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Magnetite ferrofluid with high specific absorption rate for application in hyperthermia
ARTICLE IN PRESS
Journal of Magnetism and Magnetic Materials 311 (2007) 228–233 www.elsevier.com/locate/jmmm
Magnetite ferrofluid with high specific absorption rate for application in hyperthermia Li-Ying Zhang, Hong-Chen Gu, Xu-Man Wang National Key Laboratory of Micro/Nano Fabrication Technology, Key Laboratory for Thin Film and Microfabrication of MOE, Research Institute of Micro/Nano Science and Technology, Shanghai Jiaotong University, Shanghai 200030, PR China Available online 8 December 2006
Abstract A magnetite ferrofluid coated by dextran with a high specific absorption rate (SAR) of 75 W/g in an AC field of 55 kHz and 200 Oe was prepared by the gel crystallization method with ultrasonic treatment. For comparison, uncoated magnetite particles with a mean diameter of 50 nm were also fabricated. Several possible mechanisms such as Brownian, Neel and diffusion relaxation processes on heating effects and their influence on SAR are discussed. Several factors which can increase the value of SAR were discussed, including dextran coating, ultrasonic treatment, proper particle size and the presence of defects and disorder in the particles. r 2006 Elsevier B.V. All rights reserved. Keywords: Magnetic fluid hyperthermia; AC losses; Magnetic nanoparticle; Ferrofluid; Brownian relaxation; Neel relaxation
0. Introduction In recent years, magnetic fluid hyperthermia (MFH) has attracted much attention due to considerable heating effects in an AC-magnetic field. It can increase the temperature in tumors to 41–46 1C and therefore kill tumor cells. The applicability for tumor treatment is discussed in Ref. [1]. Among lots of magnetic materials, magnetite is a very promising candidate since its biocompatibility was already proven. So far, magnetite Fe3O4 or maghemite g-Fe2O3 with different sizes and coated by different surfactants were prepared, and their heating effects at various AC-magnetic fields were investigated by several groups [2–7]. The highest values of 960 W/g of specific power absorption rate (SAR) were reported by Hergt et al., which they obtained on suspensions of bacterial magnetosomes at 410 kHz and a field amplitude of 10 kA/m [8]. However, clinical applications are not approved yet up to now. One of the main reasons is the restricted SAR of commonly used particle systems because the heating efficiency cannot be raised simply by increasing the AC-magnetic field amplitude H and field frequency f. Corresponding author. Tel.: +86 21 62932515; fax: +86 21 62804389.
E-mail addresses: [email protected] (L.-Y. Zhang), [email protected] (H.-C. Gu). 0304-8853/$ - see front matter r 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jmmm.2006.11.179
Otherwise, the inductive heating of the healthy tissue would grow prohibitively high. So it is important to enhance the SAR of magnetic materials in order to reduce the tissue load and improve the reliability of therapy. It is well known that the heating of magnetic particles in AC-magnetic field is mainly due to three loss processes: hysteresis losses, relaxation losses and resonance losses. Since resonance relaxation usually occurs at very high frequency, it can be neglected for hyperthermia applications. The hysteresis loss results from the hysteresis properties of magnetic materials, and can be easily estimated from the area of the hysteresis loop by taking into account the proportionality of power with frequency. The relaxation losses can be induced by several relaxation processes existing in the magnetization process. In a fluid, the magnetization reversal usually proceeds via one of the two mechanisms: Brownian and Neel relaxation processes. For particles with high anisotropy where the moment is fixed in the easy direction, the moment can align with the field by physical rotation with a relaxation time of [9] 3ZV H , (1) kT where Z is the viscosity coefficient of the fluid, k is the Boltzmann constant, and VH is the hydrodynamic volume of the particle. When the anisotropy is low, alignment
tB ¼
ARTICLE IN PRESS L.-Y. Zhang et al. / Journal of Magnetism and Magnetic Materials 311 (2007) 228–233
occurs via the usual Stoner–Wohlfarth process subject to thermal activation where the relaxation time is given by the Neel–Arrhenius law [9] tN ¼ t0 expðDE=kTÞ,
(2)
where t0 is typically in the order of a few ns, and if one ignores the magnetic dipole–dipole interaction between particles the energy barrier DE can be expressed as DE ¼ KV+mH ¼ KV(1+H/HK), where KV is the magnetocrystalline anisotropy energy, mH is the interaction between the magnetic moment of the particle (m) and the external field (H), and HK is the anisotropy field, which for a particle system with uniaxial anisotropy and a random distribution of easy axis HK ¼ 0.96K/MSB, where MSB is saturation magnetization of the bulk material [9,10]. For a magnetite with MSB ¼ 93 emu/g, the calculated HK is 1393 Oe. The magnetization reversal proceeds by whichever process has the shorter relaxation time, and the effective relaxation time is given by 1 1 1 ¼ þ . t tB tN
(3)
The relaxation losses can be expressed as [11] P ¼ pm0 w0 H 2 f
2pf t , 1 þ ð2pf tÞ2
(4)
where m0 is the permeability of free space, H and f is the amplitude and frequency of the AC field, and w0 is magnetic field dependent and can be expressed as 3 1 coth x , w0 ¼ wi (5) x x where x is Langevin parameter (x ¼ m0MSHV/kT, MS is the domain magnetization of a suspended particle). The initial susceptibility wi is determined from differentiation of the Langevin relationship. From the above analysis, the losses, that is, the heating of the magnetic materials, not only relates to the amplitude H and frequency f of the AC-magnetic field, but also strongly depends on the physical properties of the materials, for example, the magnetocrystalline anisotropy and the particle size, shape and microstructure, as well as the dynamical size and the viscosity of the fluid. Some of these factors were observed experimentally by other groups. For example, Hergt [12] and Chan et al. [13] reported that the SAR increased with increasing initial susceptibility. Ma et al. [5] found that the magnetite particles with size of 46 nm had the highest SAR, whereas Hergt observed the highest SAR on about 30 nm particle suspensions [8]. It was also found that the size distribution width of nanoparticles has crucial influence on the SAR and can be raised greatly through a size selection process [12]. In addition, Chan discovered that the preparation method also strongly influenced the SAR and SAR can be raised with an ultrasonic treatment and coating by dextran [13].
229
The gel crystallization method has earlier been used to prepare magnetite particles of narrow size distribution with mean diameters ranging between 30 and 1100 nm [14]. In this paper, we prepared dextran-coated magnetite nanoparticles with this method with an additional ultrasonic treatment. For comparison, we also prepared uncoated magnetite particles using the same method. The magnetic properties and the heating effects in the AC field were investigated. The possible heating mechanisms were also discussed. 1. Experimental The uncoated Fe3O4 particles (sample A) were prepared as follows: 0.33 M KOH and 0.15 M KNO3 solutions were mixed in a three-necked round bottom flask. The mixture solution was stirred at 200 rpm and treated by an ultrasonic agitation simultaneously in a 60 1C water bath. And then, 0.17 M FeSO4 was added to the flask at a vigorous stir of 300 rpm. After being kept for 30 min at a constant temperature of 60 1C, the ultrasonic was removed and the mixture was heated to 90 1C and aged for 4 h. Pure nitrogen gas was flowed throughout the entire duration of the experiment. The dextran-coated Fe3O4 particles were prepared using the same method except for adding 7.8 g dextran to the reaction reagent. The obtained samples were washed several times with distilled water by using a powerful permanent magnet. The dextran-coated particles were dispersed in water and formed a stabilized ferrofluid (sample B). The density of the ferrofluid is 1.018 g/cm3, and the mass percent of Fe3O4 in the fluid is 1.34%. The morphology of the particles was investigated on a JOEL JEM 2010 transmission electron microscope (TEM). The crystal structure was characterized by an X-ray diffractometer (XRD, Bruker AXS) with Cu Ka1 radiation. Fourier transform infrared spectroscopy (FTIR, FTS 135 BIO-RAD) was used to verify the coated particles. Mo¨ssbauer spectra (MS, with a source of 57Co) were collected to obtain the micromagnetic structure and hyperfine parameters. The viscosity of the fluid was measured on a DV-III Brookfield Digital Rheometer at 25 1C. Magnetic losses of the samples were investigated by the quasi-static magnetic properties with a vibration sample magnetometer (VSM, Lakeshore 7300) and calorimetrical measurement was carried on a self-made ACmagnetic field with a frequency of 55 kHz and an amplitude of 200 Oe. 2. Results and discussion 2.1. Morphology and structure The TEM images of samples A and B are shown in Figs. 1(a) and (b). The uncoated particles have a polyhedral shape and deviate from spheres. The mean diameter is estimated to be 50 nm, which is near to the single domain size of 54 nm for Fe3O4. The dextran-coated
ARTICLE IN PRESS 230
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Fig. 1. TEM images of magnetite particles: (a) uncoated, and (b) dextran coated.
a
Relative transmission
particles are difficult to disperse and the size is hard to estimate from the TEM image due to their strong agglomerate state. According to the XRD results (not shown), both samples demonstrate a spinel crystal structure with a lattice constant a0 ¼ 8.322 A˚. Sample B has broad diffraction peaks and relatively weak intensity compared with Sample A, which indicates that the dextran-coated particles have relative small size and less crystallization state. According to Scherrer formula, the mean size of the dextran-coated particles is 19 nm and of uncoated is 32 nm, which is less than the size estimated from TEM. One can found that the size of dextran-coated particles is less than the uncoated ones even at the same experimental conditions. Fig. 2 shows the Mo¨ssbauer spectra (MS) of the magnetite particles of the two samples. Sample A has two clear separated peaks that can be fitted by two sextets corresponding to the A- and B-sites of inverse spinel structure. The isomer shifts (IS) relative to iron metal of the two sites are 0.31 and 0.64 mm/s, the quadruple splittings (QS) are 0.001 and 0.007 mm/s, and the hyperfine fields Hhf are 49.0 and 45.6 T, which is in agreement with the typical values for Fe3O4 [15,16]. However, the MS of sample B demonstrate a broadened sextet that can be fitted by two sextets and a doublet. The appearance of 6% of doublet may result from the superparamagnetic particles existing in the samples, which is consistent with the TEM and XRD results. The IS of the two sites are 0.34 and 0.41 mm/s, which is different from the sample A. The Hhf are 45.4 and 39.3 T, which is much lower than bulk materials and sample A. The lower values may be interpreted by the existence of collective magnetic excitation processes due to the fine particle size. In addition, according to the fitted results, the two sextets are clearly separated indicating the samples are Fe3O4 not other iron oxides such as a-Fe2O3 or g-Fe2O3. It is worth noting that magnetite is a ferrimagnetic material with typical inverse spinel structure, the divalent ions Fe2+ being placed in the B-sites and the trivalent ions Fe3+ equally distributed in the A- and B-sites, according to
b
-8
-4
0
4
8
Relative velocity (mm/s) Fig. 2. Mo¨ssbauer spectra of magnetite particles: (a) uncoated, and (b) dextran coated.
the notation [Fe3+]A[Fe3+Fe2+]B. Theoretically, the population ratio of iron ions in A- and B-sites is 1:2. Actually, the ratio is 1:1.8 reported for bulk Fe3O4 [17]. However, according to the fitting results, the relative resonance area ratio of A- and B-sites is 1:0.9 for sample A and 1:0.5 for sample B. These much lower values indicate an inexact stoichiometry and especially the presence of vacancies and structural defects and local variations inside the particles and/or at the particle boundary [16]. The reduction of area ratio between the A- and B-sites may result in a decrease of magnetization.
ARTICLE IN PRESS L.-Y. Zhang et al. / Journal of Magnetism and Magnetic Materials 311 (2007) 228–233
0.5
c
571
0.6
1022
0.7
1418 1345 1143
b
3345
Absorbance
0.8
1636
0.9
calculate the volume fraction median diameter, Dm, and the standard deviation, s, of the distribution [19]: " #1=3 18kT wini 1 1=2 Dm ¼ , (6) pM SB 3M S H 0
a
2919
1.0
0.4 4000
3500
3000
2500
2000
1500
1000
231
500
Wavenumber (cm-1) Fig. 3. The IR spectra of: (a) uncoated magnetite particles, (b) dextrancoated magnetite particles and (c) pure dextran.
Fig. 3 shows the IR spectra of samples A and B, as well as pure dextran. The particles were freeze-dried firstly and mixed with KBr powder and compressed to pellets before measurement. As shown in Fig. 3, the band at 571 cm1is the characteristic peak of Fe3O4. The band near 3345, 1639 and 1418 cm1 are ascribed to the hydroxy characteristic peak of water absorbed in the surface or the OH-stretching bands and the bending vibration peak of the hydroxy group. From the IR spectra of three samples, it can be seen that the magnetite particles were indeed coated by dextran. However, the spectra of dextran-coated particles just have little difference with the ones of pure dextran, which indicated that the interactions between dextran and magnetite particles are intermolecular interactions [18]. 2.2. Magnetic properties and losses The hysteresis properties of samples A and B were investigated at room temperature (not shown). The uncoated particles demonstrate hysteresis properties with coercivity of 155 Oe, whereas, the dextran-coated particles are superparamagnetic with no coercivity and remanence. The saturation magnetization sS of dextran-coated particles is 51 emu/g, whereas it is 76 emu/g for the uncoated particles. These values are much lower than the typical value MSB ¼ 93 emu/g for bulk materials. The decreased MS for nanoparticles is attributed to the disordered surface spins as well as disordered magnetic structure from the above MS results. Especially for dextran-coated nanoparticles, the decreased value is also due to the absorption of the surfactant molecules on the particle surface, which causes the spins of the iron atoms close to the surface to be pinned. According to the Langevin theory for superparamagnetism, the magnetic size can be determined [19]. Assuming a lognormal distribution of particle volume, the magnetization curves at room temperature can be used to
1=2 1 3wini 1 s ¼ ln , 3 H0 MS
(7)
where wini is the initial susceptibility, and MS and MSB the saturation magnetization of the ferrofluid and the bulk, respectively. The parameter 1/H0 is defined as the value for which a tangent to the curve M vs. 1/H at high fields crosses the 1/H axis. From the magnetization curve measured for dextran-coated particles, a mean size of Dm ¼ 18 nm and the standard deviation of the distribution s ¼ 0.47 were determined. This magnetically determined value is somewhat smaller than the XRD result (19 nm). From measured hysteresis loops, one can easily estimate the magnetic loss caused by the hysteresis properties by integrating the loop area. For the dextran-coated sample, there is no hysteresis loss contribution according to their superparamagnetic properties without any hysteresis, whereas, for sample A the hysteresis loss can be estimated according to the values of coercivity 155 Oe and saturation magnetization 76 emu/g. For an ensemble of aligned uniaxial particles with the external AC-field parallel to the easy axis, the upper physical limit of power density attainable by means of hysteresis losses is given in the case of a nearly rectangular hysteresis loop by 4m0MSHS(Hs ¼ 2K/(m0Ms)). For the case of statistically oriented particles, one has approximately the relative remanence Mr/ MS ¼ 0.5 and coercivity HC ¼ 0.5HS. Hysteresis loss is reduced by about a factor of 0.25 in compared to the aligned case [17]. And therefore, according to the HC and MS one may estimate the loss by 2m0MSHC for sample A of about 2.3 J/kg, which gives for a frequency of 55 kHz a loss power of 126 W/g. This evaluation is a very rough approximation since the hysteresis loop in the AC field (so-called Rayleigh loops) is greatly different from the hysteresis loops measured in a static field. To avoid the evaluation errors and to obtain the absolute heating results, the SAR of two samples was measured calorimetrically at an AC-magnetic field with a frequency of 55 kHz and an amplitude of 200 Oe, which is in the range for biomedical applications for hyperthermia [20]. In the experiment, the increase of temperature was recorded after applying the AC-magnetic field to a sample of known heat capacity that contains the particles to be investigated. From the measured temperature rate, the SAR was calculated as P C i mi DT SAR ¼ i , mFe Dt where Ci and mi is the heat capacity of every component whose temperature will be increased when applied
ARTICLE IN PRESS L.-Y. Zhang et al. / Journal of Magnetism and Magnetic Materials 311 (2007) 228–233
AC-field. At 55 kHz and 200 Oe, a value of 4.5 W/g is found for sample A and 57 W/g for sample B. The value of 4.5 W/g is much lower than 126 W/g calculated from the hysteresis loop of sample A. Since the mean particle size of sample A is 50 nm from TEM, which is near the single domain size, and the particles were hardly dispersed in water, there are no Brownian or Neel relaxation losses contributing to the SAR, and therefore, the SAR of sample A is mainly due to the hysteresis loss. The saturation field for sample A is about 5000 Oe, which is much higher than 200 Oe of the applied AC-magnetic field, that is, the loop is far from the saturation state at 200 Oe. And therefore, the hysteresis loss at 200 Oe will be much lower than that at a saturating field due to the rapidly reduced loop area with decreasing field amplitude [21]. This is the reason that the particles with large coercivity and high hysteresis loss dominated by single domain behavior are unsuitable for hyperthermia because in hyperthermia rarely the full hysteresis loop of such samples can be used since there are restrictions of the field amplitude mainly due to technical reasons or the biocompatibility issue for medical applications. In addition, as mentioned above, the value of 126 W/g is a very rough approximation due to the different loops in an AC and in a static field. From the calorimetrical measurement, it also can be noticed that the SAR value for dextran-coated ferrofluid is much higher than the uncoated single domain particles, and from the superparamagnetism of the sample B one can find that there is no hysteresis loss contributing to the SAR. As mentioned in the introduction, the heating of the ferrofluid may result from relaxation processes, for example, Brownian or Neel relaxation mechanism. Since the viscosity of the fluid is only associated with Brownian relaxation time, we changed the viscosity of the ferrofluid using glycerol and immobilized the fluid using agarose to investigate the contribution of Brownian mechanism to SAR. Fig. 4 shows the SAR of dextran-coated magnetite ferrofluid in dependence on the viscosity of the fluid. The SAR increases with the viscosity from 57 W/g for original fluid with a viscosity of 1.00 mPa s and reaches a maximum of 76 W/g for the fluid with 1.96 mPa s. The tendency of the relationship of SAR with viscosity is in agreement with the results predicted theoretically by Rosensweig [11]. This indicates that the Brownian relaxation process has contributions to SAR. According to the Debye model [22], the losses will reach a maximum at otB ¼ 1, thus, from the frequency of 55 kHz of the AC field, it is possible to estimate the relaxation time and hence the dynamic size of the particle in terms of Eq. (1). Using values of Z ¼ 1.00 mPa s, of water at the temperature of 293 K, the hydrodynamic diameter was calculated as dH ¼ 20 nm. This value is much lower than that measured on photo correlation spectroscopic (PCS) of about 90 nm mainly due to the strong aggregation state just as observed on TEM. The heating effect of the immobilized fluid in gel was also investigated. The SAR in this case was 35 W/g,
80
75 SAR (W/gsFe)
232
70
65
60
55 1
2
3
4
5
6
Viscosity of ferrofluid (mPa•s) Fig. 4. The SAR of dextran-coated magnetite ferrofluid measured calorimetrically in dependence on the viscosity of the fluid.
indicating that there are other contributions to the SAR. Since Neel relaxation is difficult to identify by the experimental method directly, we used values of f ¼ 55 kHz and K ¼ 1.35 104 J/m3 at a temperature of 293 K to estimate the particle size. The calculated diameter d is 16 nm in terms of Eq. (2), which is somewhat smaller than the above determined sizes of 19 and 20 nm of XRD and VSM. Since the particle size has a distribution, and Neel relaxation time is very sensitive to the size, there must have been contributions to SAR resulting from the Neel relaxation mechanism. In addition, since there may exist many vacancies, structural defects and local variations inside the particles and/or at the particle boundary according to the above MS results, other losses, such as magnetic after effects resulting from diffusion relaxation processes, may also have contributed to SAR. The heating of dextran-coated magnetite ferrofluid in dependence on the amplitude H of the AC field was also investigated. The increase of temperature vs measurement time at different H is shown in Fig. 5. The inset shows the rate of temperature increase DT/Dt as a function of amplitude H. It can be seen that DT/Dt increases with increasing H, and for low amplitudes a square law is found below 9 kA/m, whereas for high amplitudes this relationship changes. In fact, the relationship between the SAR and H is more complicated than a square or third order power law. From Eq. (4), one can find that the loss power P is not only in proportion to H2 but also has the function of w0,t and f. From Eqs. (2) and (5) it can be seen that both w0 and tN are related to H. At low fields, the influence of H on w0 and tN can be neglected; however, at high field the influence is strong and therefore the square law is unsuitable. 3. Conclusions Dextran-coated magnetite ferrofluids were prepared by the gel crystallization method with ultrasonic treatment.
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ΔT/Δt (°C/min)
70
Temperature (°C)
60
8 7 6 5 4 3 2 1 0
50
Applied field (Oe): 60 80 103 123 150 170 190
100 150 200 250 2
6
2
2
H (10 A /m )
50
40
30
20 -2
0
2
4
6
8
10
12
14
Time (min) Fig. 5. The increase in temperature vs. measurement time at different ACmagnetic fields for dextran-coated magnetite ferrofluid. The inert shows the temperature increase rate as a function of amplitude H of the AC field.
For comparison, magnetite particles with diameter of 50 nm were also prepared. The highest SAR for ferrofluid has the value of 75 W/g, which is much higher than 4.5 W/g for the 50 nm uncoated particles at 55 kHz and 200 Oe. The heating for uncoated particles is mainly due to hysteresis loss, whereas for magnetite ferrofluid it results from the Brownian and Neel relaxation mechanism. The magnetic after effect due to diffusion relaxation mechanism may also contribute to SAR. According to our results, the SAR of magnetite ferrofluid can be increased by several methods, such as coating with dextran, ultrasonic treatment, adjusting the viscosity, preparing monodispersed particles, as well as having defects and disorders present in the particles. Acknowledgments The authors would like to thank the Key Laboratory for Magnetism and Magnetic Materials of MOE in Lanzhou
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University for magnetic properties and Mo¨ssbauer spectra measurement. The authors also thank the Instrumental Analysis Center of SJTU for TEM, XRD and FTIR measurements. This work was supported by the National 863 high-tech program (2005AA302H10). References [1] R. Hergt, R. Hiergeist, I. Hilger, et al., Recent Res. Dev. Mater. Sci. 3 (2002) 723. [2] D.C.F. Chan, D.B. Kirpotin, P.A. Bunn, J. Magn. Magn. Mater. 122 (1993) 374. [3] N.A. Brusentsov, V.V. Gogosov, T.N. Brusentsov, et al., J. Magn. Magn. Mater. 225 (2001) 113. [4] A. Jordan, R. Scholz, K. Maier-Hauff, et al., J. Magn. Magn. Mater. 225 (2001) 118. [5] M. Ma, Y. Wu, J. Zhou, et al., J. Magn. Magn. Mater. 268 (2004) 33. [6] R. Muller, R. Hergt, M. Zeisberger, et al., J. Magn. Magn. Mater. 289 (2005) 13. [7] X. Wang, H. Gu, Z. Yang, J. Magn. Magn. Mater. 293 (2005) 334. [8] R. Hergt, R. Hiergeist, M. Zeisberger, et al., J. Magn. Magn. Mater. 293 (2005) 80. [9] M.B. Mantecon, K. O’Grady, J. Magn. Magn. Mater. 296 (2006) 124. [10] P.C. Morais, A.L. Tronconi, F.A. Tourinho, et al., Sol. Stat. Commun. 101 (1997) 693. [11] R.E. Rosensweig, J. Magn. Magn. Mater. 252 (2002) 370. [12] R. Hergt, R. Hiergeist, M. Zeisberger, et al., J. Magn. Magn. Mater. 280 (2004) 358. [13] D.C. Chan, D.B. Kirpotin, P.A. Bunn, Scientific and Clinical Applications of Magnetic Carriers, Plenum Press, New York, 1997. [14] T. Sugimoto, E. Matijevic, J. Colloid. Interface Sci. 74 (1980) 227. [15] J.M. Daniels, A. Rosencwaig, J. Phys. Chem. Solids 30 (1969) 1561. [16] E. Bonetti, L. Del Bianco, S. Signoretti, et al., J. Appl. Phys. 89 (2001) 1806. [17] U. Gonser, Mo¨ssbauer Spectroscopy, Springer, Berlin, 1975. [18] X.Q. Xu, H. Shen, J.R. Xu, et al., Appl. Surf. Sci. 252 (2005) 494. [19] E. Kneller, Theory of the magnetization curve of small crystals, in: H.P.J. Wijn (Ed.), Encyclopedia of Physics, Ferromagnetism, Springer, NewYork, 1966. [20] A. Jordan, R. Scholz, P. Wust, et al., J. Magn. Magn. Mater. 201 (1999) 413. [21] R. Hergt, W. Andra¨, C.G. Ambly, et al., IEEE Trans. Magn. 34 (1998) 3745. [22] P. Debye, Polar Molecules, The Chemical Catalog Company, NewYork, 1929.
Journal of Magnetism and Magnetic Materials 311 (2007) 228–233 www.elsevier.com/locate/jmmm
Magnetite ferrofluid with high specific absorption rate for application in hyperthermia Li-Ying Zhang, Hong-Chen Gu, Xu-Man Wang National Key Laboratory of Micro/Nano Fabrication Technology, Key Laboratory for Thin Film and Microfabrication of MOE, Research Institute of Micro/Nano Science and Technology, Shanghai Jiaotong University, Shanghai 200030, PR China Available online 8 December 2006
Abstract A magnetite ferrofluid coated by dextran with a high specific absorption rate (SAR) of 75 W/g in an AC field of 55 kHz and 200 Oe was prepared by the gel crystallization method with ultrasonic treatment. For comparison, uncoated magnetite particles with a mean diameter of 50 nm were also fabricated. Several possible mechanisms such as Brownian, Neel and diffusion relaxation processes on heating effects and their influence on SAR are discussed. Several factors which can increase the value of SAR were discussed, including dextran coating, ultrasonic treatment, proper particle size and the presence of defects and disorder in the particles. r 2006 Elsevier B.V. All rights reserved. Keywords: Magnetic fluid hyperthermia; AC losses; Magnetic nanoparticle; Ferrofluid; Brownian relaxation; Neel relaxation
0. Introduction In recent years, magnetic fluid hyperthermia (MFH) has attracted much attention due to considerable heating effects in an AC-magnetic field. It can increase the temperature in tumors to 41–46 1C and therefore kill tumor cells. The applicability for tumor treatment is discussed in Ref. [1]. Among lots of magnetic materials, magnetite is a very promising candidate since its biocompatibility was already proven. So far, magnetite Fe3O4 or maghemite g-Fe2O3 with different sizes and coated by different surfactants were prepared, and their heating effects at various AC-magnetic fields were investigated by several groups [2–7]. The highest values of 960 W/g of specific power absorption rate (SAR) were reported by Hergt et al., which they obtained on suspensions of bacterial magnetosomes at 410 kHz and a field amplitude of 10 kA/m [8]. However, clinical applications are not approved yet up to now. One of the main reasons is the restricted SAR of commonly used particle systems because the heating efficiency cannot be raised simply by increasing the AC-magnetic field amplitude H and field frequency f. Corresponding author. Tel.: +86 21 62932515; fax: +86 21 62804389.
E-mail addresses: [email protected] (L.-Y. Zhang), [email protected] (H.-C. Gu). 0304-8853/$ - see front matter r 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jmmm.2006.11.179
Otherwise, the inductive heating of the healthy tissue would grow prohibitively high. So it is important to enhance the SAR of magnetic materials in order to reduce the tissue load and improve the reliability of therapy. It is well known that the heating of magnetic particles in AC-magnetic field is mainly due to three loss processes: hysteresis losses, relaxation losses and resonance losses. Since resonance relaxation usually occurs at very high frequency, it can be neglected for hyperthermia applications. The hysteresis loss results from the hysteresis properties of magnetic materials, and can be easily estimated from the area of the hysteresis loop by taking into account the proportionality of power with frequency. The relaxation losses can be induced by several relaxation processes existing in the magnetization process. In a fluid, the magnetization reversal usually proceeds via one of the two mechanisms: Brownian and Neel relaxation processes. For particles with high anisotropy where the moment is fixed in the easy direction, the moment can align with the field by physical rotation with a relaxation time of [9] 3ZV H , (1) kT where Z is the viscosity coefficient of the fluid, k is the Boltzmann constant, and VH is the hydrodynamic volume of the particle. When the anisotropy is low, alignment
tB ¼
ARTICLE IN PRESS L.-Y. Zhang et al. / Journal of Magnetism and Magnetic Materials 311 (2007) 228–233
occurs via the usual Stoner–Wohlfarth process subject to thermal activation where the relaxation time is given by the Neel–Arrhenius law [9] tN ¼ t0 expðDE=kTÞ,
(2)
where t0 is typically in the order of a few ns, and if one ignores the magnetic dipole–dipole interaction between particles the energy barrier DE can be expressed as DE ¼ KV+mH ¼ KV(1+H/HK), where KV is the magnetocrystalline anisotropy energy, mH is the interaction between the magnetic moment of the particle (m) and the external field (H), and HK is the anisotropy field, which for a particle system with uniaxial anisotropy and a random distribution of easy axis HK ¼ 0.96K/MSB, where MSB is saturation magnetization of the bulk material [9,10]. For a magnetite with MSB ¼ 93 emu/g, the calculated HK is 1393 Oe. The magnetization reversal proceeds by whichever process has the shorter relaxation time, and the effective relaxation time is given by 1 1 1 ¼ þ . t tB tN
(3)
The relaxation losses can be expressed as [11] P ¼ pm0 w0 H 2 f
2pf t , 1 þ ð2pf tÞ2
(4)
where m0 is the permeability of free space, H and f is the amplitude and frequency of the AC field, and w0 is magnetic field dependent and can be expressed as 3 1 coth x , w0 ¼ wi (5) x x where x is Langevin parameter (x ¼ m0MSHV/kT, MS is the domain magnetization of a suspended particle). The initial susceptibility wi is determined from differentiation of the Langevin relationship. From the above analysis, the losses, that is, the heating of the magnetic materials, not only relates to the amplitude H and frequency f of the AC-magnetic field, but also strongly depends on the physical properties of the materials, for example, the magnetocrystalline anisotropy and the particle size, shape and microstructure, as well as the dynamical size and the viscosity of the fluid. Some of these factors were observed experimentally by other groups. For example, Hergt [12] and Chan et al. [13] reported that the SAR increased with increasing initial susceptibility. Ma et al. [5] found that the magnetite particles with size of 46 nm had the highest SAR, whereas Hergt observed the highest SAR on about 30 nm particle suspensions [8]. It was also found that the size distribution width of nanoparticles has crucial influence on the SAR and can be raised greatly through a size selection process [12]. In addition, Chan discovered that the preparation method also strongly influenced the SAR and SAR can be raised with an ultrasonic treatment and coating by dextran [13].
229
The gel crystallization method has earlier been used to prepare magnetite particles of narrow size distribution with mean diameters ranging between 30 and 1100 nm [14]. In this paper, we prepared dextran-coated magnetite nanoparticles with this method with an additional ultrasonic treatment. For comparison, we also prepared uncoated magnetite particles using the same method. The magnetic properties and the heating effects in the AC field were investigated. The possible heating mechanisms were also discussed. 1. Experimental The uncoated Fe3O4 particles (sample A) were prepared as follows: 0.33 M KOH and 0.15 M KNO3 solutions were mixed in a three-necked round bottom flask. The mixture solution was stirred at 200 rpm and treated by an ultrasonic agitation simultaneously in a 60 1C water bath. And then, 0.17 M FeSO4 was added to the flask at a vigorous stir of 300 rpm. After being kept for 30 min at a constant temperature of 60 1C, the ultrasonic was removed and the mixture was heated to 90 1C and aged for 4 h. Pure nitrogen gas was flowed throughout the entire duration of the experiment. The dextran-coated Fe3O4 particles were prepared using the same method except for adding 7.8 g dextran to the reaction reagent. The obtained samples were washed several times with distilled water by using a powerful permanent magnet. The dextran-coated particles were dispersed in water and formed a stabilized ferrofluid (sample B). The density of the ferrofluid is 1.018 g/cm3, and the mass percent of Fe3O4 in the fluid is 1.34%. The morphology of the particles was investigated on a JOEL JEM 2010 transmission electron microscope (TEM). The crystal structure was characterized by an X-ray diffractometer (XRD, Bruker AXS) with Cu Ka1 radiation. Fourier transform infrared spectroscopy (FTIR, FTS 135 BIO-RAD) was used to verify the coated particles. Mo¨ssbauer spectra (MS, with a source of 57Co) were collected to obtain the micromagnetic structure and hyperfine parameters. The viscosity of the fluid was measured on a DV-III Brookfield Digital Rheometer at 25 1C. Magnetic losses of the samples were investigated by the quasi-static magnetic properties with a vibration sample magnetometer (VSM, Lakeshore 7300) and calorimetrical measurement was carried on a self-made ACmagnetic field with a frequency of 55 kHz and an amplitude of 200 Oe. 2. Results and discussion 2.1. Morphology and structure The TEM images of samples A and B are shown in Figs. 1(a) and (b). The uncoated particles have a polyhedral shape and deviate from spheres. The mean diameter is estimated to be 50 nm, which is near to the single domain size of 54 nm for Fe3O4. The dextran-coated
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Fig. 1. TEM images of magnetite particles: (a) uncoated, and (b) dextran coated.
a
Relative transmission
particles are difficult to disperse and the size is hard to estimate from the TEM image due to their strong agglomerate state. According to the XRD results (not shown), both samples demonstrate a spinel crystal structure with a lattice constant a0 ¼ 8.322 A˚. Sample B has broad diffraction peaks and relatively weak intensity compared with Sample A, which indicates that the dextran-coated particles have relative small size and less crystallization state. According to Scherrer formula, the mean size of the dextran-coated particles is 19 nm and of uncoated is 32 nm, which is less than the size estimated from TEM. One can found that the size of dextran-coated particles is less than the uncoated ones even at the same experimental conditions. Fig. 2 shows the Mo¨ssbauer spectra (MS) of the magnetite particles of the two samples. Sample A has two clear separated peaks that can be fitted by two sextets corresponding to the A- and B-sites of inverse spinel structure. The isomer shifts (IS) relative to iron metal of the two sites are 0.31 and 0.64 mm/s, the quadruple splittings (QS) are 0.001 and 0.007 mm/s, and the hyperfine fields Hhf are 49.0 and 45.6 T, which is in agreement with the typical values for Fe3O4 [15,16]. However, the MS of sample B demonstrate a broadened sextet that can be fitted by two sextets and a doublet. The appearance of 6% of doublet may result from the superparamagnetic particles existing in the samples, which is consistent with the TEM and XRD results. The IS of the two sites are 0.34 and 0.41 mm/s, which is different from the sample A. The Hhf are 45.4 and 39.3 T, which is much lower than bulk materials and sample A. The lower values may be interpreted by the existence of collective magnetic excitation processes due to the fine particle size. In addition, according to the fitted results, the two sextets are clearly separated indicating the samples are Fe3O4 not other iron oxides such as a-Fe2O3 or g-Fe2O3. It is worth noting that magnetite is a ferrimagnetic material with typical inverse spinel structure, the divalent ions Fe2+ being placed in the B-sites and the trivalent ions Fe3+ equally distributed in the A- and B-sites, according to
b
-8
-4
0
4
8
Relative velocity (mm/s) Fig. 2. Mo¨ssbauer spectra of magnetite particles: (a) uncoated, and (b) dextran coated.
the notation [Fe3+]A[Fe3+Fe2+]B. Theoretically, the population ratio of iron ions in A- and B-sites is 1:2. Actually, the ratio is 1:1.8 reported for bulk Fe3O4 [17]. However, according to the fitting results, the relative resonance area ratio of A- and B-sites is 1:0.9 for sample A and 1:0.5 for sample B. These much lower values indicate an inexact stoichiometry and especially the presence of vacancies and structural defects and local variations inside the particles and/or at the particle boundary [16]. The reduction of area ratio between the A- and B-sites may result in a decrease of magnetization.
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0.5
c
571
0.6
1022
0.7
1418 1345 1143
b
3345
Absorbance
0.8
1636
0.9
calculate the volume fraction median diameter, Dm, and the standard deviation, s, of the distribution [19]: " #1=3 18kT wini 1 1=2 Dm ¼ , (6) pM SB 3M S H 0
a
2919
1.0
0.4 4000
3500
3000
2500
2000
1500
1000
231
500
Wavenumber (cm-1) Fig. 3. The IR spectra of: (a) uncoated magnetite particles, (b) dextrancoated magnetite particles and (c) pure dextran.
Fig. 3 shows the IR spectra of samples A and B, as well as pure dextran. The particles were freeze-dried firstly and mixed with KBr powder and compressed to pellets before measurement. As shown in Fig. 3, the band at 571 cm1is the characteristic peak of Fe3O4. The band near 3345, 1639 and 1418 cm1 are ascribed to the hydroxy characteristic peak of water absorbed in the surface or the OH-stretching bands and the bending vibration peak of the hydroxy group. From the IR spectra of three samples, it can be seen that the magnetite particles were indeed coated by dextran. However, the spectra of dextran-coated particles just have little difference with the ones of pure dextran, which indicated that the interactions between dextran and magnetite particles are intermolecular interactions [18]. 2.2. Magnetic properties and losses The hysteresis properties of samples A and B were investigated at room temperature (not shown). The uncoated particles demonstrate hysteresis properties with coercivity of 155 Oe, whereas, the dextran-coated particles are superparamagnetic with no coercivity and remanence. The saturation magnetization sS of dextran-coated particles is 51 emu/g, whereas it is 76 emu/g for the uncoated particles. These values are much lower than the typical value MSB ¼ 93 emu/g for bulk materials. The decreased MS for nanoparticles is attributed to the disordered surface spins as well as disordered magnetic structure from the above MS results. Especially for dextran-coated nanoparticles, the decreased value is also due to the absorption of the surfactant molecules on the particle surface, which causes the spins of the iron atoms close to the surface to be pinned. According to the Langevin theory for superparamagnetism, the magnetic size can be determined [19]. Assuming a lognormal distribution of particle volume, the magnetization curves at room temperature can be used to
1=2 1 3wini 1 s ¼ ln , 3 H0 MS
(7)
where wini is the initial susceptibility, and MS and MSB the saturation magnetization of the ferrofluid and the bulk, respectively. The parameter 1/H0 is defined as the value for which a tangent to the curve M vs. 1/H at high fields crosses the 1/H axis. From the magnetization curve measured for dextran-coated particles, a mean size of Dm ¼ 18 nm and the standard deviation of the distribution s ¼ 0.47 were determined. This magnetically determined value is somewhat smaller than the XRD result (19 nm). From measured hysteresis loops, one can easily estimate the magnetic loss caused by the hysteresis properties by integrating the loop area. For the dextran-coated sample, there is no hysteresis loss contribution according to their superparamagnetic properties without any hysteresis, whereas, for sample A the hysteresis loss can be estimated according to the values of coercivity 155 Oe and saturation magnetization 76 emu/g. For an ensemble of aligned uniaxial particles with the external AC-field parallel to the easy axis, the upper physical limit of power density attainable by means of hysteresis losses is given in the case of a nearly rectangular hysteresis loop by 4m0MSHS(Hs ¼ 2K/(m0Ms)). For the case of statistically oriented particles, one has approximately the relative remanence Mr/ MS ¼ 0.5 and coercivity HC ¼ 0.5HS. Hysteresis loss is reduced by about a factor of 0.25 in compared to the aligned case [17]. And therefore, according to the HC and MS one may estimate the loss by 2m0MSHC for sample A of about 2.3 J/kg, which gives for a frequency of 55 kHz a loss power of 126 W/g. This evaluation is a very rough approximation since the hysteresis loop in the AC field (so-called Rayleigh loops) is greatly different from the hysteresis loops measured in a static field. To avoid the evaluation errors and to obtain the absolute heating results, the SAR of two samples was measured calorimetrically at an AC-magnetic field with a frequency of 55 kHz and an amplitude of 200 Oe, which is in the range for biomedical applications for hyperthermia [20]. In the experiment, the increase of temperature was recorded after applying the AC-magnetic field to a sample of known heat capacity that contains the particles to be investigated. From the measured temperature rate, the SAR was calculated as P C i mi DT SAR ¼ i , mFe Dt where Ci and mi is the heat capacity of every component whose temperature will be increased when applied
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AC-field. At 55 kHz and 200 Oe, a value of 4.5 W/g is found for sample A and 57 W/g for sample B. The value of 4.5 W/g is much lower than 126 W/g calculated from the hysteresis loop of sample A. Since the mean particle size of sample A is 50 nm from TEM, which is near the single domain size, and the particles were hardly dispersed in water, there are no Brownian or Neel relaxation losses contributing to the SAR, and therefore, the SAR of sample A is mainly due to the hysteresis loss. The saturation field for sample A is about 5000 Oe, which is much higher than 200 Oe of the applied AC-magnetic field, that is, the loop is far from the saturation state at 200 Oe. And therefore, the hysteresis loss at 200 Oe will be much lower than that at a saturating field due to the rapidly reduced loop area with decreasing field amplitude [21]. This is the reason that the particles with large coercivity and high hysteresis loss dominated by single domain behavior are unsuitable for hyperthermia because in hyperthermia rarely the full hysteresis loop of such samples can be used since there are restrictions of the field amplitude mainly due to technical reasons or the biocompatibility issue for medical applications. In addition, as mentioned above, the value of 126 W/g is a very rough approximation due to the different loops in an AC and in a static field. From the calorimetrical measurement, it also can be noticed that the SAR value for dextran-coated ferrofluid is much higher than the uncoated single domain particles, and from the superparamagnetism of the sample B one can find that there is no hysteresis loss contributing to the SAR. As mentioned in the introduction, the heating of the ferrofluid may result from relaxation processes, for example, Brownian or Neel relaxation mechanism. Since the viscosity of the fluid is only associated with Brownian relaxation time, we changed the viscosity of the ferrofluid using glycerol and immobilized the fluid using agarose to investigate the contribution of Brownian mechanism to SAR. Fig. 4 shows the SAR of dextran-coated magnetite ferrofluid in dependence on the viscosity of the fluid. The SAR increases with the viscosity from 57 W/g for original fluid with a viscosity of 1.00 mPa s and reaches a maximum of 76 W/g for the fluid with 1.96 mPa s. The tendency of the relationship of SAR with viscosity is in agreement with the results predicted theoretically by Rosensweig [11]. This indicates that the Brownian relaxation process has contributions to SAR. According to the Debye model [22], the losses will reach a maximum at otB ¼ 1, thus, from the frequency of 55 kHz of the AC field, it is possible to estimate the relaxation time and hence the dynamic size of the particle in terms of Eq. (1). Using values of Z ¼ 1.00 mPa s, of water at the temperature of 293 K, the hydrodynamic diameter was calculated as dH ¼ 20 nm. This value is much lower than that measured on photo correlation spectroscopic (PCS) of about 90 nm mainly due to the strong aggregation state just as observed on TEM. The heating effect of the immobilized fluid in gel was also investigated. The SAR in this case was 35 W/g,
80
75 SAR (W/gsFe)
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70
65
60
55 1
2
3
4
5
6
Viscosity of ferrofluid (mPa•s) Fig. 4. The SAR of dextran-coated magnetite ferrofluid measured calorimetrically in dependence on the viscosity of the fluid.
indicating that there are other contributions to the SAR. Since Neel relaxation is difficult to identify by the experimental method directly, we used values of f ¼ 55 kHz and K ¼ 1.35 104 J/m3 at a temperature of 293 K to estimate the particle size. The calculated diameter d is 16 nm in terms of Eq. (2), which is somewhat smaller than the above determined sizes of 19 and 20 nm of XRD and VSM. Since the particle size has a distribution, and Neel relaxation time is very sensitive to the size, there must have been contributions to SAR resulting from the Neel relaxation mechanism. In addition, since there may exist many vacancies, structural defects and local variations inside the particles and/or at the particle boundary according to the above MS results, other losses, such as magnetic after effects resulting from diffusion relaxation processes, may also have contributed to SAR. The heating of dextran-coated magnetite ferrofluid in dependence on the amplitude H of the AC field was also investigated. The increase of temperature vs measurement time at different H is shown in Fig. 5. The inset shows the rate of temperature increase DT/Dt as a function of amplitude H. It can be seen that DT/Dt increases with increasing H, and for low amplitudes a square law is found below 9 kA/m, whereas for high amplitudes this relationship changes. In fact, the relationship between the SAR and H is more complicated than a square or third order power law. From Eq. (4), one can find that the loss power P is not only in proportion to H2 but also has the function of w0,t and f. From Eqs. (2) and (5) it can be seen that both w0 and tN are related to H. At low fields, the influence of H on w0 and tN can be neglected; however, at high field the influence is strong and therefore the square law is unsuitable. 3. Conclusions Dextran-coated magnetite ferrofluids were prepared by the gel crystallization method with ultrasonic treatment.
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ΔT/Δt (°C/min)
70
Temperature (°C)
60
8 7 6 5 4 3 2 1 0
50
Applied field (Oe): 60 80 103 123 150 170 190
100 150 200 250 2
6
2
2
H (10 A /m )
50
40
30
20 -2
0
2
4
6
8
10
12
14
Time (min) Fig. 5. The increase in temperature vs. measurement time at different ACmagnetic fields for dextran-coated magnetite ferrofluid. The inert shows the temperature increase rate as a function of amplitude H of the AC field.
For comparison, magnetite particles with diameter of 50 nm were also prepared. The highest SAR for ferrofluid has the value of 75 W/g, which is much higher than 4.5 W/g for the 50 nm uncoated particles at 55 kHz and 200 Oe. The heating for uncoated particles is mainly due to hysteresis loss, whereas for magnetite ferrofluid it results from the Brownian and Neel relaxation mechanism. The magnetic after effect due to diffusion relaxation mechanism may also contribute to SAR. According to our results, the SAR of magnetite ferrofluid can be increased by several methods, such as coating with dextran, ultrasonic treatment, adjusting the viscosity, preparing monodispersed particles, as well as having defects and disorders present in the particles. Acknowledgments The authors would like to thank the Key Laboratory for Magnetism and Magnetic Materials of MOE in Lanzhou
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University for magnetic properties and Mo¨ssbauer spectra measurement. The authors also thank the Instrumental Analysis Center of SJTU for TEM, XRD and FTIR measurements. This work was supported by the National 863 high-tech program (2005AA302H10). References [1] R. Hergt, R. Hiergeist, I. Hilger, et al., Recent Res. Dev. Mater. Sci. 3 (2002) 723. [2] D.C.F. Chan, D.B. Kirpotin, P.A. Bunn, J. Magn. Magn. Mater. 122 (1993) 374. [3] N.A. Brusentsov, V.V. Gogosov, T.N. Brusentsov, et al., J. Magn. Magn. Mater. 225 (2001) 113. [4] A. Jordan, R. Scholz, K. Maier-Hauff, et al., J. Magn. Magn. Mater. 225 (2001) 118. [5] M. Ma, Y. Wu, J. Zhou, et al., J. Magn. Magn. Mater. 268 (2004) 33. [6] R. Muller, R. Hergt, M. Zeisberger, et al., J. Magn. Magn. Mater. 289 (2005) 13. [7] X. Wang, H. Gu, Z. Yang, J. Magn. Magn. Mater. 293 (2005) 334. [8] R. Hergt, R. Hiergeist, M. Zeisberger, et al., J. Magn. Magn. Mater. 293 (2005) 80. [9] M.B. Mantecon, K. O’Grady, J. Magn. Magn. Mater. 296 (2006) 124. [10] P.C. Morais, A.L. Tronconi, F.A. Tourinho, et al., Sol. Stat. Commun. 101 (1997) 693. [11] R.E. Rosensweig, J. Magn. Magn. Mater. 252 (2002) 370. [12] R. Hergt, R. Hiergeist, M. Zeisberger, et al., J. Magn. Magn. Mater. 280 (2004) 358. [13] D.C. Chan, D.B. Kirpotin, P.A. Bunn, Scientific and Clinical Applications of Magnetic Carriers, Plenum Press, New York, 1997. [14] T. Sugimoto, E. Matijevic, J. Colloid. Interface Sci. 74 (1980) 227. [15] J.M. Daniels, A. Rosencwaig, J. Phys. Chem. Solids 30 (1969) 1561. [16] E. Bonetti, L. Del Bianco, S. Signoretti, et al., J. Appl. Phys. 89 (2001) 1806. [17] U. Gonser, Mo¨ssbauer Spectroscopy, Springer, Berlin, 1975. [18] X.Q. Xu, H. Shen, J.R. Xu, et al., Appl. Surf. Sci. 252 (2005) 494. [19] E. Kneller, Theory of the magnetization curve of small crystals, in: H.P.J. Wijn (Ed.), Encyclopedia of Physics, Ferromagnetism, Springer, NewYork, 1966. [20] A. Jordan, R. Scholz, P. Wust, et al., J. Magn. Magn. Mater. 201 (1999) 413. [21] R. Hergt, W. Andra¨, C.G. Ambly, et al., IEEE Trans. Magn. 34 (1998) 3745. [22] P. Debye, Polar Molecules, The Chemical Catalog Company, NewYork, 1929.