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Mechanisms of hyperthermia in magnetic nanoparticles

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2013 J. Phys. D: Appl. Phys. 46 312001
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IOP PUBLISHING

JOURNAL OF PHYSICS D: APPLIED PHYSICS

J. Phys. D: Appl. Phys. 46 (2013) 312001 (6pp)

doi:10.1088/0022-3727/46/31/312001

FAST TRACK COMMUNICATION

Mechanisms of hyperthermia
in magnetic nanoparticles
G Vallejo-Fernandez1 , O Whear1 , A G Roca1 , S Hussain2 , J Timmis2 ,
V Patel2 and K OGrady1,2
1
2

Department of Physics, The University of York, York YO10 5DD, UK

Liquids Research Ltd, Unit 3B Mentec, Deiniol Road, Bangor LL57 2UP, UK

Received 2 April 2013, in final form 4 June 2013

Published 10 July 2013
Online at stacks.iop.org/JPhysD/46/312001
Abstract
We report on a theoretical framework for magnetic hyperthermia where the amount of heat
generated by nanoparticles can be understood when both the physical and hydrodynamic size
distributions are known accurately. The model is validated by studying the magnetic, colloidal
and heating properties of magnetite/maghemite nanoparticles of different sizes dispersed in
solvents of varying viscosity. We show that heating arising due to susceptibility losses can be
neglected with hysteresis loss being the dominant mechanism. We show that it is crucial to
measure the specific absorption rate of samples only when embedded in a solid matrix to avoid
heating by stirring. However the data shows that distributions of both size and anisotropy must
be included in theoretical models.
(Some figures may appear in colour only in the online journal)

where f0 = 109 s1 , K is the anisotropy constant of the

particles (3 105 ergs cm3 in the case of magnetite particles)
[4], V their volume, H is the applied field, HK is the anisotropy
field, kB is Boltzmanns constant and T is the temperature
of measurement. Equation (2) for the Brownian relaxation
is controlled by hydrodynamic parameters. Hence Vh is the
hydrodynamic volume and is the viscosity of the medium.
The hydrodynamic volume Vh is not a well defined parameter
because in colloidal dispersions the particles are coated with
one or more dispersants which may form multiple layers on
the surface. Also as the particles move, entrained molecules
of the carrier liquid will also contribute to the overall value of
Vh . Generally Vh is measured using techniques such as photon
correlation spectroscopy (PCS). In practice a 10 nm diameter
particle coated with oleic acid, one of the most commonly
used dispersants, has a typical hydrodynamic size of about
2575 nm.
The existence of two relaxation times leads to a combined
relaxation time given by

Magnetic hyperthermia occurring in colloids of magnetic

nanoparticles has been demonstrated to reduce tumour size in
human beings [1]. However, at the present time the mechanism
by which the heat is generated is not fully understood [2]. In
this Fast Track Communication we report a detailed study of
the heating properties of magnetic nanoparticles of different
sizes for hyperthermia applications. In particular we have
modified the colloidal properties for three samples with
different particle sizes so as to control the mechanisms leading
to heat dissipation.
Several heating mechanisms are possible, associated with
susceptibility loss, hysteresis loss and viscous heating, i.e.
stirring. Susceptibility loss occurs in superparamagnetic
particles and has two relaxation times associated with Neel
relaxation and Brownian rotation of the particles as they are
in a liquid environment [3]. The Neel (N ) and Brownian (B )
relaxation times are given by



1
KV (1 H /HK )2
N =
(1)
exp
f0
kB T
B =
0022-3727/13/312001+06$33.00

3Vh
,
kB T

(2)
1

N B
.
N + B

2013 IOP Publishing Ltd

(3)
Printed in the UK & the USA

J. Phys. D: Appl. Phys. 46 (2013) 312001

Fast Track Communication

Above a critical diameter in zero or a small field (Dp (0)) the

particles will be blocked and hence heating due to susceptibility
losses will not occur. This critical diameter is given by [5],


6kB T ln(tf0 ) 1/3
,
(4)
Dp (0) =
K
where t is the time of measurement. Above Dp (0) the particles
will switch and heating due to hysteresis loss will occur.
Dp (0) denotes the critical size in zero field. For hyperthermia
applications an ac field of up to 200 Oe at a frequency of around
100 kHz is generally used [6]. The low amplitude of the field
will limit the fraction of blocked particles that undergo reversal
and, hence, hysteresis heating. At 111.5 kHz, the value used
in our experiments, the coercivity (Hc ) variation with size (D)
is given by [7],


 
54.6kB T 1/2
,
(5)
Hc = HK 1
KD 3

Figure 1. The critical diameters (Dp (0) = 13.5 nm and

Dp (H ) = 19.4 nm for K = 3 105 ergs cm3 ) separating
contributions to heating arising from ac, hysteresis losses and
stirring at a frequency of 111.5 kHz and an applied field of 250 Oe.
The distribution shown is that for sample C.

where the factor 54.6 is the value of 6 ln(tf0 ) evaluated

at 111.5 kHz. This means that particles above a given
diameter (Dp (H )) will not contribute to either susceptibility
or hysteresis loss heating. The value of this diameter depends
upon the applied field H and can be written as



H Ms 2/3
Dp (0),
(6)
Dp (H ) = 1
0.96K

where 0 is the dc initial susceptibility and is the combined

relaxation time from superparamagnetic Neel and Brownian
processes. In real systems a distribution of particle volumes
and hydrodynamic sizes and, hence, relaxation times occurs
given by
 Vp (0)
eff
N =
N (V )f (V ) dV
(9)

where Ms is the saturation magnetisation of the particles and

the factor 0.96 arises due to the random distribution of easy
axes i.e. HK = 0.96K/Ms [8]. We have used a value of K
of 3 105 erg cm3 which corresponds to an average particle
elongation of r = 1.8. From transmission electron microscopy
(TEM) images (e.g. figure 2) this choice seems reasonable
and is the value reported for particles prepared by a similar
route [4]. Only those particles with a diameter Dp (0) < D <
Dp (H ) will contribute to hysteresis loss heating. This is shown
in figure 1.
For particles with D > Dp (H ) the moments cannot switch
in the 250 Oe field. The majority of the particles are not aligned
with the solenoidal field and viscous heating due to stirring
of the particles in the colloid will occur. At a frequency
of 100 kHz (6 106 rpm) this effect, which will be more
pronounced for aggregated particles, probably accounts for
some of the anomalously large heating effects that have been
reported (e.g. [9]). The presence of a solenoidal field with a
finite RMS value will also lead to the gradual alignment of
bigger particles and aggregates thus accounting for non-linear
heating rates that have also been reported (e.g. [10]).
This leads to three contributions to the heat generated in
the system: susceptibility losses (Pac ), hysteresis loss (Phys )
and magnetic stirring (Pstir ). The power generated through
susceptibility losses is given by [3],
Pac = f

H 2 ,


Beff =

B (Vh )f (Vh ) dVh ,

(10)

where Neff and Beff are the effective relaxation times,

f (V ) is the distribution of physical volumes and f (Vh )
is the distribution of hydrodynamic volumes, Vp (0) is the
volume of a particle having a diameter Dp (0) and Vh (0) is
the hydrodynamic volume of a particle having a physical
diameter Dp (0).
In the case of hysteresis heating the amount of heat
generated is proportional to the frequency multiplied by the
area of the loop. However, it is only the irreversible part of
the magnetisation that contributes to this effect. Since the
particles are randomly oriented and, hence, their remanence
is equal to 0.5Ms , and only particles with a diameter D
[Dp (0) < D < Dp (H )] are blocked and can be switched
in the field H , Phys can be written as

Phys = 2Ms

VP (H )

Hc (V )f (V ) dV ,

(11)

Vp (0)

where Vp (H ) is the volume of a particle having a

diameter Dp (H ).
A distribution of anisotropy constants is likely to occur
although a uniform value of K has been assumed in our
calculations. The effect of this assumption is to imply that
the actual switching field distribution (SFD) will be broader
than the particle size distribution. A simple qualitative
consideration of the effect of a distribution of K shows that it
would broaden the overall energy barrier distribution. Hence

(7)

where f is the frequency of measurement (= 1/t) and

is

the complex part of the ac susceptibility.

can be written as
2f



=
,
0
1 + (2f )2

Vh (0)

(8)
2

J. Phys. D: Appl. Phys. 46 (2013) 312001

Fast Track Communication

calculations based on a constant value of K will give an

overestimate of the expected heating. Assuming a Gaussian
distribution of K with a standard deviation of 0.2 times the
mean, a reduction in the calculated value of the specific
absorption rate (SAR) of about 50% would result depending on
the region of the SFD that generated the hysteresis heating. For
each grain size the limitation of hysteresis heating would be at
a value of V associated with the median value of the anisotropy
constant. There is no known technique for the measurement of
the distribution of anisotropy constants in fine particle systems.
Hence at the present time our theory is as accurate as possible.
The calculation of the heat generated by the frictional
drag on the particle (Pstir ) is extremely complex. We have
no value for the drag coefficient between a coated nanoparticle
and the liquid. However, the flow of the liquid around such
particle will almost certainly be turbulent and hence none of
the standard equations of hydrodynamics apply. Nonetheless
magnetic stirring of the liquid will lead to a frictional heating
effect. This effect is not only impossible to calculate but also
impossible to control. Stirring may also lead to a lag between
the alignment of the moment and the field which will create
another form of magnetic heating similar to the susceptibility
loss.
The amount of heat generated by magnetic nanoparticles
is normally quantified in terms of the SAR which represents
the power generated per unit mass of magnetic material in
the solution. Depending on the exact procedure followed to
measure the SAR, widely differing results may be obtained.
Furthermore factors such as container shape and sample
volume can lead to different SAR values for the same particles
[11]. SAR is given by
SAR =

C T
,
t

is independent of the colloid environment. The matrix used

will only affect Brownian and viscous heating effects. For
in vivo applications the viscosity is likely to be significantly
greater than in a colloid, for example the viscosity of blood
is 10 cP, and hence dynamic effects will be suppressed if not
eliminated.
The physical median particle size (Dm ) for each sample
was measured by TEM using a 200 keV JEOL 2011 TEM.
Samples were prepared by placing one drop of a dilute
suspension of the particles in hexane on a carbon coated grid
and allowing the solvent to evaporate. Over 500 particles were
measured using a Zeiss particle size analyser to ensure good
statistics. This technique uses an equivalent area process to
obtain the particle diameter. The data were fitted to a lognormal
distribution.


(ln D ln D)2
1
dD (13)
exp
f (D) dD =
2 2
2 D
Measuring a large number of particles is essential to determine
the standard deviation of the distribution ( ) accurately. Note
that is the standard deviation of ln(D). Figures 2(a), (b)
and (c) show typical bright field TEM images for the samples
studied in this work. Figure 2(d) shows the particle size
distribution for each sample. The median particle size and
standard deviation for each distribution are summarized in
table 1. We note that the TEM images show a proportion of
elongated particles. This is a facet of the preparation process.
High resolution TEM imaging (not shown) indicates that the
elongated particles are not polycrystalline.
A PCS (Malvern Instruments Zetasizer) was used to
measure the hydrodynamic size distribution for each sample.
The viscosity of the colloids was measured at 27 C using a
Wells-Brookfield cone and plate viscometer. Details of the
median hydrodynamic size (Dh ) and the standard deviation of
the distribution (h ) as well as the viscosity () are summarized
in table 1.
Figure 3 shows the susceptibility loss peak given by
the complex part of the ac susceptibility (

) for the
samples dispersed in Isopar V. The position of the ac
loss peak varies over an order of magnitude depending
on the physical/hydrodynamic properties of the samples.
Interestingly, there is no monotonic variation of the position of
the peak with the median physical particle size. This highlights
the importance of the distribution of hydrodynamic sizes when
calculating susceptibility losses. The solid lines in figure 3 are
calculated fits from equations (8), (9) and (10). The calculation
of

(f ) from equation (8) used a value of 0 measured for
each sample using an alternating gradient force magnetometer.
This data shows that for typical frequencies of 100 kHz used
in hyperthermia applications the susceptibility losses are due to
Brownian relaxation. It is well established that in these colloids
two susceptibility mechanisms occur as given by equations (1)
and (2). The volume dependence in these formulae indicates
that a transition from Neel to Brownian reversal occurs at
8 nm depending on the viscosity of the colloid. At this size
the Neel relaxation frequency is of the order of MHz and will
make little contribution at 100 kHz. This susceptibility loss

(12)

where C is the specific heat of the colloid, is the concentration

of Fe per ml of solution, is the density of the colloid
and T /t represents the heating rate. Equation (12) does
not take into account the heat capacity of the sample holder.
The heating of the sample holder will use a significant
proportion of the power generated. Hence, it is crucial that all
measurements are made using identical conditions in the same
volume of sample. However, this also suggests that it might
not be possible to compare measurements made in different
measurement systems.
All samples studied in this work were supplied by Liquids
Research Ltd [12]. The particles were prepared by the coprecipitation method [13], with controlled growth conditions
giving a narrow size distribution. The particles are nominally
Fe3 O4 but the exact composition will lie between Fe3 O4 and
Fe2 O3 . The samples were dispersed in two solvents with
different viscosities to study the effect of the viscosity of the
suspension on the heating properties of the samples and did
not have identical surfactant coatings. The solvents used were
the isoparaffin oils Isopar M and Isopar V [14], which have
viscosities of 3.0 cP and 10.8 cP, respectively. The samples
were also dispersed in a wax to eliminate heating effects arising
from Brownian relaxation of the particles and viscous heating.
The critical diameter above which hysteresis heating will occur
3

J. Phys. D: Appl. Phys. 46 (2013) 312001

Fast Track Communication

Figure 2. TEM images (a), (b), (c) and particle size distributions (d) for samples studied in this work. The solid lines are calculated from
equation (13).

changing the capacitor and coil configuration. This allowed us

to study the heating characteristics of the samples at different
fields and constant frequency. All measurements were made
under identical conditions and concentrations and are therefore
comparable. Figure 4 shows the SAR for all samples as a
function of the applied field. For Isopar M and Isopar V,
C = 2206 J kg1 K1 and for the wax C = 2140 J kg1 K1 .
The mass ratio of particles to liquid = 20 mg Fe ml1
for all samples. This concentration of iron corresponds to
approximately 28 mg of Fe3 O4 per ml or a ferrofluid with a
concentration of 30 G. In colloids of these concentrations and
with the dispersion quality that can be seen in the TEM images,
the effect of dipoledipole interactions will be small. However,
we cannot exclude the possibility that aggregates or flocculates
of particles would affect the hysteresis. These results together
with those for hysteresis loss are shown in table 2.
Table 2 shows the contribution to the SAR from hysteresis
and susceptibility loss effects for all samples which were
calculated from equations (11) and (7), respectively. From the
calculated data it is clear that the contribution to the SAR from
susceptibility loss is very small except for sample A where it
is 17% of the total. For samples B and C it is insignificant.
Hence for in vivo use with tissue having a minimum viscosity
of 10 cP there will be little or no contribution to the SAR from
susceptibility loss.

Table 1. Particle and hydrodynamic size parameters for samples

dispersed in isopar M and isopar V.
Solvent

Dm (nm)
(cP) Dh (nm) h
Sample 0.1
0.01 0.1 1
0.05

Isopar M A
B
C
Isopar V A
B
C

10.3
11.7
15.2
10.3
11.7
15.2

0.16
0.15
0.19
0.16
0.15
0.19

3.0

10.8

22
27
19
20
36
25

0.53
0.39
0.44
0.43
0.31
0.39

is beyond the range of our susceptometer but its contribution

at 111.5 kHz is negligible as shown in figure 3. For samples
dispersed in wax Neel relaxation will be the only susceptibility
loss mechanism as the particles will not be able to physically
rotate.
The heating properties of the colloids were measured
using a Nanotherics Magnetherm system [15]. The system
consists of a sample coil enclosure, a function generator and
a power amplifier forming a resonant circuit. The system
is monitored by an output from the coil to an oscilloscope.
The samples were placed in a 15 ml tube (10 mm 100 mm)
which was then placed inside an expanded polystyrene jacket
which acted as an insulator. The ac frequency is varied by
4

J. Phys. D: Appl. Phys. 46 (2013) 312001

Fast Track Communication

Figure 3. Imaginary part of the ac susceptibility

as a function of

the frequency of measurement for samples dispersed in Isopar V.
Solid lines calculated from equations (8), (9) and (10).

The other immediate result from table 2 is the significant

contribution of viscous heating (stirring) to the SAR which
reduces with viscosity. The values in wax indicate that
3040% of the SAR is generated by viscous heating. The
dynamic effects are complex because they are determined by
hydrodynamic parameters. Reference to table 1 shows that
sample B has the largest hydrodynamic size which accounts
for the larger contribution of stirring to the SAR for this sample.
One clear conclusion that can be drawn form these results is
that measurements made in water based colloids will not be
representative of heating effects in vivo.
Table 2 also shows the measured values of SAR together
with calculated values of hysteresis heating from equation
(11). The results for the samples dispersed in wax can
be compared with the calculated values for hysteresis loss
because in the solid matrix and at a frequency of 111.5 kHz
only hysteresis heating can occur. On first inspection the
agreement between the measured and calculated values is quite
poor. However the integral across the active region of the
particle size distribution is very sensitive to the value of K
used (K = 3.0 105 ergs cm3 ) which affects the values of
Vp (0) and Vp (H ) in equation (11). Depending where these
parameters lie on the particle size distribution large variations
are possible. This problem is due to the extreme sensitivity
of the value of the shape anisotropy constant (Ks ) to particle
elongation at low aspect ratios (r). For example a change in r
from 1.8 to 3.0 varies Ks by 70% leading to a reduction in the
SAR value for sample C by a factor 7. Inspection of the TEM
image for this sample shown in figure 2(c) shows that there
is a significant fraction of the particles having aspect ratios of
3.0 or greater with the majority having aspect ratios of greater
than the value of 1.8 used to obtain the data in table 2. Hence
numerical agreement between calculated and measured values
would not be expected. This is particularly true for sample C
with Dm = 15.2 nm because at this size the colloid is unstable
and sedimentation was seen to occur. This accounts for the

Figure 4. Measured SAR values for samples dispersed in Isopar M

(top), Isopar V (centre) and wax (bottom). Solid lines are guides to
the eye.

very low value of SAR observed. For a complete agreement to

be achieved it will be necessary for the distribution of particle
elongation and hence the distribution of Ks to be included in the
model. An attempt at this challenging measurement is being
undertaken.
In conclusion, heating arising in magnetic nanoparticles
dispersed in solvents of different viscosity can be understood
when the distributions of physical and hydrodynamic sizes
are known to high accuracy. For the materials described here
the contribution of susceptibility loss to the SAR is small at
111.5 kHz and hysteresis heating is dominant. Measurements
of samples dispersed in wax show that the contribution of
stirring is about 43% of the heating effect. These effects are
uncontrollable and will not occur in vivo. Meaningful SAR
values should be obtained from measurements of samples in a
solid form.
5

J. Phys. D: Appl. Phys. 46 (2013) 312001

Fast Track Communication

Table 2. Experimental and calculated SAR values in W g1 at a frequency of 111.5 kHz and an applied field of 250 Oe. For the calculated
values a carrier viscosity of 3 cP was assumed.
Sample

Dm (nm)

SAR Isopar M
Experimental

SAR Isopar V
Experimental

SAR Wax
Experimental

SARHyst
From equation (11)

SARac
From equation (7)

A
B
C

10.3
11.7
15.2

38.2
41.9
32.4

33.8
27.9
10.2

27.2
24.5
21.2

7.1
29.5
138.3

1.4
1.7
0.7

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Acknowledgments
OW acknowledges financial support from the UK Institute of
Physics under the Top 40 work placements scheme. AGR
acknowledges financial support from the Spanish Ministerio
de Educacion, through Programa Nacional de Movilidad de
Recursos Humanos of Plan Nacional of I-D+i 20082011.
This work was funded in part by the MULTIFUN FP7 project
under contract number 262943.

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