe₂O₃ and CuO which reveals that the reactions for the synthesis of spinel ferrite did not happen. In addition, the peak related to the citric acid was also observed in this sample. After the calcination at 400 °C, these peaks disappeared and the peaks related to spinel ferrite were detected which confirms the proper reaction between the raw materials. However, small amounts of remaining iron oxide are observed in the patterns. It is envisaged that citric acid has manifold functions in the synthesis procedure. First, it is a chelating agent and inhibits the precipitation of raw materials to preserve homogeneity in the final product. Second, it is a fuel agent that produces heat to proceed with the reactions. Marjeghal et al. (Marjeghal et al., 2023) investigated the effects of citric acid to metal nitrates molar ratios in synthesizing SrFe₁₂O₁₉ nanostructures via the sol–gel combustion method. They reported that the crystallite size of SrFe₁₂O₁₉ is significantly affected and at higher amounts of citric acid, the size of the nanoparticles decreased.

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Fig. 4

XRD patterns of Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ samples calcined at different temperatures.

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The mechanism of the sol–gel combustion method to synthesize Cu_0.5Zn_0.5-xNi_xFe₂O₄ is probably based on reaction 1.

During reaction 1, a large amount of thermal energy is released. By increasing the calcination temperature to 700 °C, no important change happened in the XRD patterns. The only changes are the increase of intensity and reduce the width of the peaks showing an improvement in the crystallinity of the powders and crystallite growth. The results showed that the lattice parameter value drops from 8.355 Å to 8.351 Å as the calcination temperature rises. This result may be explained by structural flaws, polyvalence of cations, and cations redistributed between octahedral and tetrahedral locations (Paswan et al., 2021). Paswan et al. (Paswan et al., 2021). reported that calcination temperature can change the oxygen positional parameter. They reported that the calcination may induce redistribution of cations which results in modifications to the radius of tetrahedral and octahedral sites, enabling the lattice structure to be altered to attain the minimal potential energy necessary for stability. The crystallite size (D) was measured via the Scherrer equation (Eq. 1) (Hassanzadeh-Tabrizi, 2011; Hassanzadeh-Tabrizi, 2023).

Fig. 5 shows the effect of calcination temperature on the magnetic properties of the Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ sample. As can be seen, except for the as-prepared sample, other specimens showed ferrimagnetic behavior. The magnetic characteristics of samples were extracted from Fig. 5 and summarized in Table 1. The as-prepared sample revealed paramagnetic characteristics because this sample comprises nonmagnetic phases based on the XRD results. After calcination and formation of the spinel ferrite phase, good magnetic properties appeared in the samples. The small coercivity (Hc) of the calcined specimens causes these materials to be classified as soft magnets. The saturation magnetization (Ms) increased by increasing the calcination temperature. Based on the XRD results, higher calcination temperatures result in larger crystallite sizes, more crystallization of products, reduction of grain boundary, and improvement of the superexchange interaction between iron–oxygen–iron. These changes may improve Ms in the samples calcined at 400 °C. One important explanation for lower Ms of magnetic materials with smaller crystallite sizes is the surface spin disorder effect. Low symmetry close to the particle surface and broken exchange bonds are believed to be the causes of the surface spin disorder. In addition, reduction in porosity may be another reason for the increase of Ms with increasing calcination temperature. In other words, when the porosity reduces, the particles come closer and more magnetic moments align themselves which may increase Ms (Kaur et al., 2015). However, the coercivity of the samples decreased with increasing the calcination temperature. According to reported research, coercivity rises with a reduction of particle size until a maximum value is attained at the critical diameter that corresponds to the state where the multi-domain transitions to the single-domain happen. However, with reducing lower than this critical size the amount of Hc reaches zero which named this behavior as superparamagnetic. In the present work, as mentioned, the amount of Hc reduces with an increase in grain size due to higher calcination temperature. This finding shows that the particle size in our samples is higher than the critical size and the particles are multi-domain. In addition, it was reported that the porosity may affect the coercivity. When pores are present, domain walls cannot move freely and must be aligned with a strong magnetic field, which results in a higher coercivity (Kaur et al., 2015). As it is known, higher calcination temperatures result in sintering the powders and reduction in porosity which may reduce the Hc. It was reported magnetic nanoparticles with high Ms values, are required for medical applications involving hyperthermia. Large thermal energy dissipation in the tumor cells is a result of high Ms values. Moreover, large Ms values allow for greater control over the movement of magnetic nanoparticles in the blood when an external magnetic field is applied. It's crucial to consider that magnetic nanoparticles must meet two requirements in order to be used in cases of hyperthermia. First, they must have a high heating power. Second, their stability should be high. Superparamagnetic nanoparticles are chosen for good stability. In this case, the superparamagnetic nanoparticles become non-magnetic in the absence of an applied magnetic field. Therefore, they can preserve their colloidal stability and prevent aggregation (Obaidat et al., 2015).

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Fig. 5

Effect of calcination temperature on the magnetic properties of Cu_0.5Zn_0.4Ni_0.1Fe₂O₄.

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Figs. 6 a and b show the SEM images of the Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ sample calcined at 400 °C at two different magnifications. As can be seen, the sample has a sponge-like microstructure with lots of porosities. Different sizes of agglomerates are observed in the powders. This kind of structure is expected in the sol–gel combustion method. As reaction 1 revealed, lots of gas is produced in the synthesis procedure which leaves many holes in the products during removal. The particle size distribution histogram (Fig. 6 c) taken from SEM images shows a relatively wide particle size distribution mostly from 50 to 350 nm. The standard deviation for the SEM result is about 72 nm. This wide range of particle distribution is due to the reason that not only the sizes of particles but also the sizes of agglomerates were measured in the calculations. TEM analysis is necessary to reduce the effect of agglomerates on the particle size distribution. The formation of aggregated nanoparticles is a typical phenomenon in nano-size powders. Nanoparticles have a high surface which creates high surface energy. Therefore, nanoparticles stick together to plummet their surfaces and make an energetically more stable state (Azimi-Fouladi et al., 2018). Energy dispersive X-ray spectroscopy (EDS) is carried out to further investigate the chemical composition and elemental analysis of the produced spinel ferrite (Fig. 6 d). As can be seen, the Cu, Fe, Zn, Ni and O elements are detected in nanoparticles. No impurities were observed in the samples. This finding corroborates the XRD results and confirms the formation of the product with high purity. The Cu:Zn:Ni:Fe:O atomic ratio for this sample is equal to 0.49:0.38:0.01:0.21:0.39 (7.2 %:5.6 %:1.46 %:29.4 %:56.34 %), respectively which are nearly 0.5:0.4:0.1:2:4. These results are in agreement with the molecular formula of Cu_0.5Zn_0.4Ni_0.1Fe₂O₄.

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Fig. 6

A and b) sem images, c) particle size distribution histogram and d) eds analysis of cu_0.5Zn_0.4Ni_0.1Fe₂O₄ nanoparticles.

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TEM was utilized to study the size and morphology of the nanoparticles more precisely. TEM image and its particle size distribution histogram are shown in Fig. 7. As can be seen, the nanoparticles reveal irregular morphology with some degree of agglomeration. Most of the particles are in the range of 20 to 100 nm. The standard deviation for the TEM result is about 38 nm. These findings show lower particle size and narrower particle size distribution in comparison to the results obtained from SEM images. These differences between SEM and TEM results confirm the powder agglomeration. It was reported that the optimum dimension of the nanoparticles for most medical applications is usually between 10 and 50 nm. In this size range, magnetic nanoparticles often exhibit superparamagnetic. In this range of size, they exhibit a single magnetic domain in order to minimize their magnetic energy. When a nanoparticle is in the superparamagnetic state, it has a huge magnetic moment and responds to applied magnetic fields quickly, with very little coercivity and remanence. It functions similarly to a big paramagnetic atom (Obaidat et al., 2015).

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Fig. 7

A) tem image and b) particle size distribution histogram of cu_0.5Zn_0.4Ni_0.1Fe₂O₄ nanoparticles.

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To further investigate the effect of nickel substitution contents on the Cu_0.5Zn_0.5-xNi_xFe₂O₄ cubic structure, the Rietveld refinement approach was utilized to study the obtained X-ray diffraction results using the MAUD software. The background parameter was determined using the Chebyshev function. A pseudo-Voigt function was utilized to fit the profiles of the diffraction patterns. The findings of the Rietveld refinement study of the Cu_0.5Zn_0.5-xNi_xFe₂O₄ samples with various amounts of nickel substitution are shown in Fig. 8. It was found that all of the peaks of Cu_0.5Zn_0.5-xNi_xFe₂O₄ samples were well-fitting, with low Rietveld discrepancy factors and low Chi-squared (χ²). It shows the refined XRD patterns are in good agreement with the X-ray diffraction data obtained by the experiment. All specimens reveal a single-phase ferrite structure. No impurity phase or new peaks were observed up to x = 0.5 of nickel substitution, showing complete solubility of cations in the spinel structure. The peaks at (1 1 1), (2 2 0), (3 1 1), (2 2 2), (4 0 0), (4 2 2), (5 1 1) and (4 4 0) can be attributed to the reflection of the cubic spinel structure. With the increase of nickel ions, a small peak shift occurred which confirms the successful substitution of Ni²⁺. The changes of the unit cell density (ρ, g/cm³), lattice parameter (a, Å) and crystallite size (D, nm) of the Cu_0.5Zn_0.5-xNi_xFe₂O₄ samples as a function of the nickel ion contents (x) are shown in Fig. 9 a. The lattice parameter of the Cu_0.5Zn_0.5-xNi_xFe₂O₄ samples decreased with the rising Ni²⁺ amount in the structure. This can be attributed to the substitution of the larger ionic radius of Zn²⁺ (0.74 Å, (Miyaji et al., 2005) with the smaller ionic radius of Ni²⁺ (0.69 Å, (Faur-Brasquet et al., 2002). Phugate et al. (Phugate et al., 2020) reported that doping of spinel ferrites can cause a redistribution of metal cations in the cubic structure and change the lattice constant. In addition, Gurav et al. (Gurav et al., 2013) investigated the effects of Zn²⁺and Zr⁴⁺co-substituted on Li_0.5Fe_2.5O₄ nanoparticles and reported that the oxygen positional parameter changes from the ideal situation due to ion doping in the spinel structure.

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Fig. 8

Rietveld refinement analysis of Cu_0.5Zn_0.5-xNi_xFe₂O₄ (x = 0.1, 0.2, 0.3, 0.4 and 0.5) samples.

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Fig. 9

(a) Changes of the lattice parameter, unit cell density and (b) crystallite size of Cu_0.5Zn_0.5-xNi_xFe₂O₄ with different nickel ion substitution (x = 0.1, 0.2, 0.3, 0.4 and 0.5).

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The unit cell density of the Cu_0.5Zn_0.5-xNi_xFe₂O₄ specimens was also found to rise with the addition of nickel ions due to the substitution of the lower atomic weight element (Zn, 65.4 g/mol, (Chang et al., 2001) with the higher atomic weight element (Ni, 58.71 g/mol, (Poonkothai and Vijayavathi, 2012). The crystallite size of Cu_0.5Zn_0.5-xNi_xFe₂O₄ specimens with different amounts of x is shown in Fig. 9 b. As can be seen with increasing the nickel substitution, the crystallite size of the mixed spinel ferrites depletes. The decreasing trend in the crystallite size with increasing nickel substitution may be attributed to the greater difference between the ionic radius of nickel and copper compared to zinc and copper, which probably makes it more difficult for the ions to diffuse into the spinel ferrite lattice. Slower diffusion of the ions results in the inhibition of crystallite growth.

The hysteresis loops of Cu_0.5Zn_0.5-xNi_xFe₂O₄ (x = 0.1, 0.2, 0.3, 0.4 and 0.5) calcined at 400 °C are shown in Fig. 10. All ferrite samples exhibit soft magnetic behavior based on the magnetization curves. The magnetic behaviors comprising saturation magnetization and coercivity were extracted from the hysteresis loops and are shown in Fig. 11 a. As can be seen, saturation magnetization reduces with increasing nickel substitution. Different parameters have been reported to affect the magnetic characteristics of a spinel ferrite such as composition, cations rearrangement in A and B sites, porosity, crystal defects, particle size, magnetocrystalline anisotropy, etc. (Kodama, 1999). In the present study, two parameters may have more effects on the saturation magnetization of the samples due to nickel substitution. First, changes in the strength of magnetic interaction caused by variations in cation distribution can be used to elucidate this occurrence. As it is known the net magnetic moment in spinel ferrites (μ_B) is defined based on Neel’s sub-lattice rule (equation 2).

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Fig. 10

M−H loops of Cu_0.5Zn_0.5-xNi_xFe₂O₄ (x = 0.1, 0.2, 0.3, 0.4 and 0.5) samples.

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Fig. 11

(a) Magnetic properties and (b) effective anisotropy constant (K_eff) of the Cu_0.5Zn_0.5-xNi_xFe₂O₄ (x = 0.1, 0.2, 0.3, 0.4 and 0.5) samples.

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One important magnetic factor for spinel ferrite nanomaterials is the anisotropy constant or anisotropy energy density (K_eff). For instance, K_eff affects the Néel relaxation time (Yanes et al., 2007; Enpuku et al., 2020). Magnetic nanoparticles used in magnetic storage medium need to have a high K_eff, whereas a small K_eff is preferred in magnetic particle imaging (Kahmann et al., 2021). The K_eff can be calculated using equation 5 (Zhou et al., 2017; Wu et al., 2017).

The heat generation ability of the magnetic Cu_0.5Zn_0.5-xNi_xFe₂O₄ (x = 0.1, 0.2, 0.3, 0.4 and 0.5) nanoparticles was assessed under AC magnetic fields of 200 and 400 Oe with the frequency of 200 kHz and the results are shown in Fig. 12 a and b. After applying the AC field, it is found that the temperature rises with increasing time. Furthermore, as the field amplitude increases, the temperature also rises. Thus, by adjusting the magnetic field's duration and amplitude, the therapeutic regime for treating hyperthermia can be reached. As can be seen, the heating capacity of samples reduces with increasing nickel substitution. It should be noted that the effective temperature range for treating cancerous tissue with hyperthermia is between 42 and 47 °C (Nguyen et al., 2020). Lower temperatures have little effect on the cancerous cells, while higher temperatures can have a variety of effects on the healthy cells. The initial temperature of the magnetic fluid was 37 °C for all the samples. The temperature of the fluid containing Cu_0.5Zn_0.5-xNi_xFe₂O₄ samples with x = 0.1, 0.2, 0.3, 0.4 and 0.5 raised to about 49.5 °C, 48.2 °C, 47.6 °C and 46 °C, respectively at the magnetic field of 400 Oe in 10 min. In addition, it is observed that there is a direct relation between the thermal response of the samples and the intensity of the magnetic field so that the heating generation ability of samples reduces with the reduction in magnetic field. Four distinct mechanisms may be responsible for the heat generation of magnetic nanoparticles disseminated in a liquid medium or inside a biological system. They comprise Eddy current, hysteresis loss, Brownian loss and Néel relaxation (Myrovali et al., 2023; Patade et al., 2020; Salmanian et al., 2021). Due to the insulation nature of spinel ferrites, the produced nanoparticles have relatively little eddy current loss. Therefore, hysteresis loss, Néel loss, and Brownian loss may be the active mechanisms in this system. The hysteresis loss in ferromagnetic nanoparticles is ascribed to the shifting of domain walls upon exposure to an alternating magnetic field. Through hysteresis loss, the magnetic nanoparticles that exhibit hysteresis behavior can generate thermal energy. The primary cause of heat creation via Néel relaxation is a shift in the magnetic moment's direction. Anisotropy energy, which tends to keep the magnetic orientation, prevents this. The last mechanism of heat creation, known as Brownian relaxation, results from the physical rotation of magnetic nanoparticles in a liquid media. The viscosity of the medium prevents this spinning. The Brown mechanism is a well-known heat-generating process for fluids with low viscosity. It is noteworthy that heat generation is more favorable when all of the aforementioned mechanisms are combined. The higher heat generation ability of the sample with x = 0.1 is due to higher saturation magnetization as shown in Fig. 11 a.

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Fig. 12

Heat generation capability of the Cu_0.5Zn_0.5-xNi_xFe₂O₄ (x = 0.1, 0.2, 0.3, 0.4 and 0.5) samples with 200 (a) and 400 (b) Oe field amplitudes and constant frequency of 200 kHz.

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It is important to consider that in vitro and in vivo magnetic hyperthermia experiments could not be the same. In other words, the type and viscosity of the tissue in which the magnetic nanoparticles are distributed affect how much heat is generated. For instance, the physical rotation of the nanoparticles is limited in real conditions because of the increased viscosity of cancer cells and in vivo conditions (Vijayakanth and Chintagumpala, 2023). In order to examine the impact of the medium on heat generation, the Cu_0.5Zn_0.5-xNi_xFe₂O₄ samples with x = 0.1 samples were immersed in a viscous water/agar combination. Fig. 13 a displays the Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ samples' heating capacity at various media. It is evident that when viscosity increases, heat generation reduces. This indicates the importance of Brownian relaxation for heat production. The temperature difference between pure water and water containing 4 wt% agar for the samples is around 8 % at a magnetic field of 200 Oe. However, this difference decreases to 5 % at 400 Oe of the magnetic field.

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Fig. 13

(a) Heat generation capability of the Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ sample in H₂O with different amounts of agar and (b) SAR value of Cu_0.5Zn_0.5-xNi_xFe₂O₄ (x = 0.1, 0.2, 0.3, 0.4 and 0.5) samples at different field amplitudes and constant frequency of 200 kHz.

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One important need for magnetic nanoparticle hyperthermia treatment is that they have a high specific absorption rate (SAR). SAR measures the rate at which heat is produced per unit mass of magnetic nanoparticles (Tahir et al., 2024; Choopannezhad and Hassanzadeh-Tabrizi, 2023). This allows for lower magnetic field strength and frequency to be employed, as well as a reduction in the dosage of nanoparticles needed for treating hyperthermia. In the case of nanoparticles with low SAR values, they must be used in larger quantities. This is challenging since the capacity of cells to take in and tolerate nanoparticles is limited. Equation 5 was used to estimate the SAR in watts per gram of magnetic powder in order to have a better understanding of the relationship between hyperthermia efficiency and the associated magnetic characteristics of the Cu_0.5Zn_0.5-xNi_xFe₂O₄ samples (Papadopoulos et al., 2020). When an AC magnetic field is applied, the SAR value displays the capacity of magnetic particles for heating. A larger SAR shows higher heating efficacy at lower dosage levels of nanoparticles, improving the management of hyperthermia.

It is noteworthy that based on medical tolerance investigations conducted on healthy people, the Brezovich criterion establishes a safety limit where the H × f value cannot be greater than 5 × 10⁸ A/ms (∼6 × 10⁶ Oe/s). It was reported that this strict restriction can be exceeded up to ten times when it comes to body regions (Obaidat et al., 2015; Mahmoudi et al., 2018; Rafizadeh-Sourki and Hassanzadeh-Tabrizi, 2022). In the present study, the H × f value is 8 × 10⁴ Oe/s which is in the limit for the clinical hyperthermia use.

4 Conclusion

Magnetic Cu_0.5Zn_0.5-xNi_xFe₂O₄ cubic spinel nanoparticles were produced through a sol–gel combustion method. The effects of heat treatment and nickel substitution on the structure and magnetic properties of the synthesized spinel ferrites were investigated. The potential use of samples as hyperthermia agents was also studied. The as-prepared sample comprised Fe₂O₃ and CuO. These peaks disappeared after the calcination at 400 °C and the peaks related to spinel ferrite developed. TEM investigation exhibited that most of the particles are in the range of 20 to 100 nm. The results showed that the as-prepared samples do not have magnetic characteristics due to the non-reaction of the raw materials and the non-formation of the spinel ferrite structure. Heat treatment of the samples improved their saturation magnetization. A porous structure with a nanosized dimension was obtained via the sol–gel combustion method. Nickel ion substitution in the structure resulted in a reduction in saturation magnetization and an increase in coercivity. In addition, the lattice parameter of samples decreased with an increasing Ni²⁺ content, whereas the unit cell density increased. The role of heat treatment on magnetic properties was the opposite of the substitution of nickel ions, and it caused an increase in saturation magnetization and a decrease in coercivity. The chemical composition, cation rearrangement in A and B sites and changes in the crystallite size of the samples were known to be the most important factors controlling magnetic properties. Hyperthermia results revealed that Cu_0.5Zn_0.5-xNi_xFe₂O₄ nanoparticles with x = 0.1 with higher saturation magnetization and coercivity exhibit better heating efficiency and could increase the temperature from 37 °C to 49.5 °C at a magnetic field of 400 Oe and frequency of 200 kHz. A maximum SAR value of 52.2 W/g was obtained for the Cu_0.5Zn_0.4Ni_0.1Fe₂O₄ sample, which is deemed suitable for magnetic hyperthermia treatment. The viscosity of the hyperthermia environment had an important effect on the heating generation of samples. The results showed that when viscosity rises, heat generation decreases which is due to the disruption of the Brownian relaxation mechanism. This reduction in heating generation in the viscous medium was higher at the lower magnetic field.

Funding: No applicable.

Availability of Data: All the data was reported.

Consent to publication: All the authors have given their consent for publication of the study.

Conflict of interest: The authors declare no competing interests.

CRediT authorship contribution statement

S.A. Hassanzadeh-Tabrizi: Conceptualization, Methodology, Software, Data curation, Writing – original draft preparation, Visualization, Investigation, Supervision, Software, Validation, Writing – review & editing, Formal analysis.