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Magnetic heating of silica-coated manganese ferrite nanoparticles
Journal of Magnetism and Magnetic Materials 409 (2016) 80–86
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Journal of Magnetism and Magnetic Materials journal homepage: www.elsevier.com/locate/jmmm
Magnetic heating of silica-coated manganese ferrite nanoparticles Yousaf Iqbal a, Hongsub Bae a, Ilsu Rhee a,n, Sungwook Hong b a b
Department of Physics, Kyungpook National University, Daegu 702-701, Republic of Korea Division of Science Education, Daegu University, Gyeongsan 712-714, Republic of Korea
art ic l e i nf o
a b s t r a c t
Article history: Received 20 November 2015 Received in revised form 8 February 2016 Accepted 23 February 2016 Available online 24 February 2016
Manganese ferrite nanoparticles were synthesized using the reverse micelle method; these particles were then coated with silica. The silica-coated nanoparticles were spherical in shape, with an average diameter of 14 nm. The inverse spinel crystalline structure was observed through X-ray diffraction patterns. The coating status of silica on the surface of the nanoparticles was confirmed with a Fourier transform infrared spectrometer. The superparamagnetic properties were revealed by the zero coercive force in the hysteresis curve. Controllable heating at a fixed temperature of 42 °C was achieved by changing either the concentration of nanoparticles in the aqueous solution or the intensity of the alternating magnetic field. We found that at a fixed field strength of 5.5 kA/m, the 2.6 mg/ml sample showed a saturation temperature of 42 °C for magnetic hyperthermia. On the other hand, at a fixed concentration of 3.6 mg/ml, a field intensity of 4.57 kA/m satisfied the required temperature of 42 °C. & 2016 Elsevier B.V. All rights reserved.
Keywords: Magnetic heating Manganese ferrite nanoparticles Silica coating Magnetic hyperthermia
1. Introduction Magnetic nanoparticles have been widely researched for possible application in medical uses such as contrast agents in magnetic resonance imaging [1–5], magnetic hyperthermia [6,7], and nano drug delivery system [8–13]. In particular, ferrite nanoparticles have attracted great attention because of their easy synthesis, high chemical stability, and high saturation magnetization. They have the chemical structure of MFe2O4, where M represents the divalent metal ions of Mn2 þ , Fe2 þ , Co2 þ , Ni2 þ , etc. The ferrites have a cubic inverse spinel structure in which 32 O2 ions constitute a facecentered cubic structure, eight Fe3 þ ions are located at the center of eight tetrahedral sites, and eight M þ and Fe3 þ ions are located at the center of 16 octahedral sites. The magnetic moment of the Fe3 þ ions on the octahedral sites is antiparallel to that of the Fe3 þ ions on the tetrahedral sites. Thus, the magnetic moment of the ferrites is due to the magnetic moment of M2 þ . The magnetic moment of M2 þ comes from its unpaired 4d electrons, resulting in 5, 4, 3, and 2 μB for the Mn-, Fe-, Co-, and Ni-ferrites, respectively. These theoretical values of the magnetic moment are close to the experimental values of 4.6, 4.1, 3.7, and 2.3 μB, respectively [13]. Ferrite nanoparticles are toxic, thus surface modification is needed in order to apply them to the human body. This surface modification is also required for labeling various chemicals for drugs, targeting ligands, etc. on their surfaces. Various biocompatible n
Corresponding author. E-mail address: [email protected] (I. Rhee).
http://dx.doi.org/10.1016/j.jmmm.2016.02.078 0304-8853/& 2016 Elsevier B.V. All rights reserved.
materials are used to achieve this surface modification, and include silica, polyethylene glycol (PEG), chitosan, dextran, carbon, gold, oleic acid, titania, etc. [1–3,14–18]. Titania and silica are nontoxic oxides of titanium and silicon, respectively. Titania coating is useful for photocatalytic activities and hydrolysis [18–20]. Silica coating plays a vital role in preventing magnetic nanoparticle agglomeration, and providing a suitable surface for drug loading [21] and chemical inertness in biological systems [22]. The Food and Drug Administration confirmed that silica coating is safe for use in human body [23]. Hyperthermia is a cancer treatment that exploits the fact that cancer tissues are killed if they are exposed to 42 °C for half an hour [24,25]. The blood vessels of cancer cells are not complete, so excess heat is not effectively released through blood flow. External hyperthermia uses an external heat source that is concentrated on the cancer cells. On the other hand, internal hyperthermia injects the heat source directly into the site of the cancer tissue. With the magnetic hyperthermia method, magnetic nanoparticles are injected into the cancer site. Then, these magnetic nanoparticles generate heat in the presence of an external magnetic field to raise the temperature of the cancer site to 42 °C. Intensive research on magnetic hyperthermia using magnetic nanoparticles, especially iron oxide nanoparticles, has been performed. Various basic studies and animal experiments for magnetic hyperthermia are currently under way. However, no clinical application has been reported yet. In this study, manganese ferrite (MnFe2O4) nanoparticles were prepared for use in magnetic hyperthermia. The particles were coated with silica for biocompatibility. The superparamagnetic
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properties of magnetic nanoparticles are required in biomedical applications, since they exhibit their magnetic properties only in the presence of an external magnetic field. The particle size necessary for this superparamagnetic behavior is a few tens of nanometers in diameter. The applicability of nanoparticles to hyperthermia treatments can be tested by checking the heating effects of nanoparticles in an alternating magnetic field. The other requirement for hyperthermia applications is the ability to control the temperature of the nanoparticles to 42 °C. The malignant tissues are killed in an environment of 42 °C for half an hour, but temperatures higher than 46 °C burn the normal surrounding tissues. Thus, controlling the temperature to 42 °C is essential for hyperthermia treatments. In this paper, we report the heating effects of manganese ferrite nanoparticles in an alternating magnetic field. The concentration and field dependence of the heating effects will be presented.
2. Experimental method We fabricated manganese ferrite nanoparticles by precipitating them in a water-in-oil nanoreactor. This reverse micelle method has been used for the synthesis of monodispersed and controlledsize nanoparticles [26]. In this method, co-precipitation of manganese ferrite nanoparticles occurs inside the nano-sized water droplets that are enclosed by a surfactant and distributed in the oil phase. Those encapsulated water droplets that are distributed in the oil phase act like mini-reactors, or so-called reverse micelles. The size of the mini-reactors depends on the molar ratio of water to surfactant. The application of the silica coating on the surface of the nanoparticles was performed simultaneously with the synthesis of the manganese ferrite nanoparticles. In brief, the water-in-oil system was obtained by mixing two different solutions by mechanical stirring at 500 rpm. The two solutions were a transparent solution of 3.5 g sodium dodecylbenzenesulfonate (NaDBS) dissolved into 30 ml xylene (isomers plus ethyl benzene, 98.5%), and a 1.8 ml aqueous solution containing stoichiometric amounts of MnCl2–4H2O and iron (III) nitrate nanohydrate (Fe (NO3)3–9H2O, 98%). The transparent solution became a milky whitish color upon the addition of the aqueous solution. The resultant water-in-oil system was continuously stirred for about 16 h, followed by an additional 1 h of stirring under nitrogen protection. After stirring, the system was heated to 90 °C at the rate of 2 °C/min, and 1 ml hydrazine (34 wt-% water solution) was added. The addition of the hydrazine caused a change in color (from dark brown to black). The resultant system was kept at 90 °C for 3 h, and then cooled down to 40 °C in about 1.5 h. During this process, manganese ferrite nanoparticles were formed inside the mini-reactors of the reverse micelle (water-inoil) system. The coating of the ferrite nanoparticles with silica was performed by adding 4 ml of tetraethyl orthosilicate (TEOS) into the manganese ferrite nanoparticle solution at 40 °C and stirring for about 6 h at 500 rpm. The silica shells were formed on the surface of the manganese ferrite nanoparticles by the hydrolysis of the TEOS inside the encapsulated water droplet by the micelles. The silica-coated manganese ferrite nanoparticles were separated from the oil phase using acetone and subsequent centrifugations at 13,000 rpm. The particles were dried at ambient temperature for 8 h to obtain a powder sample. The powder samples were dispersed in water for characterization. An aqueous solution of the manganese ferrite nanoparticles was prepared to observe the heating effect of the magnetic nanoparticles in an alternating magnetic field. A 20 mg powder sample of the silica-coated manganese ferrite nanoparticles was dispersed in 50 ml of deionized water with ultrasonication for
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20 min. The resultant dispersion was observed to be highly stable for months. This dispersion of the manganese ferrite nanoparticles was very dilute. A concentrated sample was obtained by keeping the diluted sample in the vacuum oven at 40 °C for about 5 days. The amounts of manganese and iron in the aqueous solution were measured by using an inductively coupled plasma (ICP) technique. Five more samples were prepared by diluting the sample to 75%, 62.5%, 50%, 37.5%, and 25% for measuring the concentration dependence of the magnetic heating effect. The morphology and particle size distribution of the manganese ferrite nanoparticles were analyzed using a transmission electron microscope (TEM; H-7600, Hitachi Ltd.). The crystal structure of the bare and silica-coated manganese ferrite nanoparticles was investigated using X-ray diffraction (XRD; X'pert PRO, PANalytical). The chemical composition and concentration of the nanoparticles in the aqueous solution were measured using ICP spectrometry (Thermo Jarrell Ash IRISAP). The bonding of silica to the surface of the nanoparticles was confirmed using Fourier transform infrared spectroscopy (FTIR; Nicolet 380, Thermo Scientific USA). The magnetic measurements were carried out using a vibrating sample magnetometer (VSM; MPMS, Quantum Design). The magnetic heating effects of the nanoparticles dispersed in water were measured using an induction heating system (OSH120-B, Osung High Tech) under an alternating magnetic field at 260 kHz. The temperature of the solution was measured with a CALEX infrared thermometer (PyroUSB CF, Calex Electronics Limited).
3. Results and discussions Fig. 1-a shows a TEM image of the silica-coated manganese ferrite nanoparticles. The particle size distribution is given in Fig. 1-b, which shows the histogram of the diameter of 100 nanoparticles obtained from the TEM image. The average diameter of the coated nanoparticles is 14 nm, with a margin of 0.1 nm. The XRD patterns of the bare and silica-coated manganese ferrite nanoparticles are shown in Fig. 2. The peaks at 30.19°, 35.50°, 43.22°, 53.6°, 57.09°, and 62.6° correspond to the crystal planes of (220), (311), (400), (422), (511), and (440), respectively, matching those observed in inverse spinel ferrite [27,28]. The extra peak at around 22° to 26° for the coated particles arises from amorphous SiO2 adsorbed on the surface of the nanoparticles [29]. The lattice constant “a” was calculated to be 8.3 Å, using the (440) peak. The differences in peak angles between the bare and the silica-coated nanoparticles are negligible. The bonding of the silica to the surface of the manganese ferrite nanoparticles was checked by FTIR in the range of 400 to 4000 cm 1, as shown in Fig. 3. The absorption band at 3430 cm 1 in the figure corresponds to the stretching mode of the O–H group, while the band at 1627 cm 1 represents the vibration mode of the O–H group present at the surface of the samples [30,31]. In addition, the absorption band at 1100 cm 1 on the spectra is the characteristic peak of the anti-symmetric stretching vibrational mode of the Si–O–Si siloxane bridges. The absorption at 957 cm 1 is due to the contribution from the Si–O–H stretching vibration [32], while the band at 802 cm 1 is due to the SiO4 ring vibration [33]. The faint band at 625 cm 1 corresponds to the Fe–O stretching in the Fe–O–Si bonding [34]. In summary, the FTIR spectra confirm the bonding of the silica to the surface of the manganese ferrite nanoparticles. Fig. 4 shows the hysteresis curve of the silica-coated manganese ferrite nanoparticles at room temperature. In the inset of this figure, zero remanence and coercivity are apparent, indicating that the nanoparticles exhibit superparamagnetic properties at room temperature.
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Fig. 1. (a) TEM image of silica-coated manganese ferrite nanoparticles and (b) size distribution of nanoparticles.
Fig. 2. XRD patterns of powder samples of (a) bare manganese ferrite nanoparticles and (b) silica-coated manganese ferrite nanoparticles. The indices of the crystal plane in the figure match those of an inverse cubic spinel structure.
Fig. 3. FTIR spectra of silica-coated manganese ferrite nanoparticles.
Fig. 4. Hysteresis curve of silica-coated manganese ferrite nanoparticles at room temperature.
The amounts of manganese and iron in the concentrated aqueous solution were measured using ICP spectrometry to be 1188 and 2322 mg/L, respectively. The atomic ratio of iron to manganese is 1.95, which is approximately consistent with the chemical formula of MnFe2O4. Five more samples were prepared by diluting the concentrated sample to 75%, 62.5%, 50%, 37.5%, and 25%. The concentration of the nanoparticles in the concentrated sample was 3.5 mg/ml. Thus, the concentrations of the nanoparticles in the diluted samples were 2.6, 2.2, 1.7, 1.3, and 0.9 mg/ml, respectively. A schematic of the induction heating system used to observe the magnetic heating effect is shown in Fig. 5. The aqueous sample of nanoparticles is placed in the RF coil with a resonant frequency of 260 kHz. Field strengths of 2.3, 3.9, and 5.5 kA/m were used to observe the field strength dependence of the magnetic heating effect. The infrared (IR) thermometer located at 10 cm above the sample was used to measure the temperature of the sample. When a magnetic system is subjected to an alternating magnetic field, heat is generated owing to loss mechanisms, which can be classified as hysteresis and relaxation loss [13]. The latter can be further divided into Néel and Brown losses. Since our superparamagnetic nanoparticles show no hysteresis (see Fig. 4), we can neglect the hysteresis losses. The ferromagnetic resonance loss can also be ignored in the present study, because it occurs only in the
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Fig. 5. Induction heating system for testing the heating effect of manganese ferrite nanoparticles dispersed in an aqueous solution.
GHz frequency range, which is much higher than the 200–300 kHz used in this study. Thus, the remaining heating mechanisms for our nanoparticles are the Néel and the Brown losses. The background heating effects due to the pure water and sample container were estimated. We observed that the effect of these backgrounds was negligible. A 1 ml aqueous sample in a thermally insulated container was placed in the alternating magnetic field. The rises in temperature as a function of heating time for six samples at different concentrations of the manganese ferrite nanoparticles are shown in Fig. 6. The magnetic field intensity was fixed at 5.5 kA/m with a frequency of 260 kHz. We can see in this figure that the temperature increase for the concentrated sample is faster than that for the diluted samples. This concentration dependence of the temperature rise is as expected, since more heat generators (i.e., nanoparticles) are present in the concentrated sample. It is also observed that the temperature of all samples reached their saturation temperature after about 1000 s. At that time, the heat generation is balanced by heat loss. The saturation temperatures for the 3.5, 2.6, 2.2, 1.7, 1.3, and 0.9 mg/ml samples were 48, 42, 41, 39.5, and 35.5 °C, respectively. For magnetic hyperthermia, the temperature should be maintained at 42 °C for 30 min to kill the malignant tissues. However, the temperature should also be sustained below 46 °C, so as not to affect the normal tissues. The 2.6 mg/ml sample satisfies this condition. The heat generated by magnetic nanoparticles in an alternating magnetic field increases the temperature of constituents in the sample. The relationship between heat and temperature increase is given by:
∆Q = mW cW ∆T +msi csi ∆T +mMn cMn ∆T +mFe cFe ∆T.
Fig. 6. Temperature rise as a function of heating time for the 3.5-, 2.6-, 2.2-, 1.7-, 1.3-, and 0.9-mg/ml samples.
(1)
Here, ∆T is the temperature of the sample, and cW, csi, cMn , and cFe are the specific heats of water, silica, manganese, and iron, respectively. In addition, mW , msi , mMn , and mFe are the masses of water (1 ml), silica, manganese, and iron, respectively. The specific absorption rate (SAR) is defined as the dissipation heat generated per unit mass of magnetic nanoparticle. This is given as [35,36]: ∆Q /∆T ∆T /∆t = [ mW cW+mSi cSi+mMn cMn+mFe cFe ] mMn + mFe mMn + mFe mW cW ⎛ ∆T ⎞ ≅ ⎜ ⎟. mMn + mFe ⎝ ∆t ⎠
SAR =
Here,
ΔT Δt
(2)
is the initial rate of temperature increase. In the last step
of Eq. (2), we used the facts that the mass of water (1 g) in the sample is much larger than that of other constituents (about 30 mg), and that the specific heat of water ( cW = 4.2J/g °C ) is also csi = 0.7J/g °C larger than that of the others, which is cMn = 0. 49 J/g °C , and cFe = 0. 45J/g °C , respectively. Thus, the heat required to increase the temperature of the coated nanoparticles is much less than that needed for water in the sample. The SARs for the 3.5, 2.6, 2.2, 1.7, 1.3, and 0.9 mg/ml samples were 47.84, 53.45, 55, 58.8, 67.62, and 84.65 W/g, respectively. The
Fig. 7. Concentration dependence of initial rate of temperature rise and saturation temperature for manganese ferrite nanoparticles.
decrease in SAR with increasing particle concentration is due to the increase in the dipolar magnetic moment according to the increase in particle concentration, which affects the Néel relaxation time. The initial rate of temperature rise and saturation temperature for different concentrations is shown in Fig. 7, while the concentration dependency of the SAR is shown in Fig. 8. The saturation temperature of the 3.5 mg/ml sample was larger than 42 °C, the required temperature for magnetic hyperthermia. On the other hand, the other samples, except the 2.6 mg/ml sample, did not reach the temperature of 42 °C. In magnetic
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Fig. 8. Concentration dependence of specific absorption rate (SAR) for manganese ferrite nanoparticles.
hyperthermia, the temperature should be maintained at 42 °C. Owing to this temperature regulation, the normal tissues are prevented from burning. We already knew from Fig. 6 that for a fixed magnetic field strength, the saturation temperature can be controlled by changing the concentration of nanoparticles in the sample. Moreover, we can also control the saturation temperature of the sample with a certain concentration of nanoparticles by changing the magnetic field strength. If a smaller field strength is used for the 3.5 mg/ml sample, the saturation temperature will decrease down to 42 °C. On the other hand, the saturation temperatures of the other samples, except the 2.6 mg/ml sample, can be regulated to 42 °C with a higher field strength. One example of this is shown in Fig. 9. This figure shows that the saturation temperature of the 3.5 mg/ml sample was reduced by using the lower field intensity of 3.9 kA/m. Three coils (5.5, 3.9, and 2.3 kA/ m) did not satisfy the required temperature of 42 °C. However, a field intensity between 5.5 and 3.9 kA/m satisfies this temperature condition. The saturation temperature versus field intensity for this sample is shown in Fig. 10-a. In this figure, the temperature requirement is satisfied at a field intensity of 4.57 kA/m. The above results showed that manganese ferrite nanoparticles can be used as heat generators to control the temperature of an aqueous solution of nanoparticles at 42 °C. This was achieved either by changing the concentration of particles or by changing the field strength. The capability of nanoparticles as heat generators may be different in the biological environment. However, our measurements showed the possibility of adjusting either the concentration of particles or the field strength to cause nanoparticles to control the temperature of their surroundings, even in the application to the human body. Using the data in Fig. 8, we can determine the field intensity dependence of the SARs for the 3.5 mg/mL sample. The power generated by the nanoparticles in an AC magnetic field is given by [37]:
P = 2π 2μo Ho2 f 2
τ , 1 + 4π 2f 2 τ 2
(3)
where Ho and f are the intensity and frequency of the AC magnetic field, respectively. The effective relaxation time τ is expressed as:
1 1 1 = + . τ τB τN Fig. 9. Field intensity dependence of magnetic heating for 3.5 mg/ml sample of manganese ferrite nanoparticles.
(4)
Here, τ B and τ N represent the Brown and Néel relaxation times, respectively. For superparamagnetic nanoparticles dispersed in water,
Fig. 10. (a) Field intensity dependence of saturation temperature and (b) the square of field intensity dependence of SAR for 3.5 mg/ml sample.
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temperature of the magnetic nanoparticles, above the boiling point of the liquid medium [38]. The total power dissipation of magnetic nanoparticles behaves near the Curie point as:
(5) From the calorimetric perspective, the total power dissipation can be expressed as
⎡⎛ ⎞ ⎤ ⎛ dT ⎞ dT ⎥. −⎜ ⎟ P =ρf C ⎢ ⎜ ⎟ ⎝ ⎠ ⎝ ⎠ ⎢⎣ dt heating dt cooling ⎥⎦
Fig. 11. Temperature rise as a function of heating time for powder sample of manganese ferrite nanoparticles.
the Néel relaxation time (10 9 s) is much smaller than that of the Brown relaxation time (10 3 s). Consequently, the heat is primarily produced by the Néel relaxation loss. Fig. 10-b shows the H02 dependence of SAR for the 3.5 mg/ml sample. The temperature rise as a function of heating time for the powder sample is shown in Fig. 11. We used a field strength of 5.5 kA/m at 260 kHz. The temperature increased to 84 °C in 200 s. This high temperature was achieved because the generated heat is only used to increase the temperature of the manganese ferrite nanoparticles and silica, which have the low specific heats of 0.49 and 0.7 J/g °C, respectively. In the aqueous sample, most of the heat was used to increase the temperature of the water, resulting in a lower saturation temperature. In this powder sample, the heat is generated only by the Néel relaxation loss. The Curie temperature of the nanoparticles can be estimated by using heating and cooling curves. To correlate the heating and cooling curves with the temperature dependent magnetization, the calorimetric method has been used for the dispersion of magnetic nanoparticles in an alternating magnetic field. If the heating measurements are carried out using nanoparticle dispersion, and the temperature is restricted to the boiling point of the liquid medium (e.g., 100 °C for water), the extrapolation method can be applied to obtain the energy absorption up to the Curie
(6)
Here, ρf is the magnetic fluid density, C is the specific heat, and dT/ dt is the rate of the temperature change. From Eq. (6), it is clear that the difference between the heating and cooling rates at a given temperature T is proportional to Tc T. These two processes should intersect at temperature T¼ Tc. Therefore, we obtain the intersection point by extrapolating two processes. The temperature at the intersection point can be identified as the Curie point. We estimated the Curie temperature of manganese ferrite nanoparticles from the heating and cooling curves, which are shown in Fig. 12-a. The Curie temperature can be identified as the crossing point of the lines of the heating and cooling rates. This is shown in Fig. 12-b. The Curie temperature of manganese ferrite nanoparticles was determined to be 195 °C, which is much less than that measured for bulk manganese ferrite (i.e., 570 °C).
4. Conclusions Internal hyperthermia depends on the ability of the heat sources to control their surroundings to 42 °C. Magnetic nanoparticles act as heat generators in the presence of an alternating magnetic field. We prepared silica-coated manganese ferrite nanoparticles for hyperthermia applications. In TEM images, the silica-coated manganese ferrite nanoparticles, grown by using the reverse micelle method, showed a spherical shape with an average diameter of 14 nm. These particles were characterized by using various analytical tools. The coating status was checked by FTIR, the inverse spinel crystalline structure was confirmed by XRD, and the superparamagnetic properties were observed by a VSM. In an alternating magnetic field, the nanoparticles dispersed in water acted as heat generators to increase the temperature of the aqueous solution. The required saturation temperature of 42 °C for
Fig. 12. (a) Heating and cooling curves of aqueous solution of manganese ferrite nanoparticles and (b) the determination of Curie temperature by locating the interception of the temperature changes in heating and cooling processes.
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hyperthermia was satisfied by changing either the concentration of nanoparticles in the solution or the strength of the magnetic field. We found that the nanoparticles in the 2.6 mg/ml sample controlled the saturation temperature of the aqueous solution to 42 °C in a field strength of 5.5 kA/m at a frequency of 260 kHz. We also observed that the saturation temperature could be controlled by changing the field strength for the sample of a fixed nanoparticle concentration. In these measurements, the dependence of the SAR on the square of field strength was also confirmed. Our observations demonstrate that silica-coated manganese ferrite nanoparticles have the capability as heat generators of controlling the temperature of an aqueous solution to 42 °C. This shows the strong possibility that our manganese ferrite nanoparticles are applicable to magnetic hyperthermia, in which the temperature is controlled to 42 °C in a biological system.
Acknowledgments This work was supported by the National Research Foundation of Korea (2010-0021315).
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Magnetic heating of silica-coated manganese ferrite nanoparticles Yousaf Iqbal a, Hongsub Bae a, Ilsu Rhee a,n, Sungwook Hong b a b
Department of Physics, Kyungpook National University, Daegu 702-701, Republic of Korea Division of Science Education, Daegu University, Gyeongsan 712-714, Republic of Korea
art ic l e i nf o
a b s t r a c t
Article history: Received 20 November 2015 Received in revised form 8 February 2016 Accepted 23 February 2016 Available online 24 February 2016
Manganese ferrite nanoparticles were synthesized using the reverse micelle method; these particles were then coated with silica. The silica-coated nanoparticles were spherical in shape, with an average diameter of 14 nm. The inverse spinel crystalline structure was observed through X-ray diffraction patterns. The coating status of silica on the surface of the nanoparticles was confirmed with a Fourier transform infrared spectrometer. The superparamagnetic properties were revealed by the zero coercive force in the hysteresis curve. Controllable heating at a fixed temperature of 42 °C was achieved by changing either the concentration of nanoparticles in the aqueous solution or the intensity of the alternating magnetic field. We found that at a fixed field strength of 5.5 kA/m, the 2.6 mg/ml sample showed a saturation temperature of 42 °C for magnetic hyperthermia. On the other hand, at a fixed concentration of 3.6 mg/ml, a field intensity of 4.57 kA/m satisfied the required temperature of 42 °C. & 2016 Elsevier B.V. All rights reserved.
Keywords: Magnetic heating Manganese ferrite nanoparticles Silica coating Magnetic hyperthermia
1. Introduction Magnetic nanoparticles have been widely researched for possible application in medical uses such as contrast agents in magnetic resonance imaging [1–5], magnetic hyperthermia [6,7], and nano drug delivery system [8–13]. In particular, ferrite nanoparticles have attracted great attention because of their easy synthesis, high chemical stability, and high saturation magnetization. They have the chemical structure of MFe2O4, where M represents the divalent metal ions of Mn2 þ , Fe2 þ , Co2 þ , Ni2 þ , etc. The ferrites have a cubic inverse spinel structure in which 32 O2 ions constitute a facecentered cubic structure, eight Fe3 þ ions are located at the center of eight tetrahedral sites, and eight M þ and Fe3 þ ions are located at the center of 16 octahedral sites. The magnetic moment of the Fe3 þ ions on the octahedral sites is antiparallel to that of the Fe3 þ ions on the tetrahedral sites. Thus, the magnetic moment of the ferrites is due to the magnetic moment of M2 þ . The magnetic moment of M2 þ comes from its unpaired 4d electrons, resulting in 5, 4, 3, and 2 μB for the Mn-, Fe-, Co-, and Ni-ferrites, respectively. These theoretical values of the magnetic moment are close to the experimental values of 4.6, 4.1, 3.7, and 2.3 μB, respectively [13]. Ferrite nanoparticles are toxic, thus surface modification is needed in order to apply them to the human body. This surface modification is also required for labeling various chemicals for drugs, targeting ligands, etc. on their surfaces. Various biocompatible n
Corresponding author. E-mail address: [email protected] (I. Rhee).
http://dx.doi.org/10.1016/j.jmmm.2016.02.078 0304-8853/& 2016 Elsevier B.V. All rights reserved.
materials are used to achieve this surface modification, and include silica, polyethylene glycol (PEG), chitosan, dextran, carbon, gold, oleic acid, titania, etc. [1–3,14–18]. Titania and silica are nontoxic oxides of titanium and silicon, respectively. Titania coating is useful for photocatalytic activities and hydrolysis [18–20]. Silica coating plays a vital role in preventing magnetic nanoparticle agglomeration, and providing a suitable surface for drug loading [21] and chemical inertness in biological systems [22]. The Food and Drug Administration confirmed that silica coating is safe for use in human body [23]. Hyperthermia is a cancer treatment that exploits the fact that cancer tissues are killed if they are exposed to 42 °C for half an hour [24,25]. The blood vessels of cancer cells are not complete, so excess heat is not effectively released through blood flow. External hyperthermia uses an external heat source that is concentrated on the cancer cells. On the other hand, internal hyperthermia injects the heat source directly into the site of the cancer tissue. With the magnetic hyperthermia method, magnetic nanoparticles are injected into the cancer site. Then, these magnetic nanoparticles generate heat in the presence of an external magnetic field to raise the temperature of the cancer site to 42 °C. Intensive research on magnetic hyperthermia using magnetic nanoparticles, especially iron oxide nanoparticles, has been performed. Various basic studies and animal experiments for magnetic hyperthermia are currently under way. However, no clinical application has been reported yet. In this study, manganese ferrite (MnFe2O4) nanoparticles were prepared for use in magnetic hyperthermia. The particles were coated with silica for biocompatibility. The superparamagnetic
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properties of magnetic nanoparticles are required in biomedical applications, since they exhibit their magnetic properties only in the presence of an external magnetic field. The particle size necessary for this superparamagnetic behavior is a few tens of nanometers in diameter. The applicability of nanoparticles to hyperthermia treatments can be tested by checking the heating effects of nanoparticles in an alternating magnetic field. The other requirement for hyperthermia applications is the ability to control the temperature of the nanoparticles to 42 °C. The malignant tissues are killed in an environment of 42 °C for half an hour, but temperatures higher than 46 °C burn the normal surrounding tissues. Thus, controlling the temperature to 42 °C is essential for hyperthermia treatments. In this paper, we report the heating effects of manganese ferrite nanoparticles in an alternating magnetic field. The concentration and field dependence of the heating effects will be presented.
2. Experimental method We fabricated manganese ferrite nanoparticles by precipitating them in a water-in-oil nanoreactor. This reverse micelle method has been used for the synthesis of monodispersed and controlledsize nanoparticles [26]. In this method, co-precipitation of manganese ferrite nanoparticles occurs inside the nano-sized water droplets that are enclosed by a surfactant and distributed in the oil phase. Those encapsulated water droplets that are distributed in the oil phase act like mini-reactors, or so-called reverse micelles. The size of the mini-reactors depends on the molar ratio of water to surfactant. The application of the silica coating on the surface of the nanoparticles was performed simultaneously with the synthesis of the manganese ferrite nanoparticles. In brief, the water-in-oil system was obtained by mixing two different solutions by mechanical stirring at 500 rpm. The two solutions were a transparent solution of 3.5 g sodium dodecylbenzenesulfonate (NaDBS) dissolved into 30 ml xylene (isomers plus ethyl benzene, 98.5%), and a 1.8 ml aqueous solution containing stoichiometric amounts of MnCl2–4H2O and iron (III) nitrate nanohydrate (Fe (NO3)3–9H2O, 98%). The transparent solution became a milky whitish color upon the addition of the aqueous solution. The resultant water-in-oil system was continuously stirred for about 16 h, followed by an additional 1 h of stirring under nitrogen protection. After stirring, the system was heated to 90 °C at the rate of 2 °C/min, and 1 ml hydrazine (34 wt-% water solution) was added. The addition of the hydrazine caused a change in color (from dark brown to black). The resultant system was kept at 90 °C for 3 h, and then cooled down to 40 °C in about 1.5 h. During this process, manganese ferrite nanoparticles were formed inside the mini-reactors of the reverse micelle (water-inoil) system. The coating of the ferrite nanoparticles with silica was performed by adding 4 ml of tetraethyl orthosilicate (TEOS) into the manganese ferrite nanoparticle solution at 40 °C and stirring for about 6 h at 500 rpm. The silica shells were formed on the surface of the manganese ferrite nanoparticles by the hydrolysis of the TEOS inside the encapsulated water droplet by the micelles. The silica-coated manganese ferrite nanoparticles were separated from the oil phase using acetone and subsequent centrifugations at 13,000 rpm. The particles were dried at ambient temperature for 8 h to obtain a powder sample. The powder samples were dispersed in water for characterization. An aqueous solution of the manganese ferrite nanoparticles was prepared to observe the heating effect of the magnetic nanoparticles in an alternating magnetic field. A 20 mg powder sample of the silica-coated manganese ferrite nanoparticles was dispersed in 50 ml of deionized water with ultrasonication for
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20 min. The resultant dispersion was observed to be highly stable for months. This dispersion of the manganese ferrite nanoparticles was very dilute. A concentrated sample was obtained by keeping the diluted sample in the vacuum oven at 40 °C for about 5 days. The amounts of manganese and iron in the aqueous solution were measured by using an inductively coupled plasma (ICP) technique. Five more samples were prepared by diluting the sample to 75%, 62.5%, 50%, 37.5%, and 25% for measuring the concentration dependence of the magnetic heating effect. The morphology and particle size distribution of the manganese ferrite nanoparticles were analyzed using a transmission electron microscope (TEM; H-7600, Hitachi Ltd.). The crystal structure of the bare and silica-coated manganese ferrite nanoparticles was investigated using X-ray diffraction (XRD; X'pert PRO, PANalytical). The chemical composition and concentration of the nanoparticles in the aqueous solution were measured using ICP spectrometry (Thermo Jarrell Ash IRISAP). The bonding of silica to the surface of the nanoparticles was confirmed using Fourier transform infrared spectroscopy (FTIR; Nicolet 380, Thermo Scientific USA). The magnetic measurements were carried out using a vibrating sample magnetometer (VSM; MPMS, Quantum Design). The magnetic heating effects of the nanoparticles dispersed in water were measured using an induction heating system (OSH120-B, Osung High Tech) under an alternating magnetic field at 260 kHz. The temperature of the solution was measured with a CALEX infrared thermometer (PyroUSB CF, Calex Electronics Limited).
3. Results and discussions Fig. 1-a shows a TEM image of the silica-coated manganese ferrite nanoparticles. The particle size distribution is given in Fig. 1-b, which shows the histogram of the diameter of 100 nanoparticles obtained from the TEM image. The average diameter of the coated nanoparticles is 14 nm, with a margin of 0.1 nm. The XRD patterns of the bare and silica-coated manganese ferrite nanoparticles are shown in Fig. 2. The peaks at 30.19°, 35.50°, 43.22°, 53.6°, 57.09°, and 62.6° correspond to the crystal planes of (220), (311), (400), (422), (511), and (440), respectively, matching those observed in inverse spinel ferrite [27,28]. The extra peak at around 22° to 26° for the coated particles arises from amorphous SiO2 adsorbed on the surface of the nanoparticles [29]. The lattice constant “a” was calculated to be 8.3 Å, using the (440) peak. The differences in peak angles between the bare and the silica-coated nanoparticles are negligible. The bonding of the silica to the surface of the manganese ferrite nanoparticles was checked by FTIR in the range of 400 to 4000 cm 1, as shown in Fig. 3. The absorption band at 3430 cm 1 in the figure corresponds to the stretching mode of the O–H group, while the band at 1627 cm 1 represents the vibration mode of the O–H group present at the surface of the samples [30,31]. In addition, the absorption band at 1100 cm 1 on the spectra is the characteristic peak of the anti-symmetric stretching vibrational mode of the Si–O–Si siloxane bridges. The absorption at 957 cm 1 is due to the contribution from the Si–O–H stretching vibration [32], while the band at 802 cm 1 is due to the SiO4 ring vibration [33]. The faint band at 625 cm 1 corresponds to the Fe–O stretching in the Fe–O–Si bonding [34]. In summary, the FTIR spectra confirm the bonding of the silica to the surface of the manganese ferrite nanoparticles. Fig. 4 shows the hysteresis curve of the silica-coated manganese ferrite nanoparticles at room temperature. In the inset of this figure, zero remanence and coercivity are apparent, indicating that the nanoparticles exhibit superparamagnetic properties at room temperature.
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Fig. 1. (a) TEM image of silica-coated manganese ferrite nanoparticles and (b) size distribution of nanoparticles.
Fig. 2. XRD patterns of powder samples of (a) bare manganese ferrite nanoparticles and (b) silica-coated manganese ferrite nanoparticles. The indices of the crystal plane in the figure match those of an inverse cubic spinel structure.
Fig. 3. FTIR spectra of silica-coated manganese ferrite nanoparticles.
Fig. 4. Hysteresis curve of silica-coated manganese ferrite nanoparticles at room temperature.
The amounts of manganese and iron in the concentrated aqueous solution were measured using ICP spectrometry to be 1188 and 2322 mg/L, respectively. The atomic ratio of iron to manganese is 1.95, which is approximately consistent with the chemical formula of MnFe2O4. Five more samples were prepared by diluting the concentrated sample to 75%, 62.5%, 50%, 37.5%, and 25%. The concentration of the nanoparticles in the concentrated sample was 3.5 mg/ml. Thus, the concentrations of the nanoparticles in the diluted samples were 2.6, 2.2, 1.7, 1.3, and 0.9 mg/ml, respectively. A schematic of the induction heating system used to observe the magnetic heating effect is shown in Fig. 5. The aqueous sample of nanoparticles is placed in the RF coil with a resonant frequency of 260 kHz. Field strengths of 2.3, 3.9, and 5.5 kA/m were used to observe the field strength dependence of the magnetic heating effect. The infrared (IR) thermometer located at 10 cm above the sample was used to measure the temperature of the sample. When a magnetic system is subjected to an alternating magnetic field, heat is generated owing to loss mechanisms, which can be classified as hysteresis and relaxation loss [13]. The latter can be further divided into Néel and Brown losses. Since our superparamagnetic nanoparticles show no hysteresis (see Fig. 4), we can neglect the hysteresis losses. The ferromagnetic resonance loss can also be ignored in the present study, because it occurs only in the
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Fig. 5. Induction heating system for testing the heating effect of manganese ferrite nanoparticles dispersed in an aqueous solution.
GHz frequency range, which is much higher than the 200–300 kHz used in this study. Thus, the remaining heating mechanisms for our nanoparticles are the Néel and the Brown losses. The background heating effects due to the pure water and sample container were estimated. We observed that the effect of these backgrounds was negligible. A 1 ml aqueous sample in a thermally insulated container was placed in the alternating magnetic field. The rises in temperature as a function of heating time for six samples at different concentrations of the manganese ferrite nanoparticles are shown in Fig. 6. The magnetic field intensity was fixed at 5.5 kA/m with a frequency of 260 kHz. We can see in this figure that the temperature increase for the concentrated sample is faster than that for the diluted samples. This concentration dependence of the temperature rise is as expected, since more heat generators (i.e., nanoparticles) are present in the concentrated sample. It is also observed that the temperature of all samples reached their saturation temperature after about 1000 s. At that time, the heat generation is balanced by heat loss. The saturation temperatures for the 3.5, 2.6, 2.2, 1.7, 1.3, and 0.9 mg/ml samples were 48, 42, 41, 39.5, and 35.5 °C, respectively. For magnetic hyperthermia, the temperature should be maintained at 42 °C for 30 min to kill the malignant tissues. However, the temperature should also be sustained below 46 °C, so as not to affect the normal tissues. The 2.6 mg/ml sample satisfies this condition. The heat generated by magnetic nanoparticles in an alternating magnetic field increases the temperature of constituents in the sample. The relationship between heat and temperature increase is given by:
∆Q = mW cW ∆T +msi csi ∆T +mMn cMn ∆T +mFe cFe ∆T.
Fig. 6. Temperature rise as a function of heating time for the 3.5-, 2.6-, 2.2-, 1.7-, 1.3-, and 0.9-mg/ml samples.
(1)
Here, ∆T is the temperature of the sample, and cW, csi, cMn , and cFe are the specific heats of water, silica, manganese, and iron, respectively. In addition, mW , msi , mMn , and mFe are the masses of water (1 ml), silica, manganese, and iron, respectively. The specific absorption rate (SAR) is defined as the dissipation heat generated per unit mass of magnetic nanoparticle. This is given as [35,36]: ∆Q /∆T ∆T /∆t = [ mW cW+mSi cSi+mMn cMn+mFe cFe ] mMn + mFe mMn + mFe mW cW ⎛ ∆T ⎞ ≅ ⎜ ⎟. mMn + mFe ⎝ ∆t ⎠
SAR =
Here,
ΔT Δt
(2)
is the initial rate of temperature increase. In the last step
of Eq. (2), we used the facts that the mass of water (1 g) in the sample is much larger than that of other constituents (about 30 mg), and that the specific heat of water ( cW = 4.2J/g °C ) is also csi = 0.7J/g °C larger than that of the others, which is cMn = 0. 49 J/g °C , and cFe = 0. 45J/g °C , respectively. Thus, the heat required to increase the temperature of the coated nanoparticles is much less than that needed for water in the sample. The SARs for the 3.5, 2.6, 2.2, 1.7, 1.3, and 0.9 mg/ml samples were 47.84, 53.45, 55, 58.8, 67.62, and 84.65 W/g, respectively. The
Fig. 7. Concentration dependence of initial rate of temperature rise and saturation temperature for manganese ferrite nanoparticles.
decrease in SAR with increasing particle concentration is due to the increase in the dipolar magnetic moment according to the increase in particle concentration, which affects the Néel relaxation time. The initial rate of temperature rise and saturation temperature for different concentrations is shown in Fig. 7, while the concentration dependency of the SAR is shown in Fig. 8. The saturation temperature of the 3.5 mg/ml sample was larger than 42 °C, the required temperature for magnetic hyperthermia. On the other hand, the other samples, except the 2.6 mg/ml sample, did not reach the temperature of 42 °C. In magnetic
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Fig. 8. Concentration dependence of specific absorption rate (SAR) for manganese ferrite nanoparticles.
hyperthermia, the temperature should be maintained at 42 °C. Owing to this temperature regulation, the normal tissues are prevented from burning. We already knew from Fig. 6 that for a fixed magnetic field strength, the saturation temperature can be controlled by changing the concentration of nanoparticles in the sample. Moreover, we can also control the saturation temperature of the sample with a certain concentration of nanoparticles by changing the magnetic field strength. If a smaller field strength is used for the 3.5 mg/ml sample, the saturation temperature will decrease down to 42 °C. On the other hand, the saturation temperatures of the other samples, except the 2.6 mg/ml sample, can be regulated to 42 °C with a higher field strength. One example of this is shown in Fig. 9. This figure shows that the saturation temperature of the 3.5 mg/ml sample was reduced by using the lower field intensity of 3.9 kA/m. Three coils (5.5, 3.9, and 2.3 kA/ m) did not satisfy the required temperature of 42 °C. However, a field intensity between 5.5 and 3.9 kA/m satisfies this temperature condition. The saturation temperature versus field intensity for this sample is shown in Fig. 10-a. In this figure, the temperature requirement is satisfied at a field intensity of 4.57 kA/m. The above results showed that manganese ferrite nanoparticles can be used as heat generators to control the temperature of an aqueous solution of nanoparticles at 42 °C. This was achieved either by changing the concentration of particles or by changing the field strength. The capability of nanoparticles as heat generators may be different in the biological environment. However, our measurements showed the possibility of adjusting either the concentration of particles or the field strength to cause nanoparticles to control the temperature of their surroundings, even in the application to the human body. Using the data in Fig. 8, we can determine the field intensity dependence of the SARs for the 3.5 mg/mL sample. The power generated by the nanoparticles in an AC magnetic field is given by [37]:
P = 2π 2μo Ho2 f 2
τ , 1 + 4π 2f 2 τ 2
(3)
where Ho and f are the intensity and frequency of the AC magnetic field, respectively. The effective relaxation time τ is expressed as:
1 1 1 = + . τ τB τN Fig. 9. Field intensity dependence of magnetic heating for 3.5 mg/ml sample of manganese ferrite nanoparticles.
(4)
Here, τ B and τ N represent the Brown and Néel relaxation times, respectively. For superparamagnetic nanoparticles dispersed in water,
Fig. 10. (a) Field intensity dependence of saturation temperature and (b) the square of field intensity dependence of SAR for 3.5 mg/ml sample.
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temperature of the magnetic nanoparticles, above the boiling point of the liquid medium [38]. The total power dissipation of magnetic nanoparticles behaves near the Curie point as:
(5) From the calorimetric perspective, the total power dissipation can be expressed as
⎡⎛ ⎞ ⎤ ⎛ dT ⎞ dT ⎥. −⎜ ⎟ P =ρf C ⎢ ⎜ ⎟ ⎝ ⎠ ⎝ ⎠ ⎢⎣ dt heating dt cooling ⎥⎦
Fig. 11. Temperature rise as a function of heating time for powder sample of manganese ferrite nanoparticles.
the Néel relaxation time (10 9 s) is much smaller than that of the Brown relaxation time (10 3 s). Consequently, the heat is primarily produced by the Néel relaxation loss. Fig. 10-b shows the H02 dependence of SAR for the 3.5 mg/ml sample. The temperature rise as a function of heating time for the powder sample is shown in Fig. 11. We used a field strength of 5.5 kA/m at 260 kHz. The temperature increased to 84 °C in 200 s. This high temperature was achieved because the generated heat is only used to increase the temperature of the manganese ferrite nanoparticles and silica, which have the low specific heats of 0.49 and 0.7 J/g °C, respectively. In the aqueous sample, most of the heat was used to increase the temperature of the water, resulting in a lower saturation temperature. In this powder sample, the heat is generated only by the Néel relaxation loss. The Curie temperature of the nanoparticles can be estimated by using heating and cooling curves. To correlate the heating and cooling curves with the temperature dependent magnetization, the calorimetric method has been used for the dispersion of magnetic nanoparticles in an alternating magnetic field. If the heating measurements are carried out using nanoparticle dispersion, and the temperature is restricted to the boiling point of the liquid medium (e.g., 100 °C for water), the extrapolation method can be applied to obtain the energy absorption up to the Curie
(6)
Here, ρf is the magnetic fluid density, C is the specific heat, and dT/ dt is the rate of the temperature change. From Eq. (6), it is clear that the difference between the heating and cooling rates at a given temperature T is proportional to Tc T. These two processes should intersect at temperature T¼ Tc. Therefore, we obtain the intersection point by extrapolating two processes. The temperature at the intersection point can be identified as the Curie point. We estimated the Curie temperature of manganese ferrite nanoparticles from the heating and cooling curves, which are shown in Fig. 12-a. The Curie temperature can be identified as the crossing point of the lines of the heating and cooling rates. This is shown in Fig. 12-b. The Curie temperature of manganese ferrite nanoparticles was determined to be 195 °C, which is much less than that measured for bulk manganese ferrite (i.e., 570 °C).
4. Conclusions Internal hyperthermia depends on the ability of the heat sources to control their surroundings to 42 °C. Magnetic nanoparticles act as heat generators in the presence of an alternating magnetic field. We prepared silica-coated manganese ferrite nanoparticles for hyperthermia applications. In TEM images, the silica-coated manganese ferrite nanoparticles, grown by using the reverse micelle method, showed a spherical shape with an average diameter of 14 nm. These particles were characterized by using various analytical tools. The coating status was checked by FTIR, the inverse spinel crystalline structure was confirmed by XRD, and the superparamagnetic properties were observed by a VSM. In an alternating magnetic field, the nanoparticles dispersed in water acted as heat generators to increase the temperature of the aqueous solution. The required saturation temperature of 42 °C for
Fig. 12. (a) Heating and cooling curves of aqueous solution of manganese ferrite nanoparticles and (b) the determination of Curie temperature by locating the interception of the temperature changes in heating and cooling processes.
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hyperthermia was satisfied by changing either the concentration of nanoparticles in the solution or the strength of the magnetic field. We found that the nanoparticles in the 2.6 mg/ml sample controlled the saturation temperature of the aqueous solution to 42 °C in a field strength of 5.5 kA/m at a frequency of 260 kHz. We also observed that the saturation temperature could be controlled by changing the field strength for the sample of a fixed nanoparticle concentration. In these measurements, the dependence of the SAR on the square of field strength was also confirmed. Our observations demonstrate that silica-coated manganese ferrite nanoparticles have the capability as heat generators of controlling the temperature of an aqueous solution to 42 °C. This shows the strong possibility that our manganese ferrite nanoparticles are applicable to magnetic hyperthermia, in which the temperature is controlled to 42 °C in a biological system.
Acknowledgments This work was supported by the National Research Foundation of Korea (2010-0021315).
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