Surfactant-free synthesis and magnetic hyperthermia investigation of iron oxide (Fe3O4) nanoparticles at different reaction temperatures

Materials Chemistry and Physics 230 (2019) 9–16

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Materials Chemistry and Physics journal homepage: www.elsevier.com/locate/matchemphys

Surfactant-free synthesis and magnetic hyperthermia investigation of iron oxide (Fe3O4) nanoparticles at different reaction temperatures

T

Ahmad Reza Yasemiana, Mohammad Almasi Kashia,b,∗, Abdolali Ramazania,b a b

Institute of Nanoscience and Nanotechnology, University of Kashan, Kashan, 87317−51167, Iran Department of Physics, University of Kashan, Kashan, 87317−51167, Iran

HIGHLIGHTS

GRAPHICAL ABSTRACT

NPs were synthesized at • Magnetite 40 °C ≤ T ≤ 80 °C by a surfactantR

• • • •

free co-precipitation. Structural, morphological, magnetic and hyperthermia properties were investigated. FORC analysis revealed SP fractions, ranging between 76% and 86% at TR = 80 and 40 °C. Maximum SLP was obtained to be 181 W/g for Ms = 42 emu/g and Hc = 2.5 Oe at TR = 60 °C. Balanced magnetic properties efficiently involved different heating mechanisms.

ARTICLE INFO

ABSTRACT

Keywords: Magnetite nanoparticles Superparamagnetic Co-precipitation method Magnetic properties FORC analysis Magnetic hyperthermia

The effect of reaction temperature (TR, ranging from 40 °C to 80 °C) on magnetic hyperthermia measurements was investigated in the surfactant-free co-precipitation synthesis of magnetite (Fe3O4) nanoparticles (NPs). The size, structure and magnetic properties of the synthesized NPs were studied by X-ray diffraction, field-emission scanning electron microscopy (together with energy dispersive spectroscopy), hysteresis loop and first-order reversal curve analyses. The investigations showed that all the NP samples were single domain with a superparamagnetic (SP) feature. After preparing the respective ferrofluids with a concentration of 5 mg/ml (in distilled water medium) acting as nanoheaters, hyperthermia measurements were performed under an alternating magnetic field with a frequency of 400 kHz. It was found that TR = 60 °C resulted in the maximum specific loss power (SLP) value of 181 W/g together with an SP fraction of 82%, being a suitable candidate for use in magnetic hyperthermia. In this case, the resulting saturation magnetization and SP fraction were in the middle of corresponding values obtained from TR = 40 °C and 80 °C. Our results showed that a balance between relatively high saturation magnetization and low coercive field led to the maximum SLP.

Abbreviations: TR, Reaction temperature; NPs, Nanoparticles; MNPs, Magnetic NPs; AMF, Alternating magnetic field; FESEM, Field-emission scanning electron microscopy; EDS, Energy dispersive spectroscopy; SP, Superparamagnetic; SLP, Specific loss power; FORC, First-order reversal curve ∗ Corresponding author. Institute of Nanoscience and Nanotechnology, University of Kashan, Kashan, 87317−51167, Iran. E-mail address: [email protected] (M. Almasi Kashi). https://doi.org/10.1016/j.matchemphys.2019.03.032 Received 13 November 2018; Received in revised form 25 February 2019; Accepted 8 March 2019 Available online 09 March 2019 0254-0584/ © 2019 Elsevier B.V. All rights reserved.

A.R. Yasemian, et al.

Materials Chemistry and Physics 230 (2019) 9–16

1. Introduction

different reaction temperatures (TR) while also investigating their detailed magnetic and hyperthermia properties. In this study, we aim to synthesize NPs which are not only highly compatible with clinical requirements (i.e., being biocompatible without toxicity), but also have a simple synthetic method with inexpensive and easily available precursors resulting in a high heating efficiency. Accordingly, the best candidate in terms of material type is Fe3O4 and the best method for its synthesis is the co-precipitation. Since the solvent in this suitable method is water (as the most simple and available solvent), providing the synthesis temperatures (ranging from room temperature to near water boiling point i.e. 80–90 °C) is very simple compared to some methods such as thermal decomposition which requires high temperatures (thus being costly and difficult). It is also possible to perform the synthesis under air atmosphere without surfactant. Structural, morphological, compositional and magnetic properties of the resulting Fe3O4 NPs synthesized at 40 °C ≤ TR ≤ 80 °C are investigated. Especially, first-order reversal curve (FORC) diagrams are obtained to detail magnetic properties. Finally, magnetic hyperthermia measurements of ferrofluids containing Fe3O4 NPs in distilled water medium are investigated.

Materials being transformed from the bulk state into the nanoscale undergo changes in their physical, chemical and mechanical properties. Notably, the most complex changes occur in magnetic properties of nanomaterials. Therefore, among various nanomaterials, magnetic nanomaterials have attracted special attention due to their numerous applications in the electronics industry (e.g., electronic memories and biosensors), magnetic resonance imaging, drug delivery, magnetic hyperthermia, and in the field of biomedicine [1–3]. For medical consumption, magnetic nanomaterials need to have a crystalline structure and uniform morphology along with a possibly narrow particle size distribution. Although spherical nanoparticles (NPs) are often employed as effective agents, more complex structures such as nanowires and nanotubes have also been utilized in the development of biomedical field. Among magnetic NPs (MNPs), magnetite (Fe3O4) which is an iron oxide has unique features compared to other nanomaterials [4,5]. Nanoscale magnetite with high surface-to-volume ratio shows superparamagnetic (SP) property (i.e., the disability to maintain magnetization after the magnetic field removal) at room temperature, and is non-toxic and biocompatible [6]. Iron oxide is found in the following different forms: Iron (II) oxide (FeO), Iron (III) oxide (Fe2O3) and Iron (II, III) oxide (Fe3O4). Among these, Fe2O3 also forms different crystalline states including (α-Fe2O3), (β-Fe2O3), (γFe2O3) and (ε-Fe2O3). Investigations show that the magnetite (Fe3O4) and maghemite (γ-Fe2O3) have higher biocompatibility, and Fe3O4 is more conventional for biomedical applications [7,8]. Applying iron oxide NPs for cancer treatment was first reported in 1957 by Glichrist et al. [9]. In 2004, the first magnetic hyperthermia treatment system was developed at university of Berlin [10], and a few years later, Magforce obtained European regulatory approval to treat patients with brain tumor using magnetic hyperthermia [11]. Magnetic nanostructures used for magnetic hyperthermia can be ferromagnetic or ferrimagnetic. Under better conditions, decreasing the nanostructure dimension leads to a single domain state, and further decrease in the size results in an SP phenomenon. Magnetic nanostructures, especially MNPs, can transform the obtained electromagnetic energy (involving the process of magnetization, demagnetization and inverse magnetization) into heat when exposed to an alternating external magnetic field. In fact, MNPs play the role of an energy convertor (from electromagnetic energy to heat) and act as a nanoheater. In this regard, the magnetic field applied in a certain direction can provide some energy to orient NP magnetic moments toward that direction, and transform the electromagnetic energy to heat energy when changing the field direction. In other words, to re-orient the magnetic spins, the electromagnetic energy obtained is released and transformed into heat energy. Moreover, the friction created by the rotation of magnetic nanostructures in the fluid can also lead to heat generation until reaching the physical equilibrium. In recent years, various types of magnetic materials including metal alloys, ferrites and so on have been synthesized with different methods to be applied for magnetic hyperthermia [12]. Nevertheless, some toxic nanostructures without biocompatibility do not satisfy clinical requirements. Importantly, iron oxide NPs such as magnetite (Fe3O4) satisfying almost all clinical requirements have also been synthesized by different precursors and methods. Martinez-Boubeta et al. plotted the heating curve of MNPs in a relatively high time interval of 800 s by applying different magnetic fields. In this case, the maximum applied magnetic field (Hmax = 30 mT) at f = 765 kHz resulted in ΔT = 70 °C [13]. Also, Wang et al. reported ΔT = 50 °C for Fe3O4 magnetic fluid in a maximum concentration at a high time interval of Δt = 1000 s [14]. Furthermore, Ebrahimisadr et al. reported the synthesis of Fe3O4 NPs using a coprecipitation method, so that ΔT ≈ 57 °C was obtained in the maximum concentration (12.5%) at a high time interval of Δt = 1100 s [15]. Overall, less attention has been paid to the synthesis of Fe3O4 NPs at

2. Basic principles and measurements in magnetic hyperthermia Nanostructured systems can act as nanoheaters when obtaining the activation energy in an alternating magnetic field (AMF). In order to estimate the heating efficiency of synthesized MNPs, experiments based on calorimetric measurements of magnetic hyperthermia are utilized. When applying an AMF with certain frequency and intensity, the temperature rise of ferrofluid is measured and recorded in a certain time interval. Plotting the temperature rise curve as a function of time, and calculating its initial slope, specific loss power (SLP) or specific absorption rate (SAR) values are calculated. SAR is defined as the absorbed power, normalized by the mass of MNPs and applied by an AMF with a certain frequency (f) and intensity (H0).

SLP (or SAR) =

Absorbed Power Mass of MNPs

(1)

With regard to the effective parameters involved in calorimetric measurements of SLP, the above-mentioned relation can be expressed as:

SLP = C

m sample mMNPs

T (W/g) t

(2)

where C is specific heat capacity of the solvent (e.g., equal to 4.181

J g. °C

PFM = µ 0f

(3)

for water), m sample is mass of the solvent (i.e., the suspension containing distilled water and MNPs), mMNPs is mass of MNPs and T is the initial t slope of the heating curve [16,17]. Generally, magnetic loss involving heating mechanisms in an AMF is categorized into the following four types: I) hysteresis loop loss, II) Neel relaxation and III) Brownian relaxation. I) Hysteresis loop loss: Ferromagnetic and ferrimagnetic materials have hysteresis loops, so that in the presence of an AMF, their magnetization (M − H) curve is repeated several times in a second, leading to a loss in efficiency while also rising the temperature. The temperature rise is due to the friction heat of domains with constantly varying orientation. The heat power generated is obtained from Eq. (3):

M dH

where PFM is the heat generated by ferromagnetic or ferrimagnetic particles per unit volume, µ 0 is the vacuum permeability, f expresses the frequency, and the integral term represents the hysteresis loop surface area. II) Neel relaxation: In hyperthermia therapy, SP particles are broadly utilized in the form of ferrofluids. Decreasing the size of ferromagnetic or ferrimagnetic particles to a critical level transforms them into single domain particles without domain walls. Therefore, due to 10

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the single domain occurrence and absence of domain walls, the heat generation source is no longer from the domain displacement, and consequently the tendency of particles toward SP state is the reasoning behind their various unique properties. In the Neel relaxation mechanism, the magnetic moment rotation in NPs causes the absorbed electromagnetic energy to be transformed to heat. III) Brownian relaxation: The Brownian relaxation mechanism for transforming the absorbed electromagnetic energy in an AMF into heat is caused by physical rotation of the particles themselves. In this manner, the kinetic energy of particles is transformed into heat due to the friction between particles and surrounding fluids. Evidently, increasing the particle size and decreasing the surrounding fluid viscosity enhance the Brownian relaxation contribution. For each of Neel relaxation and Brownian relaxation mechanisms, a characteristic time is defined as follows [18]: N

B

=

=

0

exp (

3

K Vm ) kB T

3. Experimental details 3.1. Synthesis of Fe3O4 NPs Magnetite (Fe3O4) NPs were synthesized by a chemical co-precipitation method. This was based on the reduction reaction of iron (II) and (III) salts in the presence of a strong base. The general chemical reaction is as follows: Fe2+ + 2Fe3+ + 8OH− → Fe3O4↓ + 4H2O

Since we used iron (II) (FeCl2.4H2O) and iron (III) (FeCl3.6H2O) chloride salts as precursors, and NaOH as the reduction agent, the resultant reaction is expressed in Eq. (9) as given below: FeCl2•4H2O + 2 (FeCl3•6H2O) + 8NaOH → Fe3O4 ↓ + 8NaCl +20H2O (9) All the chemical materials were purchased from Merck Company. To synthesize Fe3O4 NPs, molar ratios of chloride salts were selected to

(4)

Fe2 +

VH

be Fe3 + = 2 . To this end, 2 mmol (0.54 g) FeCl3.6H2O and 1 mmol (0.198 g) FeCl2.4H2O were used. In three separate syntheses labeled S1, S2 and S3, the aforementioned salts were dissolved in 40 ml distilled water (as the solvent) at TR of 40 °C, 60 °C and 80 °C, respectively, and stirred for 10 min under the air atmosphere. On the other hand, based on the stoichiometry of Eq. (9), 8 mmol NaOH tablets were separately prepared in the form of 1 M solution at the temperatures of 40 °C, 60 °C and 80 °C. At each synthesis, 1 M NaOH solution was instantly added to the solution of iron (II) and (III) salt precursors with the selected TR. After performing the reaction for 30 min at 40 °C, 60 °C and 80 °C, the heater was turned off while the stirring continued until the solution temperature reached room temperature. The resulting iron oxide solutions containing NPs (samples S1, S2 and S3) were washed with distilled water and ethanol. The precipitations were then separated with the help of a magnet and centrifuging (6000 rpm; 5 min) for several times.

(5)

kB T

where N and B represent characteristic times of Neel and Brownian relaxations, respectively. In Eq. (4), 0 is the magnetic attempt time ( 0 ≈ 10−9 s), denoting an average timescale between two successive thermal excitations [19]; K is the anisotropy constant, Vm is the magnetic core volume, kB is the Boltzmann constant and T is the absolute temperature. As inferred, N depends on the potential barrier (K Vm ) and heat energy (kB T ). In Eq. (5), is the fluid viscosity, VH is hydrodynamic volume of MNPs, kB is the Boltzmann constant and T is the absolute temperature. In the presence of coincident Neel and Brownian relaxation mechanisms, the effective relaxation time, eff , comprises both N and B as defined below: eff

=

N B N

+

B

(6)

SLP fH02

1

3.2. Characterizations

The dependency between eff and characteristic times of Neel and Brownian relaxations (according to Eq. (6)) indicates that the stronger relaxation mechanism (accompanied with the lowest relaxation time) would determine the effective relaxation. In other words, B » N results in eff N , and for N » B , one obtains eff B. In the case of large MNPs, hysteresis loop loss and Brownian relaxation determine the heat amount. For small NPs in the range of SP size, the hysteresis loop loss is absent, and the heating is caused by the Neel and Brownian relaxation mechanisms [20–22]. Based on the comparison between N and B , one can state that Neel relaxation depends on magnetic anisotropy whereas the Brownian relaxation is fluid dependent. Effective parameters involving the heat amount generated in magnetic hyperthermia by ferrofluids include type of material, particle size, anisotropy, viscosity, concentration, particle polydispersity, and magnetic field intensity and frequency [23]. For instance, for the particle size parameter influencing SLP value [24–27], different sizes of a material have been reported to reach an optimum SLP. As a specific example, different optimal diameters such as 10 nm [28], 11.2 nm [29], 12 nm [30], 16 nm [27] and 19 nm [31] have been suggested for magnetite (Fe3O4). The difference between the optimal sizes is related to different tuning methods of the heating process including field intensity and frequency. However, compared to intrinsic loss power (ILP) defined in Eq. (7), SLP varies in value in different studies since parameters such as the anisotropy is introduced as an effective variable in determining hyperthermia properties [32].

ILP =

(8)

After synthesizing the Fe3O4 NP samples, their crystalline structure and crystallite size were investigated using X-ray diffraction (XRD; Philips, model X'Pert Pro; Cu Kα radiation with λ = 0.154 nm) analysis. Moreover, morphology, mean NP diameter and energy dispersive spectroscopy (EDS) elemental analysis of the samples were obtained by field-emission scanning electron microscopy (FESEM; MIRA3 TESCAN). The magnetic properties were investigated by measuring hysteresis loops using a vibrating sample magnetometer (VSM; Magnetic Danesh Pajoh Co.) at room temperature. In addition, FORC analysis was performed to provide more details on magnetic characteristics of Fe3O4 NPs and evaluate hysteresis loop results [33]. The procedure to perform the FORC analysis was as follows: A magnetic field (Hmax) was initially applied to positively saturate the sample. This field was then reduced to a reversal field Hr (Hr < Hmax) with certain steps and swept back to Hmax, resulting in the first reversal curve of the NP sample. Meanwhile, magnetization M (H, Hr) was measured at each step. By continuing this procedure, sets of minor FORCs were obtained. The FORC distribution is defined as given in Eq. (10):

1 2

(H, Hr ) =

2M(H,

Hr ) H Hr

(10)

Hc and Hu axes are defined by Eqs. (11) and (12) as follows:

Hc =

Hu =

(7) 11

H

Hr 2

(11)

H + Hr 2

(12)

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The Hc axis specifies the coercive field distribution of magnetic domains and the Hu axis indicates the presence or absence of magnetic interactions between constituent domains of NPs [34–36]. 3.3. Hyperthermia measurements Initially, ferrofluid of each sample was prepared by dissolving 15 mg dried NP powder in 3 ml distilled water. The resultant solution was then put in an ultrasonic bath (50 Hz) for 30 min to obtain high dispersibility. The heat generated by NPs was measured using a homemade AC hyperthermia magnetic system. A cylindrical glass tube containing NP solution with a concentration of 5 mg/ml was placed in the system sample holder located in the middle of an inductive coil generating a sine waveform with Hmax = 400 Oe and f = 400 kHz. The length and inner and outer diameters of the double-layer coil were 7.8 and 4.5 and 6.7 cm, respectively. During the measurements, the circulating movement of cold water around the coil kept its temperature constant to 20 °C. To decrease non-adiabatic conditions occurring due to the heat transfer between the sample and the surrounding environment, the inner space of the solenoid was filled with glass wool. For better clarity of the hyperthermia measurements, a schematic view is presented in Fig. 1. The hyperthermia measurements of each NP sample were performed within a time interval of 360 s with a time step of 60 s. It should be noted that, ΔT-time curve was plotted and SLP value was calculated according to Eq. (2). In this case, the initial slope of the ΔTtime curve was calculated within the first 60 s. To record and monitor the ferrofluid temperature, a resistance temperature detector (PT100) with 0.1 °C precision was used. 4. Results and discussion

Fig. 2. (a) The XRD patterns of samples S1, S2 and S3. (b) The matching of sample S2 peaks with the reference card.

4.1. Structural characteristics Fig. 2(a) shows the XRD patterns of samples S1, S2 and S3 and Fig. 2(b) shows the matching of peaks with the reference card (JCPDS No. 01-075-0449) for a typical synthesis (S2). Also, the distance between crystalline lattice planes (d-spacing) obtained from the XRD analysis and calculated theoretical data of the reference card (d-value) for sample S2 are shown in Table (1). The average particle diameters of the three samples are also reported in Table (2). These sizes were estimated using the Scherrer equation:

dXRD =

0.9 cos

Table 1 The distance between crystalline lattice planes (d-spacing) obtained from XRD analysis and calculated theoretical data of the reference card (d-value) for sample S2.

(13)

where λ is the wavelength of X-ray with Cu Kα radiation, β (in terms of radian) represents FWHM, and θ is the Bragg diffraction angle. By matching observed peaks with the reference card together with

2θ (degree)

(hkl)

d-spacing [XRD] (Å)

d-value [Ref. card] (Å)

30.3124 35.7896 43.5272 53.7163 57.4780 63.0160

(220) (311) (400) (422) (511) (440)

2.94868 2.50899 2.07924 1.70643 1.60338 1.47393

2.9380 2.5080 2.0775 1.6962 1.5992 1.4690

Fig. 1. Schematic representation of hyperthermia measurements involving water cooling and magnetic hyperthermia systems along with a double-layer coil. 12

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Table 2 Reaction temperature (TR), magnetic characteristics (from hysteresis loop measurements), average crystallite size (d¯XRD ), mean diameter (d¯FESEM ) and superparamagnetic (SP) fraction (from FORC analysis) for different samples. Sample

̊ TR (C)

MS (emu/ g)

Mr (emu/ g)

HC (Oe)

_ dXRD (nm)

_ dFESEM (nm)

S1 S2 S3

40 60 80

28.5 42 54.2

0.07 0.18 0.98

1.5 2.5 5

7.5 ± 0.37 7.7 ± 0.39 7.9 ± 0.40

13.5 16.7 18.1

SP fraction (%) 86 82 76

Fig. 2(b) and data of Table 1, the magnetite nature of the synthesized NPs is confirmed. With the comparison between peak intensities, especially the main peak (311) in the three samples, the increase in crystallinity is evident when increasing TR from 40 °C to 80 °C. The size growth of NPs provided in Table 2 is also observed, indicating the enhancement in magnetite crystallinity with increasing TR. Basically, synthesis time and TR are two important factors in determining size and crystallinity of NPs [37,38]. Herein, TR is only changed during the co-precipitation synthesis, influencing kinetic and thermodynamic conditions of chemical reactions involved, which can lead to a decrease in the oxygen concentration dissolved in the magnetite solution. Thus, the increase in TR leads

Fig. 4. The hysteresis loops of samples S1, S2 and S3 at room temperature. The bottom-right inset details the hysteresis loops at a lower magnetic field range.

Fig. 3. The FESEM images and EDS spectra of: (a) and (b) sample S1, (c) and (d) sample S2, and (e) and (f) sample S3. The top-left insets in the FESEM images correspond to the NP diameter distribution histograms. The insets in the EDS spectra present the corresponding elemental analysis.

13

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Fig. 5. The FORC diagrams of samples (a) S1, (b) S2 and (c) S3. (d) The coercive field distribution of the NP samples.

to more complete reaction, thereby enhancing the formation of the magnetite and reducing the formation of others phases (e.g., maghemite and hematite) as could be observed when comparing XRD pattern of sample S1 (TR = 40 °C) with that of sample S3 (TR = 80 °C). It is also notable that, increasing TR increases the mean diameter (d¯FESEM ) and the crystallite size (d¯XRD ) (see Table 2), thereby enhancing the total crystallinity.

hysteresis loop measurements are inserted in Table 2. As seen, Ms values of samples S1, S2 and S3 are found to be 28.5, 42 and 54.2 emu/g, respectively. Evidently, these values are smaller than Ms of bulk Fe3O4 material (ca. 90 emu/g) [39,40]. Basically, three main reasons have been proposed to explain lower Ms of NPs than that of their bulk state as follows: i) the presence of a non-magnetic layer on the NPs’ surface (a dead magnetic layer); ii) distribution of cations and iii) surface spin disorder. The presence of oxygen can also lead to the formation of other phases (e.g., maghemite) in addition to magnetite. However, the magnetite and maghemite phases are difficult to be distinguished by the XRD analysis as they have very similar physical and structural properties. Note that the magnetite phase is stronger than maghemite phase in terms of magnetic properties, according to the literature [41–49]. Furthermore, the transformation from bulk to nanostructure state (which is accompanied with the increase in surface-tovolume ratio and decrease in Ms) occurs by intrinsic factors, whereas the oxidation factor depends on the synthesis conditions (e.g., the atmosphere type) which are relatively controllable. The increase in Ms from 28.5 to 54.2 emu/g can be justified by the fact that the oxygen dissolution in the solution decreases with increasing TR, thus reducing the surface oxidation of NPs. Alternatively, the improvement in crystallinity of particles when increasing TR leads to the enhanced formation of the magnetite phase, which consequently improves the magnetic properties including Hc. Also, the comparison between Hc values of the NP samples indicates that they are nearly SP. In this direction, increasing TR from 40 °C to 60 °C increases Hc up to approximately 65% (from 1.5 Oe to 2.5 Oe). Additionally, increasing TR from 60 °C to 80 °C leads to an improvement of 100% in Hc (see Table (2)). It should be noted that, although increasing TR increases the corresponding Ms, it weakens the SP property. Since hysteresis loop measurements do not provide unique evidence for magnetic materials and merely determine average magnetic

4.2. Morphological characteristics Fig. 3 shows FESEM images of Fe3O4 NPs synthesized when 40 °C ≤ TR ≤ 80 °C together with corresponding particle diameter distribution histograms and EDS spectra. The Fe3O4 NPs observed in these images have almost spherical-like morphology. Also, as expected, the distribution histograms show the increase in mean diameter of NPs when increasing TR. The mean diameter values are inserted in Table (2). The slight difference (e.g., ∼6 nm for sample S1) between d¯XRD and d¯FESEM evaluated from the XRD and FESEM analyses, respectively, can indicate that the agglomeration of Fe3O4 NPs is not considerable. It is also inferred that the Fe3O4 NPs are polycrystalline in nature since d¯XRD is smaller than d¯FESEM . On the other hand, the presence of size distribution of the NPs could be attributed to the absence of surfactant in the synthesis process. 4.3. Magnetic characteristics (hysteresis loop and FORC measurements) The magnetic properties of NP samples were initially investigated using hysteresis loop measurements by applying a magnetic field of 9 kOe at room temperature. Fig. 4 shows hysteresis loops of Fe3O4 NPs synthesized at different TR. The quantitative results including saturation magnetization (Ms), remanence magnetization (Mr) and coercivity (Hc) extracted from the 14

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4.4. Magnetic hyperthermia measurements As mentioned in section 3.3, the magnetic hyperthermia measurements of the Fe3O4 NP samples synthesized at TR ranging from 40 °C to 80 °C were performed by a home-made system with Hmax = 400 Oe and f = 400 kHz. After preparing the ferrofluid of each NP sample with a concentration of 5 mg/ml in a vial and dispersing it by the ultrasonic bath for 30 min, it was put inside the hyperthermia system. The temperature rise measurement of the ferrofluid in the time interval of 360 s with time steps of 60 s was then performed and the values obtained were recorded. Afterward, the SLP of each sample was calculated using Eq. (2) within the first 60 s. In this regard, ΔT-time curves and SLPsample diagrams of samples S1eS3 are shown in Fig. 6(a) and (b), respectively. As can be seen, the highest temperature rise (ΔT = 36 °C) is obtained for the sample S2, thus resulting in the maximum SLP value of 181 W/g. On the other hand, sample S1 has the lowest temperature rise (ΔT = 16 °C) and SLP value (97.5 W/g). Generally, ferrofluids containing MNPs with a high Ms and low Hc show enhanced SLP value and stability, respectively [50]. This is because a high Ms causes MNPs in the AMF to show strong reactions during the time interval of magnetizing, demagnetizing and reversal magnetizing processes, thereby transforming more electromagnetic energy obtained into heat. In addition, MNPs with a high Ms can be easily and quickly conveyed to the tumor location in an indirect injection. Alternatively, having low Hc not only facilitates the contribution of Neel and Brownian relaxation mechanisms but also causes MNPs to lose their magnetization after removing the magnetic field, which is one of the clinical treatment requirements. Otherwise, the agglomeration of MNPs would act as a clot in the blood circulatory system. In the present study, the sample S2 with the highest SLP has a higher and lower Ms than that of samples S1 and S3, respectively. In terms of coercive field, the respective Hc of the sample S2 is nearer to that of sample S1 (see Table (2)). In other words, the relatively high Ms and low Hc of the sample S2 provides a suitable balance between these two magnetic parameters, which in turn leads to the maximum SLP value of 181 W/g. Moreover, the comparison between EDS spectra of the resulting NP samples (Fig. 3(b) and (d) and 3(f)) indicates that the chemical content of the elements oxygen and iron in sample S2 is in better agreement with their expected contribution to the Fe3O4 compound. With regard to the correlation between FORC analysis and the magnetic hyperthermia, one can state that the SP fraction [35,36] of Sample S1 is 10% higher than that of Sample S3, indicating its higher contributions of Neel and Brownian relaxation mechanisms to the heating efficiency. It is also found that the SP fraction of the sample S2 (82%) is lower and higher than that of samples S1 (86%) and S3 (76%), respectively. Therefore, 82% of Fe3O4 NPs are reversible in sample S2, generating heat based on the Neel and Brownian relaxation mechanisms. The rest of the NPs are considered to be single domain with irreversible magnetization rotation, generating heat through the hysteresis loop loss mechanism. In other words, while Neel and Brownian relaxation mechanisms are mainly responsible for heat generation in sample S1, the hysteresis loop loss mechanism is enhanced in the sample S3. Consequently, a balanced combination of Neel and Brownian relaxation and hysteresis loop loss mechanisms leads to the maximum SLP of sample S2.

Fig. 6. (a) ΔT-time curves and (b) SLP-sample diagrams of samples S1, S2 and S3. For hyperthermia measurements, maximum field and frequency were set to 400 Oe and 400 kHz, respectively.

properties such as Ms, Mr and Hc, the FORC analysis was used to evaluate the hysteresis loop results and investigate more details of magnetic characteristics. In fact, FORC measurements capture magnetic fingerprints of materials, revealing coercive and interaction field distributions. Two-dimensional FORC diagrams obtained from Fe3O4 NPs synthesized at TR = 40 °C, 60 °C and 80 °C are shown in Fig. 5(a) and (c), and corresponding coercive field distributions are presented in Fig. 5(d). The quantitative results of SP fractions of the NP samples are also inserted in Table (2). With the dominant FORC distributions near the origin of the diagrams (i.e., Hc = 0 Oe and Hu = 0 Oe), Fig. 5(a) and (c) indicate SP behavior of the resulting Fe3O4 NPs at different TR, confirming the hysteresis loop results. According to Fig. 5(d), the corresponding peak position of the sample S3 located in a higher coercive field than that of samples S1 and S2, confirms the higher Hc at TR = 80 °C (Hc = 5 Oe) compared to that of TR = 40 °C and 60 °C (Hc = 1.5 and 2.5 Oe, respectively). Moreover, the comparison between coercive field distribution curves of samples S1 and S2 reveals the higher distribution of the latter compared to the former. In other words, the Hc value obtained from hysteresis loop measurements is lowest for the sample S1 due to its lower coercive field distribution than that of samples S2 and S3. On the other hand, as can be seen in Table (2), the respective SP fraction is highest for the sample S1 (86%), arising from the improved contribution of SP Fe3O4 NPs at TR = 40 °C compared to TR = 60 °C and 80 °C.

5. Conclusions In summary, Fe3O4 NPs were synthesized at TR of 40 °C, 60 °C and 80 °C using the simple and cost-effective chemical co-precipitation method. The XRD analysis indicated the magnetite nature of the synthesized NPs without impurity. The FESEM images showed the formation of almost spherical-like NPs, so that increasing TR from 40 °C to 80 °C increased their mean diameter from 13.5 to 18.1 nm. The highest 15

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and lowest Ms and Hc values obtained from the hysteresis loop measurements were found to be 54.2 emu/g and 1.5 Oe at TR = 80 °C and 40 °C, respectively. Moreover, the FORC analysis confirmed the hysteresis loop results, featuring SP fractions of the Fe3O4 NPs ranged between 76% (TR = 80 °C) and 86% (TR = 40 °C). From the hyperthermia measurements (Hmax = 400 Oe and f = 400 kHz), the ferrofluid containing Fe3O4 NPs dispersed in distilled water medium and synthesized at TR = 60 °C resulted in the highest temperature rise (ΔT = 36 °C) in the presence of the AMF, thereby giving rise to the maximum SLP value (181 W/g). In fact, a balanced combination between magnetic properties including the high Ms and low Hc caused the MNPs to generate heat maximally, thus involving Neel and Brownian relaxation and hysteresis loop loss mechanisms.

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