Comparative Heating Efficiency of Cobalt-, Manganese-, and Nickel

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Biological and Medical Applications of Materials and Interfaces

Comparative Heating Efficiency of Cobalt-, Manganese-, and NickelFerrite Nanoparticles for a Hyperthermia Agent in Biomedicine Çi#dem Elif Demirci Dönmez, Palash Kumar Manna, Rachel Nickel, Selçuk Aktürk, and Johan van Lierop ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b22600 • Publication Date (Web): 24 Jan 2019 Downloaded from http://pubs.acs.org on January 29, 2019

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ACS Applied Materials & Interfaces

Comparative Heating Efficiency of Cobalt-, Manganese-, and Nickel-Ferrite Nanoparticles for a Hyperthermia Agent in Biomedicine Çiğdem E. Demirci Dönmez,∗,†,‡,¶ Palash K. Manna,‡ Rachel Nickel,‡ Selçuk Aktürk,† and Johan van Lierop∗,‡,§,k †Department of Physics, Mu˘gla Sıtkı Koçman University, 48000, Mu˘gla, Turkey ‡Department of Physics and Astronomy, University of Manitoba, Winnipeg, MB R3T 2N2, Canada ¶ORCID iD: https://orcid.org/0000-0002-3081-0691 §Manitoba Institute for Materials, University of Manitoba, Winnipeg, MB R3T 2N2, Canada

kORCID iD: https://orcid.org/0000-0001-9398-4835 E-mail: [email protected]; [email protected]

Abstract In this study, the AC magnetic hyperthermia responses of spinel CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles of comparable sizes (∼ 20 nm) were investigated to evaluate their feasibility of use in magnetic hyperthermia. The heating ability of EDT-coated nanoparticles which were dispersed in the two different carrier media, DI H2 O and EG, at concentrations of 1 and 2 mg/mL, was evaluated by estimating the SLP (which is a measure of magnetic energy transformed into heat) under magnetic fields of 15, 25 and 50 kA/m at a constant frequency of 195 kHz. The maximum value of SLP has been found to be ∼ 315 W/g for CoFe2 O4 , and ∼ 295 W/g for MnFe2 O4 and NiFe2 O4

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nanoparticles. We report very promising heating temperature rising characteristics of CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles under different applied magnetic fields that indicate the effectiveness of these nanoparticles as hyperthermia agents.

Keywords Cobalt Ferrite, Manganese Ferrite, Nickel Ferrite, Specific Loss Power, Magnetic Hyperthermia

1 Introduction Magnetic nanoparticles (MNPs) are one of the most attractive materials due to their potential biomedical applications, for example in bioimaging, 1 cell labeling, 2 hyperthermia 3 and targeted drug delivery. 4 Nanoparticles offer many advantages compared to particles with larger size as the altered magnetic properties relate to increased surface to volume ratio. Their size is an advantage in biomedical applications, allowing them transport through the bloodstream, permeate across cell membranes, avoid immune system recognition. Nowadays, hyperthermia using MNPs as a potential advanced cancer therapy technique, has been paid considerable attention due to the opportunity of killing localized or deep seated cancer tumors with reduced clinical side effects. 5 Tissues are heated to temperatures just above 42 ◦ C where the cancer growth stops while healthy cells can be preserved. 6 MNPs can produce heat when subjected to an alternating current (AC) magnetic field as heat dissipating agents. The heating effect makes nanoparticles suitable to be used in magnetic hyperthermia as a fascinating therapeutic procedure. The amount of induced heat by MNPs is quantified in terms of the specific loss power (SLP). SLP depends on several physical and magnetic properties of the particles including particle size, 7,8 size distribution, 9,10 magnetocrystalline anisotropy (K), 11,12 as well as several extrinsic factors including the frequency ( f ) and amplitude of the applied magnetic 2


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field (H), 13,14 viscosity of the carrier medium (η) 15 and the concentration of the particles. 16 In general, SLP values that arise from the relaxation processes (Néel and Brownian) are roughly proportional to K, and inversely proportional to the size of the nanoparticles. 17 He et al. 11 studied maximizing specific loss power for magnetic hyperthermia and showed that for Mn0.3 Fe2.7 O4 /SiO2 nanoparticles within the core size range of 7 to 22 nm, the SLP increases monotonically with increasing nanoparticle size. They also showed that the SLP of Cox Mn(0.3-x) Fe2.7 O4 nanoparticles first increases with increasing Co concentration, then decreases past a critical concentration. In the systematic study of Cobianchi et al., 18 it has been shown that the SLP of the maghemite nanoparticles increases as the diameter increases. They also concluded that the linear response theory (LRT) model, 19 where SLP is proportional to the H 2 , explains the data for small nanoparticles (d = 10.2 nm), but fails when the size of nanoparticles becomes larger (d = 14.6 and 19.7 nm) than the critical diameter corresponding to the onset of the transition from the superparamagnetic to the ferromagnetic regime. There are several studies on the heating ability of MNPs such as magnetite (Fe3 O4 ) and maghemite (γ-Fe2 O3 ) nanoparticles that show that they are very promising candidates for biomedical applications due to their biocompatibility. 20–22 But, sufficient data is still not available for other types of ferrites. Ferrites obtained by adding ions such as Co2+ , Mn2+ and Ni2+ to magnetite have a wide range of altered magnetic properties such as saturation magnetization and magnetic anisotropy; 17,23 both parameters play very important roles in the SLP due to the aforementioned heating mechanisms. Magnetic nanoparticles for hyperthermia must be biocompatible, a property that is not well understood currently. For example, the cytotoxic response of nanoparticles strongly depends on the particle concentration. 24 Different cytotoxic properties for magnetic nanoparticles have been reported in literature. 25 It was observed by Pradhan et al. 26 that the threshold cytocompatible concentration of Fe3 O4 , CoFe2 O4 and MnFe2 O4 based magnetic fluids is 0.1 mg/mL, but CoFe2 O4 -based magnetic fluid is more cytotoxic

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than the others at higher concentration of 0.2 mg/mL. Tomitaka by et al. 27 observed that NiFe2 O4 nanoparticles are non-toxic at concentrations lower than 10 µg/mL, but toxic at concentrations of 100 µg/mL. The objective of this study was to investigate the links between the magnetism and heating properties of EDT-coated MNPs of the different ferrites CoFe2 O4 , MnFe2 O4 and NiFe2 O4 with comparable sizes. We compared their heating efficiency to reveal the feasibility for magnetic hyperthermia. The choice of ferrite nanoparticles is based on the scalability of the synthesis procedure, 28 stability against oxidation, 29 and tunability of their magnetic properties. 30,31 A series of temperature versus time measurements were performed by varying the magnetic field amplitude, the viscosity of carrier medium and the concentration of the nanoparticles as parameters that governed the heating efficiency.

2 Experimental methods Oleic acid (OA)-coated CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles of comparable sizes (∼ 20 nm) were prepared by using a method modified from the conventional organic phase process. 32 A variety of experimental techniques like x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS) and Mössbauer spectroscopy for the structural, morphological and compositional characterization was used. The temperature and field dependence of the overall magnetic properties were determined by using SQUID magnetometry. We have previously reported all the details of the conditions for synthesizing and characterizing the nanoparticles. 33 Induction heating of all the nanoparticles was performed using an Easy Heat 0224 device (Ambrell) with a solenoid coil (8 turns, 4 cm in diameter) made of a copper tube in a Helmholtz configuration cooled with a closed-loop water system. The high-frequency signal generates a high-frequency magnetic field at the center (where the magnetic field strength is the maximum) of the induction heating coil. The amplitude of applied magnetic

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field was varied from 15 to 50 kA/m at a constant frequency of 195 kHz. Two different carrier media with viscosities of 0.89 mPa·s (at ∼ 27 ◦ C) for deionized water (DI H2 O) 34 and 16.2 mPa·s (at ∼ 27 ◦ C) for ethylene glycol (EG) 34 were used for hyperthermia measurements to reveal the influence of viscosity on the heating efficiency of nanoparticles. The more viscous medium of EG compared to DI H2 O was used to inhibit the rotation of the nanoparticles (reducing the Brownian contribution to the absorption power, as discussed in detail below). The magnetic fluid was in a glass vial supported by a heat-insulated styrofoam and kept at the center of the heating coil during the measurement. The nanoparticles were ultrasonicated to ensure homogeneous dispersion in the medium prior to hyperthermia measurements. The OA-coated CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles were re-coated with N-(trimethoxysilylpropyl)-ethylenediaminetriacetate, trisodium salt, 35% in water (EDT), to make them well dispersed hydrophilic nanoparticles (one of the primary requirements for biomedical applications) and reduce the magnetic dipole-dipole interaction. Surface coating with EDT also helps to (i) improve the stability of nanoparticles in colloidal medium, and (ii) prevent agglomeration of the nanoparticles and surface oxidation to an unwanted oxide phase with lower saturation magnetization (which may affect the SLP), and (iii) provide additional biocompatibility (which is an important issue for suitability of the magnetic fluids for hyperthermia), and (iv) make the surface of the nanoparticles active to molecules like drugs, enzymes, proteins etc for combined drug delivery and magnetic hyperthermia systems. Manna et al. 35 observed that the uptake of EDT-coated nanoparticles by cells was significantly enchanced in the presence of magnetic field. Sun et al. 36 observed that the magnetic field enhanced convective diffusion of EDT-coated iron oxide nanoparticles provide higher delivery efficiency compared with either passive or active targeting of blood-brain-barrier vesicular transport processes. To coat the particles’ surface by EDT, ∼ 500 µL of EDT, ∼ 15 mL DI water and ∼ 10 mg of powder of assynthesized nanoparticles of CoFe2 O4 , MnFe2 O4 and NiFe2 O4 were mixed separately,

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ultrasonicated for 2 hours at ∼ 40 ◦ C and then stirred vigorously at 90 ◦ C for 8 hours under reflux. The final solution was cooled to room temperature naturally and then stirred vigorously overnight at this temperature. After washing the mixture with ethanol and methanol several times, the nanoparticles were uniformly suspended in DI H2 O. The heating profiles of the all the magnetic fluids were recorded for 1200 s and monitored with a thermal camera (Flir AX8). The SLP of the magnetic fluid under the influence of AC magnetic field was estimated by determining the initial rate of temperature rise under non-adiabatic approximation using the following equation, 37

SLP = C

ms ∆T mm ∆t

(1)

where C is the specific heat of the solution (Cwater = 75.35 J mol−1 K−1 and Cethylene glycol = 149.6 J mol−1 K−1 38 ), ms is the mass of the solution, mm is the mass of the magnetic material and ∆T/∆t is the initial slope of the heating curve in a magnetic field, extracted from the experimental data.

3 Results and discussion 3.1

Microstructure, composition and magnetism

Preliminary results of XRD, DLS, TEM and Mössbauer spectroscopy for CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles were published previously. 33 The TEM images of CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles re-coated by EDT are shown in figures 1(a)-(c). As seen in these figures, all nanoparticles retained formation of nano-assemblies (i.e. chaining and clustering) after EDT coating. The nanoparticles dried into chains and clusters, as seen in the image, an expected aspect of the TEM grid preparation process. However this did not impact the assessment of particle size distributions from the images, as shown in figure 1. The corresponding histogram plots of the sizes using ImageJ analysis identify the 6


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Figure 1: Typical TEM images of EDT-coated of (a) CoFe2 O4 , (b) MnFe2 O4 , and (c) NiFe2 O4 nanoparticles. The corresponding size histograms ((d)-(f)) are shown with log-normal fits (red lines). particle size distribution of EDT-coated CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles are shown in figures 1(d)-(f). The log-normal fits of the size histograms yielded the average diameters (h D i) with standard deviations (σ) as h D i = 17 ± 0.1 nm and σ = 0.10 for EDT-coated CoFe2 O4 , h D i = 20 ± 0.3 nm and σ = 0.20 for EDT-coated MnFe2 O4 and

h D i = 21 ± 0.3 nm and σ = 0.17 for EDT-coated NiFe2 O4 nanoparticles.

3.2

Heating Efficiency

The different ferrites heating suspended in both DI H2 O (a) and EG at the concentrations of 1 and 2 mg/mL are shown in figures 2(a)-(d), figures 3(a)-(d) and figures 4(a)-(d). As can be seen in these figures, the rate of temperature rise is initially high and then after a certain time it slows down and maintains the maximum achievable temperature which can be attributed to the thermal losses from the fluid to the environment occurs naturally due to the lower surrounding temperature. 40,41 The rapid temperature increase at the initial stage may be primarily due to Nèel and Brownian rotation (relaxation processes)

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50 kA/m

CoFe O , 2

80

(

C)

60

Temperature

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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25 kA/m

=195 kHz

4

15 kA/m

80

(b) 2 mg/mL

(a) 1 mg/mL

DI H O

DI H O

60

2

2

40 20 80 60

40 20 80

(d) 2 mg/mL

(c) 1 mg/mL

EG

EG

60

40 20

40 0

400

800

1200 0

400

800

1200

20

Time (s)

Figure 2: The change in temperature versus time as a function of the field of 15, 25 and 50 kA/m at 195 kHz for EDT-coated CoFe2 O4 nanoparticles dispersed in DI H2 O (panels a) 1 mg/mL and b) 2 mg/mL nanoparticle concentrations) and EG (panels c) 1 mg/mL and d) 2 mg/mL nanoparticle concentrations). Shaded band with gray color shows the desired temperature level for the efficient hyperthermia. 39 of each nanoparticle activated by the switching external field. Other possible contributions to the total heat generation during the relaxation processes are eddy current and hysteresis losses. The eddy current effects can be neglected, since the size of the CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles are very small. 42,43 Hysteresis losses (that are directly proportional to the area under the hysteresis loop) are prominent for multidomain and large single domain MNPs (larger than ∼ 80 nm) that are not superparamagnetic at room temperature. 44,45 The hysteresis measurements (figure 5) indicated that CoFe2 O4 nanoparticles exhibit weak hysteresis at room temperature while the MnFe2 O4 and NiFe2 O4 nanoparticles are essentially superparamagnetic. Keeping in mind the frequency of the AC field is in the 200 kHz regime, all the nanoparticle systems should be undergoing superparamagnetic Néel relaxation (discussed below). The negligible coercivity and remanence can be attributed to the particle size distributions. Thus, we can conclude that the partial H contribution to the measured total heat generation per unit volume, P = −µ0 f H dM

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50 kA/m

MnFe O , 2

80

C)

(

25 kA/m

=195 kHz

4

15 kA/m

(a) 1 mg/mL

(b) 2 mg/mL

DI H O

60

Temperature

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


DI H O

2

60

2

40 20 80 60

40 20 80

(d) 2 mg/mL

(c) 1 mg/mL

EG

EG

60

40 20

80

40 0

400

800

1200 0

400

800

1200

20

Time (s)

Figure 3: The change in temperature versus time as a function of the field of 15, 25 and 50 kA/m at 195 kHz for EDT-coated MnFe2 O4 nanoparticles dispersed in DI H2 O (panels a) 1 mg/mL and b) 2 mg/mL nanoparticle concentrations) and EG (panels c) 1 mg/mL and d) 2 mg/mL nanoparticle concentrations). Shaded band with gray color shows the desired temperature level for the efficient hyperthermia. 39 (where µ0 is the permeability of the free space, H is the strength of magnetic field and dM is the differential magnetization, 46 comes from the hysteresis losses for CoFe2 O4 nanoparticles. The heat generation results from the relaxation processes for MnFe2 O4 and NiFe2 O4 nanoparticles. 45 The physics of the heating of non-interacting superparamagnetic particles was reviewed by Rosensweig. 19 The response of the magnetization of a ferrofluid to an AC magnetic field can be described by, χ = χ0 + iχ00

(2)

where χ is the magnetic susceptibility of the particles, χ0 and χ00 are in-phase and out-ofphase component of χ, respectively. Both χ0 and χ00 are frequency dependent. The χ00 component results in heat generation given by P = −µ0 π f χ00 H 2 . 19 The heating is mainly achieved through Nèel and Brownian rotation for superparamagnetic nanoparticles. Heat dissipation which is caused by the delay in the relaxation of the 9



50 kA/m 2

80

Temperature

(

C)

60

25 kA/m

=195 kHz

NiFe O , 4

15 kA/m

(a) 1 mg/mL

(b) 2 mg/mL

DI H O

DI H O

2

20 80 60

40 20 80

(d) 2 mg/mL

(c) 1 mg/mL

EG

EG

60

40 20

80 60

2

40

40 0

800

400

1200 0

400

800

1200

20

Time (s)

Figure 4: The change in temperature versus time as a function of the field of 15, 25 and 50 kA/m at 195 kHz for EDT-coated NiFe2 O4 nanoparticles dispersed in DI H2 O (panels a) 1 mg/mL and b) 2 mg/mL nanoparticle concentrations) and EG (panels c) 1 mg/mL and d) 2 mg/mL nanoparticle concentrations). Shaded band with gray color shows the desired temperature level for the efficient hyperthermia. 39 75

CoFe O 2

4

MnFe O

50

2

4

NiFe O 2

4

25 T=300 K

0 50

-25

M (emu/g)

M (emu/g)

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-50

-50

-1.0

-75 -10

0

0.0

-0.5

0.5

1.0

H (kOe)

-5

0

5

10

H (kOe)

Figure 5: Hysteresis loops of OA-coated of CoFe2 O4 , MnFe2 O4 , and NiFe2 O4 nanoparticles at 300 K. Inset shows corresponding expanded plots. magnetic moment of nanoparticles through either the reorientation of the magnetization within the particle (Nèel rotation) and rotation of the particle itself (Brownian rotation,

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frictional losses). Both of the relaxation mechanisms are independent from each other and occur in parallel, resulting an effective relaxation time (τe f f ). The Nèel (τ N ), Brownian (τB ) and effective relaxation times of a particle can be expressed using following formulas, 47

τ N = τ0 exp (KVM /k B T )

(3)

τB = 3VH η/k B T

(4)

τe f f =

τ N τB τ N + τB

(5)

where τ0 ≈ 10−9 s is the attempt frequency, K is the anisotropy constant, VM is the volume of the particle, k B is the Boltzmann’s constant, T is the absolute temperature, VH is the hydrodynamic volume of particle, η is the viscosity of the carrier medium. The power dissipation rate corresponds to Nèel and Brownian relaxation accordance with the theoret 19 2 2 2 ical model as predicted by Rosensweig, P = (mHωτe f f ) /[2τe f f k B TρV 1 + ω τe f f ] (where m is the particle magnetic moment, ω is the angular frequency, ρ is the density of ferrite) under linear response regime (µ0 Ms V Hmax < k B T, where Ms is the saturation magnetization of the nanoparticles, Hmax is the maximum amplitude of the applied field). According to LRT (in the single domain state it can be properly applied only in the superparamagnetic regime), the SLP varies linearly with H 2 as mentioned above. It is worth mentioning that 1/τe f f is the time corresponding to the fastest process between the Nèel and Brownian relaxation. When 2π f τe f f 1 for fast relaxation, the losses increase with the f 2 and H 2 , i.e. the SLP∝ f 2 τe f f H 2 , while 2π f τe f f 1 for slow relaxation the losses approach a frequency independent saturation value, i.e. the SLP∝ H 2 /τe f f . The LRT fails with increasing particle size and the Stoner-Wohlfarth model can be applied when 2π f τe f f ≈ 1 as the transition from superparamagnetic to blocked regime when the condition µ0 Hmax > 2µ0 Hc is satisfied. 18 It can be clearly seen from the above equations that the relaxation time depends on the particle diameter. Furthermore, the environment that surrounds nanoparticles can impact the magnetic hyperthermia’s SLP, as indictated by the 11



viscocity (η) influencing the Brownian relaxation rates (see Eqn. 4).To examine the effect of different media viscosities we measured the SLP of the nanoparticles in two different media (DI H2 O η ∼ 1 mPa·s, and ethylene glycol η ∼ 20 mPa·s at room temperature) to reflect the potential impact to the SLP from nanoparticles inside cells where the matrix viscocity varies between mPa·s to 10s of mPa·s. 48 Using the value of K determined from the fit of the temperature dependence of the coercivity, 33 the superparamagnetic critical size (Dsp ) was estimated for CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles. Using the formula KVM = 25kT. 26 The particles were assumed spherical in shape for the calculation. The estimated superparamagnetic critical size for CoFe2 O4 , MnFe2 O4 and NiFe2 O4 were found to be ∼ 10, ∼ 37 and ∼ 30 nm, respectively. The average particle size of our nanoparticles is ∼ 20 nm that indicates the loss mechanisms are different for the CoFe2 O4 , and MnFe2 O4 and NiFe2 O4 nanoparticles. A complete set of SLP( H ) experimental data at a constant frequency is shown in figure 6. The variation of SLP for different magnetic fluids of CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles follows the same trend with H. In all cases, the SLP increases with the increase of H, as expected. 11 The maximum value of SLP has been found to be ∼ 315 W/g for CoFe2 O4 , and ∼ 295 W/g for MnFe2 O4 and NiFe2 O4 nanoparticles (shown in figure 7). The P, thus SLP will reach its maximum at a particular value of m and H value when ωτe f f = 1 according to Rosensweig’s theory. 19 By considering the SLP is only due to Nèel losses for superparamagnetic nanoparticles of MnFe2 O4 and NiFe2 O4 , the relaxation time will depend on K and VM for a particular composition (identified by Mössbauer spectroscopy 33 ). In our systems, the hydrodynamic size range 33 for the nanoparticles indicates a very small value of τB ≈ 10−8 s. Therefore, the contribution to losses due to the Brownian rotation can be neglected since the product of ω = 2π f and τB is very far apart from 1. In this case, the optimum particle size to maximize the SLP (Dmax ) could be estimated using ωτ N = 1 under the maximum power loss condition with the

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300

CoFe O

(a)

2

SLP (W/g)

4

CoFe O

250

2

4

MnFe O

200

2

4

MnFe O 2

4

150

NiFe O

100

NiFe O

2

2

50 300

4

4

1 mg/mL 195 kHz

0 (b)

250 SLP (W/g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


200 150 100 50 0 10

2 mg/mL 195 kHz

20

30

40

50

H (kA/m)

Figure 6: H dependence of SLP for EDT-coated of CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles at a constant frequency of 195 kHz at concentration of (a) 1 mg/mL, and (b) 2 mg/mL dispersed in DI H2 O (filled symbols) and EG (open symbols). known K for the nanoparticles. The value of Dmax was found to be ∼ 25 and ∼ 20 nm for superparamagnetic MnFe2 O4 and NiFe2 O4 nanoparticles, respectively. The average particle size estimated from XRD is ∼ 20 nm, equal to its optimum size to maximize the SLP for NiFe2 O4 . It is clear that the SLP of the MnFe2 O4 nanoparticles can be enhanced to a higher value by slightly increase the particle size to their optimum size to maximize the SLP. The relatively higher SLP value of CoFe2 O4 compared to MnFe2 O4 and NiFe2 O4 could be due to the appearance of hysteresis losses in the transition (from superparamagnetism to blocked) region and thus increasing contribution to the heating. Hysteresis losses dominate very rapidly over the Nèel relaxation losses when the particle size of CoFe2 O4

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SLP (W/g)

350

CoFe O

DI H O

2

2

4

300

MnFe O

250

NiFe O

2

2

4

4

200 150 100 50 0 300

I

I

EG

250 SLP (W/g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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200 150 100 50 0

I

I

1

2

Concentration (mg/mL)

Figure 7: The variation of SLP values of EDT-coated of CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles as a function of concentration and viscosity of carrier medium under field of 50 kA/m at 195 kHz. gets over superparamagmetic critical size (Dsp =10 nm for CoFe2 O4 ). The Dsp , the optimum particle size for maximum SLP value (Dmax ), the experimental particle size estimated from TEM images (Dexp ) and SLP values were summarized in Table 1 . The SLP is directly proportional to the slope of heating curve (according to equation 1), ∆T/dt, is located just above the basal temperature (23 ◦ C) which is a first hint for the heating efficiency. Obviously, higher temperature rises were exhibited by all the nanoparticles at the larger field amplitude of 50 kA/m. By considering ∆T = T − Ti , the variation of the largest temperature rise at the end of heating period (t = 1200 s), ∆Tmax , was obtained

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Table 1: Magnetocrystalline anisotropy constant (K), the superparamagnetic critical size (Dsp ), the optimum particle size for maximum SLP value (Dmax ), the experimental particle size estimated from TEM images (Dexp ) and SLP values of CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles. Ferrite CoFe2 O4 MnFe2 O4 NiFe2 O4

a

K (×106 ) Dsp 3 (ergs/cm ) (nm) 2.96 10 0.04 37 0.07 30

Dmax (nm) 25 20

Dexp SLP (nm) (W/g) 20 315 20 295 20 295

a

K; 33 Considered value of ω ≈ 1.23 × 106 s−1 for f = 195 kHz; Dmax was estimated for superparamagnetic nanoparticles (MnFe2 O4 and NiFe2 O4 ) under maximum loss power condition of ωτ N = 1 between ∼ 1 and 50 ± 0.1◦ C, ∼ 11 and 58 ± 0.1◦ C and 9 and 40 ± 0.1◦ C for CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles, respectively when the amplitude of the applied field vary between 15 and 50 kA/m. The room temperature (initial temperature, Ti ) was kept constant at 23 ◦ C during the experiments. These results indicated that the desired temperature increases were exhibited for all nanoparticles. MNP colloids should at least lead to a rise 4 ◦ C, a much larger rise guarantees their heating efficiency also in subsequent vitro and vivo experiments. 49 A negligibly small slope suggests that CoFe2 O4 nanoparticles can hardly heat in a field of 15 kA/m. The CoFe2 O4 nanoparticles at concentration of 2 mg/mL in DI H2 O have a high heating rate under applied field of 50 kA/m indicates that these system easily reach a temperature of ∼ 70◦ C (above the desired temperature range of 40-44 ◦ C where the cancer cells are more susceptible to heat than healthy ones 43 for efficient hyperthermia) just within 600 s. The same temperature was achieved for the MnFe2 O4 nanoparticles within the same time at the same concentration but in more viscous solvent (EG). The maximum achievable temperature is below ∼ 70◦ C for NiFe2 O4 nanoparticles for all cases. The desired hyperthermia temperature was achieved within a much shorter time (120 s for CoFe2 O4 and MnFe2 O4 and 180 s for NiFe2 O4 nanoparticles) as compared to less 15



concentrated samples of 1 mg/mL for all nanoparticles (420, 180 and 300 s for CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles, respectively). The short exposure time of the applied magnetic field to reach the desired hyperthermia temperature range indicates all ferrite based magnetic fluids in this study are promising for efficient magnetic hyperthermia application. Desired hyperthermia temperatures (44, 46 and 52 ◦ C) were attained within 10 min at a higher (compared to our samples) concentration (1.25 g/L) of cobalt ferrite based ferrofluid with nanoparticles of size 20, 17 and 12 nm, respectively (under an AMF of strength 18.4 kA/m at 275 kHz). 50 Makridis et al. 37 observed that the begining of the hyperthermia region for larger 26 nm MnFe2 O4 nanoparticles was achieved under the field values of ≥ 200 Oe (∼ 16 kA/m) during a measurement window of 600 s (at concentration of 0.25 and 0.5 mg/mL). The exposure time is usually 30 minutes for miligram amounts of MNPs in in-vivo experiments. 51

3.2.1 Effect of viscosity In order to assess the influence of viscosity of the carrier medium on heating efficiency of the systems, the hyperthermia measurements were made for the CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles which were suspended in media with different viscosities (∼10 difference in η between DI H2 O and EG). We found that the SLP decreased when the viscosity of the carrier medium increased. In general, the reduction of SLP is due to the inability of heat generation though the particle rotation (the Brownian relaxation time is increased (rate reduced) as described by Eqn. 4 where τB ∝ η, or stopped) which is suppressed in viscous medium. The SLP of magnetic fluids depends on the suspending fluid viscosity as shown by Phong et al. 15 Since the cell matrix viscosity varies between mPa·s to 10s of mPa·s 48 the MnFe2 O4 nanoparticles would be the nanoparticle agents of choice for biomedicial applications, as shown in Figs. 6 and 7. It can be noted that in a medium of higher viscosity, like inter-cellular environment, the heating efficiency of the nanoparticles can decrease to a large extent. 52 Consequently, for 16


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in situ hyperthermia applications, magnetic nanoparticles of higher concentration should be selected and the treatment time needs to be prolonged to compensate for the heat loss. Two other reported strategies involve (i) aminosilane coating of the nanoparticles to prevent cellular internalization, 52,53 and (ii) functionalization of the nanoparticles to target membrane receptors. 52,54–56 In both cases, hyperthermic heating of the affected cells can still be achieved locally.

3.2.2 Effect of concentration The increase of particle concentration causes a significant increase of SLP for the CoFe2 O4 nanoparticles (from ∼ 167 W/g to ∼ 315 W/g) and a decrease for MnFe2 O4 (from ∼ 295 W/g to ∼ 209 W/g) and NiFe2 O4 (from ∼ 295 W/g to ∼ 188 W/g) nanoparticles when DI H2 O was used as carrier medium. The opposite trend (decrease in SLP as concentration increases) has been observed for all the nanoparticles when EG was used as carrier medium. In particular, the MNPs can coalesce at high concentrations which leads to spontaneous formation of clusters (hinted perhaps at in the TEM images for our nanoparticles) which leads to a reduction of the heating efficiency. 57 When the particles become more concentrated the inter-particle interactions such as dipole-dipole interactions increase which resulted in an increase (interactions increase TB which leads to hysteresis at a lower temperature) in hysteresis losses and decrease of the susceptibility leading to the decrease of SLP value. 58–60 The enhancement of dipolar interaction with increasing particle concentration lowers the energy barrier resulting strong effect on Nèel relaxation mechanism. 61 On the other hand, an increase in heating efficiency of magnetosomes which are in the form of chains of nanoparticles was reported. 62 All these studies show that the particle size and size distribution, geometry of clusters or chain size all contribute significantly to SLP, and the influence of the concentration of nanoparticles on magnetic heating efficiency is still poorly understood. The increase of SLP with the increasing of concentration for CoFe2 O4 (unlike the 17



MnFe2 O4 and NiFe2 O4 nanoparticles) indicates that the presence of lower optimum sample concentrations for CoFe2 O4 nanoparticles, which in turn directly affects the energy releasing efficiency per magnetization flip during the AC field oscillation, as explained by Lahiri et al. 63 It is also known from the previous studies 58,64 that the variation of hysteresis area as a function of concentration (initially increases and reaches a maximum, and then decreases) which indicates an optimum sample concentration for the highest SLP.

3.3

Comparison of heating efficiencies

To allow a comparison of the particle intrinsic properties which are independent of the external characteristics of the applied alternating magnetic field amplitude and frequency, one examines the intrinsic loss power (ILP); the SLP normalized with respect to the product of square of the amplitude of applied magnetic field and frequency: 65 ILP = SLP/H 2 f , a parameter that indicates the efficiency of the converted electromagnetic energy to heat energy. The variation of the ILP for different concentration of 1 and 2 mg/mL in DI H2 O and EG is given in figures 8(a)-(c) with a delimiter that signifies the biological safety limit of H · f . We obtained ILP values between ∼ 0.1-1.0 nHm2 kg−1 , ∼ 0.4-2.0 nHm2 kg−1 and

∼ 0.2-3.0 nHm2 kg−1 for CoFe2 O4 , MnFe2 O4 and NiFe2 O4 nanoparticles at different cases (at concentrations of 1 and 2 mg/mL and in DI H2 O and EG), respectively. Our values are comparable with the ILP values for commercial ferro-fluids are previously reported to be in the range of 0.2-3.1 nHm2 kg−1 . 66 The biological condition is such that H · f is below the safety limit (shown by black line in figures 8(a)-(c)) in majority of the cases, indicates our ferrite nanoparticles are suitable to adapt for hyperthermia application. Our values of amplitude (50, 25 and 15 kA/m) and frequency (195 kHz) lead to considerably high product H · f which is a parameter that is given with the limit of H · f < 4.85 × 108 Am−1 s−1 for the biological safety of the application of magnetic hyperthermia in human body by Brezovich et al. 67 But it was suggested that the given limit for the biological discomfort might be exceeded by a factor 10 by considering the relationship between the exposed area 18


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CoFe O 2

4

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1mg/mL, DI H O 2

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2mg/mL, DI H O

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-1 2

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H f (x10 )

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2.0 1.5 1.0 0.5 0.0 3

4

5

6

Hf

7

8

9

10

9

(x10 )

Figure 8: The variation of ILP as a function of the product of the applied field amplitude and frequency, H · f , for EDT-coated of (a) CoFe2 O4 , (b) MnFe2 O4 , and (c) NiFe2 O4 nanoparticles at concentration of 1 and 2 mg/mL and dispersed in DI H2 O and EG. The vertical lines indicates the limit for the biological safety (H · f < 4.85 × 109 Am−1 s−1 ) considering the relationship between the exposed area and the absorbed power with the coil.

19



and absorbed power with a smaller coil, typically ∼ 10 cm in diameter. 68 This suggested criterion with the value of H · f < 4.85 × 109 Am−1 s−1 may be acceptable in our study considering a very small solenoid coil of 4 cm in diameter was used.

4 Conclusion The different types of EDT-coated ferrites (CoFe2 O4 , MnFe2 O4 and NiFe2 O4 ) based magnetic nano-fluids have been successfully prepared in this study. Their heating efficiency have been determined using the temperature versus time measurements under different conditions. The hyperthermia measurements indicated that it is more easy to achieve to entrance in hyperthermia region under lower applied field of 25 and 15 kA/m for MnFe2 O4 and NiFe2 O4 compared to CoFe2 O4 nanoparticles. A very poor heating performance under low field of 15 and 25 kA/m has been observed for CoFe2 O4 under same experimental conditions. The desired temperature range for magnetic hyperthermia was achieved within a much shorter time (120 s for CoFe2 O4 in DI H2 O at 2 mg/mL and MnFe2 O4 in EG at 2 mg/mL and 180 s for NiFe2 O4 in DI H2 O at 2 mg/mL nanoparticles) as compared to less concentrated samples of 1 mg/mL for all nanoparticles (420, 180 and 300 s for CoFe2 O4 in EG at 1 mg/mL, MnFe2 O4 in EG at 1 mg/mL and NiFe2 O4 in DI H2 O at 1 mg/mL nanoparticles, respectively). The maximum value of SLP has been found to be ∼ 315 W/g for CoFe2 O4 (2 mg/mL) and ∼ 295 W/g for MnFe2 O4 (1 mg/mL) and NiFe2 O4 (1 mg/mL) based magnetic nano-fluids under similar ambient conditions. Under the suggested criterion that limit the value of H · f to < 4.85 × 109 Am−1 s−1 , the biological condition for our nano-fluids is below the safety limit in the majority of cases, and indicates that our ferrite nanoparticles are very suitable for adaption to efficient and effective magnetic hyperthermia applications. However, in-vivo biocompatibility and toxicity studies are still required prior to their use, and are in progress, currently.

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Acknowledgments ˙ The authors thank the Scientific and Technological Research Council of Turkey (TÜBITAK) and Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN2018-0501). This paper has been granted by the Mugla ˘ Sıtkı Koçman University Scientific Research Project Coordination through Project Grant Number: (14/066).

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Generation of Iron-Oxide Nanoparticles for Magnetic Hyperthermia Applications. Scientific reports 2013, 3, 1652. (58) Serantes, D.; Baldomir, D.; Martinez-Boubeta, C.; Simeonidis, K.; Angelakeris, M.; Natividad, E.; Castro, M.; Mediano, A.; Chen, D.-X.; Sanchez, A.; Balcells, L.; Martinez, B. Influence of Dipolar Interactions on Hyperthermia Properties of Ferromagnetic Particles. Journal of Applied Physics 2010, 108, 073918. (59) Salas, G.; Camarero, J.; Cabrera, D.; Takacs, H.; Varela, M.; Ludwig, R.; DaÌ´Lhring, H.; Hilger, I.; Miranda, R.; Morales, M. d. P.; Teran, F. J. Modulation of Magnetic Heating via Dipolar Magnetic Interactions in Monodisperse and Crystalline Iron Oxide Nanoparticles. The Journal of Physical Chemistry C 2014, 118, 19985–19994. (60) Fu, R.; Yan, Y.; Roberts, C. Study of the Effect of Dipole Interactions on Hyperthermia Heating the Cluster Composed of Superparamagnetic Nanoparticles. AIP Advances 2015, 5, 127232. (61) Abbasi, A. Z.; Gutiérrez, L.; del Mercato, L. L.; Herranz, F.; Chubykalo-Fesenko, O.; Veintemillas-Verdaguer, S.; Parak, W. J.; Morales, M. P.; González, J. M.; Hernando, A.; de la Presa, P. Magnetic Capsules for NMR Imaging: Effect of Magnetic Nanoparticles Spatial Distribution and Aggregation. The Journal of Physical Chemistry C 2011, 115, 6257–6264. (62) Hergt, R.; Hiergeist, R.; Zeisberger, M.; Schüler, D.; Heyen, U.; Hilger, I.; Kaiser, W. A. Magnetic Properties of Bacterial Magnetosomes as Potential Diagnostic and Therapeutic Tools. Journal of Magnetism and Magnetic Materials 2005, 293, 80–86. (63) Lahiri, B.; Muthukumaran, T.; Philip, J. Magnetic Hyperthermia in Phosphate Coated Iron Oxide Nanofluids. Journal of Magnetism and Magnetic Materials 2016, 407, 101–113. (64) Haase, C.; Nowak, U. Role of Dipole-Dipole Interactions for Hyperthermia Heating of Magnetic Nanoparticle Ensembles. Physical Review B 2012, 85, 045435. 29



(65) Kallumadil, M.; Tada, M.; Nakagawa, T.; Abe, M.; Southern, P.; Pankhurst, Q. A. Suitability of Commercial Colloids for Magnetic Hyperthermia. Journal of Magnetism and Magnetic Materials 2009, 321, 1509–1513. (66) Arteaga-Cardona, F.; Rojas-Rojas, K.; Costo, R.; Mendez-Rojas, M.; Hernando, A.; De La Presa, P. Improving the Magnetic Heating by Disaggregating Nanoparticles. Journal of Alloys and Compounds 2016, 663, 636–644. (67) Brezovich, I. A. Low Frequency Hyperthermia: Capacitive and Ferromagnetic Thermoseed Methods. Medical Physics Monograph 1988, 16, 82–111. (68) Hergt, R.; Dutz, S.; Müller, R.; Zeisberger, M. Magnetic Particle Hyperthermia: Nanoparticle Magnetism and Materials Development for Cancer Therapy. Journal of Physics: Condensed Matter 2006, 18, S2919.

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ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26


Page 32 of 41

Page 33 of 41

CoFe O , 2

80

(

C)

60

Temperature

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

50 kA/m

ACS Applied Materials & Interfaces 4

(a) 1 mg/mL

25 kA/m

=195 kHz

15 kA/m

80

(b) 2 mg/mL DI H O

DI H O

60

2

2

40

40

20 80

20 80

60

(c) 1 mg/mL

(d) 2 mg/mL EG

EG

60

40

40

20

20

0

400

800 ACS Paragon1200 0 Plus Environment Time (s)

400

800

1200

50 kA/m Page 34 of 41


80

C)

(

4

(a) 1 mg/mL DI H O

60

Temperature

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

MnFe O ,

25 kA/m

=195 kHz

15 kA/m

(b) 2 mg/mL DI H O

2

80 60

2

40

40

20 80

20 80

60

(c) 1 mg/mL

(d) 2 mg/mL EG

EG

60

40

40

20

20

0

400


400

800

1200

Page 35 of 41

NiFe O , 2

80

(

C)

60

Temperature

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

50 kA/m


(a) 1 mg/mL DI H O

25 kA/m

=195 kHz

15 kA/m

(b) 2 mg/mL DI H O

2

80 60

2

40

40

20 80

20 80

60

(c) 1 mg/mL

(d) 2 mg/mL EG

EG

60

40

40

20

20

0

400


400

800

1200


CoFe O 2

4

MnFe O

50

2

4

NiFe O 2

4

25 T=300 K

0 50

-25

M (emu/g)

M (emu/g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

75

Page 36 of 41

-50

0

-50

-1.0

-75 -10

-0.5

0.0

0.5

1.0

H (kOe)

-5

0 ACS Paragon Plus Environment

H (kOe)

5

10

Page 37 of 41

300

SLP (W/g)

SLP (W/g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

CoFe O


(a)

2

CoFe O

250

2

2

4

MnFe O 2

150

4

NiFe O 2

100

4

NiFe O 2

50

1 mg/mL 195 kHz

0 (b)

250 200 150 100 50 0 10

4

MnFe O

200

300

4

2 mg/mL 195 kHz

20

30

40


H (kA/m)

50

4

350

SLP (W/g)

SLP (W/g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37


DI H O

Page 38 ofO 41 CoFe 2

2

4

300

MnFe O

250

NiFe O

2

2

200 150 100 50 3000

I

I

EG

250 200 150 100 50 0

I

I

1

2


Concentration (mg/mL)

4

4

Page 39 of 41

2


4

3.5 (a)

1mg/mL, DI H O 2

3.0

2mg/mL, DI H O

ILP (nHm kg )

2

2

-1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

CoFe O

2.5


2.0 1.5 1.0 0.5 0.0 3

4

5

6

Hf


7

8 9

(x10 )

9

10

MnFe O 2

3.5

1mg/mL, DI H O 2

ILP (nHm kg )

3.0

2

Page 40 of 41

4

(b)

-1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43


2mg/mL, DI H O 2

2.5


2.0 1.5 1.0 0.5 0.0 3

4

5

6


7

8 9

H f (x10 )

9

10

Page 41 of 41

2

4

3.5 (c)

1mg/mL, DI H O 2

ILP (nHm kg )

3.0

2mg/mL, DI H O 2

1mg/mL, EG

2.5

2mg/mL, EG

2

-1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

NiFe O


2.0 1.5 1.0 0.5 0.0 3

4

5

6

Hf


7

8 9

(x10 )

9

10

Comparative Heating Efficiency of Cobalt-, Manganese-, and Nickel

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