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Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL, USA
Department of Chemistry, The University of Alabama, Tuscaloosa, AL, USA
ar t ic l e i nf o
a b s t r a c t
Article history:
Received 5 March 2014
Received in revised form
2 September 2014
Accepted 25 March 2015
Available online 30 March 2015
Heating of nanoparticles (NPs) using an AC magnetic eld depends on several factors, and optimization
of these parameters can improve the efciency of heat generation for effective cancer therapy while
administering a low NP treatment dose. This study investigated magnetic eld strength and frequency,
NP size, NP concentration, and solution viscosity as important parameters that impact the heating efciency of iron oxide NPs with magnetite (Fe3O4) and maghemite (-Fe2O3) crystal structures. Heating
efciencies were determined for each experimental setting, with specic absorption rates (SARs) ranging
from 3.7 to 325.9 W/g Fe. Magnetic heating was conducted on iron oxide NPs synthesized in our laboratories (with average core sizes of 8, 11, 13, and 18 nm), as well as commercially-available iron oxides
(with average core sizes of 8, 9, and 16 nm). The experimental magnetic coil system made it possible to
isolate the effect of magnetic eld parameters and independently study the effect on heat generation.
The highest SAR values were found for the 18 nm synthesized particles and the maghemite nanopowder.
Magnetic eld strengths were applied in the range of 15.147.7 kA/m, with eld frequencies ranging from
123 to 430 kHz. The best heating was observed for the highest eld strengths and frequencies tested,
with results following trends predicted by the Rosensweig equation. An increase in solution viscosity led
to lower heating rates in nanoparticle solutions, which can have signicant implications for the application of magnetic uid hyperthermia in vivo.
& 2015 Elsevier B.V. All rights reserved.
Keywords:
Magnetic uid hyperthermia
Iron oxide nanoparticles
Magnetic eld strength
Magnetic eld frequency
Specic absorption rate
1. Introduction
Magnetic uid hyperthermia (MFH) using localized iron oxide
NPs offers a signicant benet over whole body and regional hyperthermia, which can lead to several vascular and cardiac disorders [13]. MFH has also been shown to kill cells faster as
compared to traditional hyperthermia methods, which can play an
essential role in reducing the therapy administration time for
cancer treatment [4]. MFH can reduce side effects in patients while
amplifying treatment of cancer using superparamagnetic NPs,
which can be specically targeted using antibodies or peptide
sequences [5, 6] and directed to cancerous tissue through the
enhanced permeation and retention (EPR) effect [7]. Magnetic
elds in the kHz to MHz range have been investigated for heat
generation in various MFH systems using superparamagnetic and
ferromagnetic iron oxide NPs [8, 9]. To be used effectively for
cancer treatment, the least possible dose of NPs should be
n
http://dx.doi.org/10.1016/j.jmmm.2015.03.085
0304-8853/& 2015 Elsevier B.V. All rights reserved.
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
SAR (W /g) =
ms cp T
mnp t
(1)
P = o o H 2f
2 f
1 + (2f)2
(2)
97
98
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
Table 1
Properties of NPs investigated for magnetic heating.
Nanoparticles
Particle ID
uidMAG D
Water
uidMAG PAD
4.3 7 0.1
6.4 7 0.1
8.6 7 0.1
8.3 7 0.2
Water
6.2 7 0.1
10.8 70.2
6.4 7 0.0
8.17 0.0
1.6 7 0.0
Hexane 8 72
117 2
137 4
187 4
Water
167 9
Maghemite without
coating
a
TDMNP8
TDMNP11
TDMNP13
TDMNP18
Maghemite
nanopowder
Magnetization at
10,000 Oe M (emu/g)e
Magnetic susceptibility o e
8 72
197 7c;60d
807 6
0.127 0.03
9 72
297 9c;55d
467 1
0.05 70.01
50
0.04
67
57 g
0.13
0.11 g
357 10c;54d
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
2.4. NP characterization
Images of each of the iron oxide NPs were collected using
transmission electron microscopy (TEM, FEI Technai F-20, Hillsboro, OR). The mean particle size of NPs was found by performing
size analysis on TEM images using NIH Image J software. The hydrodynamic diameters of aqueous NP dispersions were measured
using a Malvern ZEN3600 dynamic light scattering (DLS) device
(Malvern, Worcestershire, UK).
X-ray photoelectron spectroscopy (XPS) was used to determine
the oxidation state of the iron oxide NPs. Here, samples of iron
oxide NPs were washed with acetone to remove the surface
coating of oleic acid and oleylamine, followed by placing them
under vacuum in a vacuum oven set to ambient temperature until
they dried for 24 h. The samples were then deposited onto copper
tape for XPS analysis, which was carried out on a Kratos AXIS 165
Multitechnique Electron Spectrometer (Manchester, UK) using a
monochromatic aluminum source set to 10 mA, 12 kV. High resolution scans were performed with the analyzer pass energy set
to 20 mA and the dwell time set to 2000 ms. Two sweeps were
performed for each scan. Because it has been shown that the C 1s
peak is unsuitable for use as a reference for charge correction on
iron oxide samples [37], the O 1s peak at 530.0 eV binding energy
was used for this purpose.
High resolution scans of the Fe 2p region of iron oxides have
been previously shown to be useful for qualitative studies of the
ionic and oxidation states of iron, and the presence or absence of a
satellite peak between the Fe 2p1/2 and Fe 2p3/2 has been used to
differentiate between magnetite and maghemite [37], as only
maghemite samples produce a satellite peak attributed to Fe 2p3/2.
The position of the Fe 2p3/2 peak is typically 711 eV, with the satellite peak located approximately 8 eV higher [37].
2.5. Chacterization of magnetic properties of NPs
Magnetization curves were acquired using a Digital Measurement Systems vibrating sample magnetometer (VSM). The magnetometer was calibrated using a high purity nickel standard.
Powder samples were carefully weighed on an analytical balance.
The samples were placed on Scotchs tape and the tape folded over
to make a sandwich with the particles trapped inside the tape. The
99
excess Scotchs tape was trimmed off with scissors. The samples
were afxed to a quartz sample holder using silicon vacuum
grease. Samples of uidMAG D NPs were dried from aqueous solution to give free-standing lms. The lms were weighed on an
analytical balance and then afxed to the quartz sample holder.
Full hysteresis curves were obtained with a saturating eld of
10,000 Oe. The step size was 10 Oe in the range from 1000 to
1000 Oe.
2.6. Magnetic heating of NPs
All magnetic heating experiments were performed using a
custom-designed hyperthermia coil (Induction Atmospheres, Rochester, NY) (Fig. 1). A 5 kW power supply (Ameritherm, Model
Novastar 5 kW, Scottsville, NY) is connected to a heat station to
which the coils are attached. The hollow coils are designed to allow circulating chilled water to pass through, in order to minimize
temperature rise in the coils. A circulating chiller bath (Koolant
Koolers Model JT1000, Kalamazoo, MI) was set to circulate water
through the coils at 18 C. A 4 cm inner diameter coil with two
turns in a distance of 1.2 cm was separated from two identical
turns by a gap of 2 cm. This 4-turn coil was used for all heating
experiments, as it had a sufciently wide coil diameter to allow
insulation to t between the coil and samples to minimize nonspecic heating of samples due to the heating of the coil surfaces.
An additional 6-turn coil (4 cm inner diameter) could be placed in
series with the magnetic heating coil, and was used to modulate
the frequency applied to the NP dispersions (frequency modulator
coil shown on left side in Fig. 1). A copper bar can be placed across
any number of the coils to allow a total of seven testing frequencies at each voltage setting (including one with the frequency
modulator removed).
Each NP dispersion was taken at a measured volume of 1.2 mL
and lled in a plastic micro-centrifuge tube, which was positioned
in the axial and radial center of the top two turns of the coil and
surrounded by a layer of insulating foam. The magnetic eld
strength was adjusted by altering the voltage setting in the heating
station circuitry, which in turn changed the current supplied to the
coil. The frequency was modied by placing the frequency modulating coil in series with the hyperthermia coil and adjusting the
copper bar so that the circuit would bypass from zero to all six
100
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
Table 2
SAR values for magnetic heating of NPs at xed eld strengths and frequencies.
Nanoparticle
type
Field
strength, H
(kA/m)
Frequency, f
(kHz)
uidMAG D
(8.6 mg/mL)
15.1
22.8
35.8
38.2
47.7
38.2
194
3.7 7 1.2
15.3 7 2.9
26.8 7 2.9
29.9 7 1.0
43.3 7 4.4
15.17 2.1
23.17 2.8
29.9 7 1.0
105.6 7 5.0
41.7 7 2.3
6.5 7 1.5
14.6 7 1.5
30.17 2.1
33.47 1.2
52.8 7 4.3
75.7 7 2.3
325.9 7 16.0
249.17 4.7
uidMAG PAD
TDMNP8
TDMNP11
TDMNP13
TDMNP18
Maghemite NP
47.7
22.8
35.8
47.7
47.7
47.7
47.7
38.2
38.2
123
143
194
430
194
194
194
194
194
430
430
2.7 7 0.9
11.17 2.1
19.4 7 2.1
21.6 7 0.7
31.3 7 3.2
10.9 7 1.5
16.7 7 2.0
21.6 7 0.7
76.4 7 3.6
30.2 7 1.7
4.7 7 1.1
10.6 7 1.1
21.8 7 1.5
24.27 0.9
38.2 7 3.1
54.8 7 1.7
235.87 11.6
174.2 7 3.3
a
Iron oxide crystal structure determined by XPS for normalizing SAR values
per gram NP.
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
101
Fig. 2. Representative TEMs of particles investigated: A) FluidMAG D NPs, B) TDMNP11 NPs, C) TDMNP18 NPs, D) maghemite nanopowder.
Fig. 3. XPS spectra used to determine the iron oxide structure of uidMAG D,
maghemite nanopowder, TDMNP 18, TDMNP 13, and TDMNP 11 NPs.
102
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
Fig. 4. Effect of magnetic eld strength on temperature rise for uidMAG D NPs
(f 194 kHz, [NP]8.6 mg/mL).
4.3
6.4
8.6
45.5 76.4
43.9 73.2
43.3 74.4
32.9 7 4.6
31.8 7 2.3
31.3 7 3.2
a
Iron oxide crystal structure determined by XPS for normalizing SAR values
per gram NP.
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
103
Fig. 5. Effect of magnetic eld frequency on temperature rise for uidMAG D NPs
(H 38.2 kA/m, [NP] 8.6 mg/mL).
104
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
viscosities points to a reduction in the Brownian relaxation component of heating as found by Chen et al. for iron oxide NPs in
0.9 cP to 43.2 cP glycerol solutions [35]. Because blood and cell
proteins attach rapidly to foreign objects such as magnetic NP
through opsonization [45], particles that heat primarily through
Brownian relaxation are not likely to be candidates for MFH
therapy.
Bf 2
1 + (Bf )2
(3)
1
1 + B2f 2
=
P
ABf 2
(5)
4. Conclusions
P= A
1
1
B
=
+
P
A
ABf 2
(4)
Fig. 6. Effect of viscosity on SAR values for uidMAG D and maghemite nanopowder dispersed in water and various alginate solutions (H38.2 kA/m, f 430 kHz, [uidMAG
D] 8.6 mg/mL, [Maghemite nanopowder] 1.6 mg/mL). uidMAG D was not tested at 481 cP.
R.R. Shah et al. / Journal of Magnetism and Magnetic Materials 387 (2015) 96106
Fig. 7. Linear t of SAR data to t Rosensweigs equation. SAR values from magnetic
heating data for FluidMAG D experiments conducted at f 194 kHz were plotted as
a function of H2 in Fig. 7A. In Fig. 7B, heating data with variable frequency at a xed
H 38.2 kA/m were plotted according to Eq. (5).
Acknowledgments
The authors gratefully acknowledge the support of the National
Cancer Institute under NIH grant R21CA141388, and The University
of Alabama through funds supporting graduate student tuition and
stipends. They also thank Dr. Yuping Bao for use of dynamic light
scattering equipment in her lab. This work used instruments in the
Central Analytical facility, which is supported by The University of
Alabama.
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