SUBJECT AREAS:

APPLIED PHYSICS
NANOTECHNOLOGY
NANOPARTICLES

Hyperthermic effects of dissipative

structures of magnetic nanoparticles in
large alternating magnetic fields
Hiroaki Mamiya1 & Balachandran Jeyadevan2

NANOBIOTECHNOLOGY
1

Received
8 July 2011
Accepted
28 October 2011
Published
15 November 2011

Correspondence and

National Institute for Materials Science, Tsukuba 305-0047, Japan, 2The University of Shiga Prefecture, Hikone 522-8533 Japan.

Targeted hyperthermia treatment using magnetic nanoparticles is a promising cancer therapy. However, the
mechanisms of heat dissipation in the large alternating magnetic field used during such treatment have not
been clarified. In this study, we numerically compared the magnetic loss in rotatable nanoparticles in
aqueous media with that of non-rotatable nanoparticles anchored to localised structures. In the former, the
relaxation loss in superparamagnetic nanoparticles has a secondary maximum because of slow rotation of
the magnetic easy axis of each nanoparticle in the large field in addition to the known primary maximum
caused by rapid Neel relaxation. Irradiation of rotatable ferromagnetic nanoparticles with a high-frequency
axial field generates structures oriented in a longitudinal or planar direction irrespective of the free energy.
Consequently, these dissipative structures significantly affect the conditions for maximum hysteresis loss.
These findings shed new light on the design of targeted magnetic hyperthermia treatments.

requests for materials

should be addressed to
H.M. (MAMIYA.
[email protected])

umour-targeted magnetic hyperthermia has recently attracted much attention1. Preferential accumulation
of magnetic nanoparticles in tumour tissue is achieved by conjugating nanoparticles with tumour-homing
peptides2 or antibodies3. When the accumulated nanoparticles are exposed to a large alternating magnetic
field, H5Hacsin(2pf?t), where Hac is the amplitude of the field, f is the frequency, and t is time, they begin to rotate
because of magnetic torque. Simultaneously, the direction of the magnetic moment, m, in each nanoparticle
reverses with a certain probability. Consequently, heat equivalent to the magnetic loss dissipates locally in the
tumour tissue. If the properties of the irradiated field are limited (i.e., Hac?f , constant)1 to ensure biomedical
safety, then nanoparticles that maximise the in vivo efficiency of heat dissipation, PH/(Hac?f), are required, where
PH is the specific energy dissipation rate (specific loss power) per unit mass of nanoparticles. The actual rotations
of the nanoparticles are disordered because the microviscosity of the local environment in cancer cells is not
constant4,5, and effective elasticity depends on the binding conditions between nanoparticles and membranes. To
minimise the effect of irregular rotations in magnetic hyperthermia, two guiding principles have been proposed
on the basis of simple models that consider a linear response of thermodynamic equilibrium states or magnetic
field-driven reversals.
The first guiding principle6 is to use the relaxation loss in superparamagnetic iron oxide nanoparticles (SPIONs)
with a sufficiently low energy barrier DU for reversal. If a linear response of their thermodynamic equilibrium state
is considered at low Hac, the out-of-phase component of AC susceptibility x0 can be expressed as follows:


x~x0:2pf :t 1z2pf :t2 ,
1
where x0 is the initial susceptibility per unit mass of SPIONs. When reversal and rotation occur in a nanoparticle in
parallel, the characteristic time t is given by the following equation:
{1
t{1 ~t{1
N ztB ,

where tN is the Neel relaxation time for reversal, and tB is the Brownian relaxation time for rotation.
Consequently, the heating efficiency PH/(Hac?f ) 5 pm0x0?Hac for individual monodisperse nanoparticles has a
single maximum at the peak frequency 2pfp 5 t21. For a sufficiently small SPION, t is determined only by tN
because tN is much shorter than tB. In this case, it has been assumed that the conditions for maximising the
efficiency are unaffected by uncontrolled rotation of the nanoparticles.
However, in some experiments, dual peaks have been observed for the frequency dependence of x0 / PH/
(Hac?f )7,8 despite the prediction of a single peak at a 2pfp value of t21 (5 tN21 1 tB21). For this reason, size
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distribution7 or aggregation8 of the nanoparticles was considered
based on the linear response theory. In an earlier study7, the lowfrequency peak observed for the susceptibility was attributed to
Brownian relaxation of larger nanoparticles, while the high-frequency
peak was attributed to Neel relaxation of smaller nanoparticles. In
another study8, the low- and high-frequency peaks were attributed to
individual and agglomerated nanoparticles, respectively. Thus the
observed dual peaks have been theoretically explained by the coexistence of two kinds of nanoparticles. In other words, these explanations are based on the assumption that a single kind of nanoparticle
will produce only a single peak at t21 (5tN21 1 tB21). However, this
assumption has never been theoretically verified under a large AC
magnetic field, where the linear response theory does not hold.
The second guiding principle is to use hysteresis loss in ferromagnetic nanoparticles9. In mechanical models such as the Stoner
Wohlfarth model for single domain particles, m is reversed in the
time scale of Larmor precession (picoseconds) when DU disappears
at the switching field Hsw, because thermal fluctuations are not considered. Such fast reversals are considered to dominate the response
to high frequency AC magnetic field because the Brownian relaxations of large ferromagnetic nanoparticles are generally slow compared with the oscillation of the field. In this case, the work done in
one cycle is given by the area inside the hysteresis loop, f?Ms?Hsw,
where Ms is the spontaneous magnetisation and f is a coefficient
related to the rectangularity of the loop. In the simple case of rectangular hysteresis loops, f is 0 for Hac , Hsw and 4 for Hac $ Hsw.
Consequently, the maximum efficiency, PH/(Hac?f ) 5 f?Ms?(Hsw/
Hac)/r, where r is the density of magnetite, is achieved when Hac is
adjusted to Hsw. Because Hsw depends on the magnetic anisotropy
field HK specific to each nanoparticle, it has been assumed that, in
cases where reversal is much faster than rotation, the amount of
hysteresis loss is unaffected by the inhomogeneous rotations of nanoparticles in cancer cells.
In recent experimental studies10,11, the observed PH of immobilised
ferromagnetic nanoparticles was lower than that of the same nanoparticles dispersed in a fluid. Kim et al.10 attributed the difference to
variation in the rates of convective heat transfer. Muller et al.11 suggested that the orientation or agglomeration of the nanoparticles, or
interaction effects, may be responsible for the observed difference.
The orientation of nanoparticles is important because it is related to
the magnetic torque intrinsic in rotatable ferromagnetic nanoparticles. However, there has been no theoretical study on magnetic fielddriven reversals of m in ferromagnetic nanoparticles with easy axes
that simultaneously rotate under the magnetic torque.
There are many reported inconsistencies between experimental
results and predictions based on the above two guiding principles
for optimising hyperthermia treatment. These guiding principles are
based on the simple models established at the two limits: in zero
magnetic field or at zero temperature. Under the conditions for
hyperthermia (Hac ? 0, T ? 0), where T is temperature, the validity
of the guiding principles has not been theoretically verified even for
an ideal system of non-interacting monodisperse nanoparticles.
Consequently, we attempted to simulate the thermally assisted magnetic response of individual superparamagnetic/ferromagnetic iron
oxide nanoparticles exposed to a large AC magnetic field like that

used in hyperthermia treatment. The simulation was performed

in the following two extreme cases: non-rotatable nanoparticles
strongly anchored to structures resembling organelles, and rotatable
nanoparticles in an aqueous phase mimicking cytoplasm. In the
simulations, the thermally activated reversals of m were calculated
between the meta-stable directions. Simultaneously, the rotations of
the spheroidal nanoparticles were computed in the inertialess limit
(Brownian dynamics simulation), where the frictional torque always
balances with magnetic torque and with Brownian torque (details are
reported in the Methods section). The results allow examination
of whether the relaxation loss for tN tB and the hysteresis loss at
Hac < Hsw are independent of the ability of the nanoparticles to
rotate under the conditions for hyperthermia treatment.

Results
The magnetic response to an AC magnetic field Hacsin(2pf?t) at T 5
310 K was simulated for individual monodisperse spheroidal magnetite nanoparticles with non-magnetic surfactant layers in non-rotatable
and rotatable situations (see the Methods section for details). Results
are presented for the following representative nanoparticles: nearly
spherical nanoparticles with an aspect ratio, k, of 1.1 and an equatorial
diameter, 2RM, of 18 nm, and elongated spheroidal particles with k 5
1.4 and 2RM 5 24 nm. The parameters of these nanoparticles are
summarised in Table 1. The former nanoparticles with tN (Hac50)
of 20 ns can be considered as typical SPIONs, while the latter with tN
(Hac 5 0) of 23107 s (1 year) can be regarded as typical ferromagnetic
nanoparticles in the frequency range of hyperthermia treatment
((2pf )21 of approximately 1 ms). Results for nanoparticles with other
sizes and shapes are shown in the Supplementary Information.
The magnetisation curves of the non-rotatable nearly spherical
nanoparticles at low Hac (1 kA/m) are shown in Fig. 1. A linear
response without hysteresis was observed at f 5 100 kHz. Such
superparamagnetic behaviour is reasonable because the estimated
tN(Hac 5 0) for the nanoparticles is 20 ns. Hysteresis appeared in
the curves at f 5 1,000 kHz. As f increased further, the area inside the
hysteresis loop grew. This area corresponds to the work done in one
cycle. Therefore, PH/(Hac?f ) also increased with f, and a single maximum was observed at a peak frequency, fp, of 10,000 kHz (Fig. 1 (b)).
Figure 2(a) shows the Hac dependence using a contour plot of PH/
(Hac?f ). As Hac increased, fp shifted towards higher frequencies. As
indicated by the dashed line in Fig. 2(a), this shift can be explained by
the values of tN(Hac) calculated using the conventional Browns
equation as follows12:




tN Hac {1 ~f0: 1{h2 1zh exp {Kd V=kB T 1zh2
, 3


z1{h exp {Kd V=kB T 1{h2
where h is mH/(2 KdV), Kd is the shape anisotropy constant, V is the
volume of the magnetic core, and kB is the Boltzmann constant.
Therefore, the emergence of a single peak in PH/(Hac?f ) can be
attributed to Neel relaxation loss, as expected for SPIONs.
For the nearly spherical nanoparticles with a low Hac (1 kA/m),
the magnetisation curves in the rotatable case were the same as those
in the non-rotatable case (see Fig. 1). An equivalent maximum
appeared in the f-dependence of PH/(Hac?f ) in the linear response

Table 1 | Parameters of the simulated nanoparticles: including the aspect ratio k, equatorial diameter 2RM, thickness of the surfactant layer
dR, density of magnetite r, spontaneous magnetisation Ms, anisotropy field HK, viscosity g, Neel relaxation time tN(H 5 0), and Brownian
relaxation time tB. The value of tN(H 5 0) was estimated using equation (3), while the value of tB was estimated using equation (4).

Nearly spherical nanoparticle

Elongated spheroidal
nanoparticle

2RM
(nm)

dR
(nm)

r
(kg/m3)

Ms
(kA/m)

HK
(kA/m)

g
(mPa s)

tN(H 5 0)
(sec)

tB
(sec)

1.1
1.4

18
24

4.5
6.0

5200
5200

450
450

17
57

1.0 /
1.0 /

231028
23107

831026
231025

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Figure 1 | Magnetic response of nearly spherical nanoparticles (typical

SPIONs). The open and solid symbols show the values of non-rotatable
and rotatable nanoparticles, respectively. (a) Steady magnetisation curves
with low Hac (1 kA/m) at various frequencies, (b) frequency dependence of
the efficiency of heat dissipation with low and intermediate values of Hac.

Figure 3 | Magnetic response of nearly spherical nanoparticles (typical

SPIONs) with an applied AC field with Hac 5 8 kA/m and f 5 30 kHz.
(a) Steady magnetisation curves, (b) mean orientation of the long (easy)
axis of the nanoparticles, ,cosh.. Orientations are indicated in the inset
images.

range (Hac 5 1 kA/m) (Fig. 1(b)). This behaviour is consistent with

the above assumption because the estimated tN (Hac 5 0) of 20 ns is
much shorter than tB 5 8 ms (Table 1). The shift of this peak with
increasing Hac is analogous to that in the non-rotatable case
(Fig. 2(b)). However, another maximum of PH/(Hac?f ) was observed
at Hac 5 8216 kA/m and f 5 30 kHz in the contour plot shown in
Fig. 2(b). A secondary maximum like this has not previously been
theoretically predicted for individual monodisperse nanoparticles.
Figure 3(a) shows the magnetisation curves calculated under these
conditions. Unlike the non-rotatable case, an S-shaped hysteresis
loop without remanence existed. At the same time, the mean
orientation of the long (easy) axes of the nanoparticles showed
butterfly-shaped hysteresis, as shown Fig. 3(b). Because such behaviour cannot be explained using the present linear response theory,
its origin is discussed in the next section from the viewpoint of the
rotation of the long axis of SPION.

The magnetisation curves at f 5 10,000 kHz for the elongated

spheroidal nanoparticles, which are typical ferromagnetic nanoparticles, in the non-rotatable case are shown in Fig. 4(a). The curve was
reversible at Hac 5 20 kA/m, and hysteresis appeared in the curve at
Hac 5 26 kA/m. As Hac increased further, the area inside the hysteresis loop grew. When Hac became larger than 32 kA/m, the expansion of the area was saturated and the shape of the magnetisation
curve approached that predicted by the StonerWohlfarth model.
PH/(Hac?f ) was almost zero at low Hac, then at approximately
30 kA/m it began increasing rapidly with Hac, followed by a gradual
decreases with increases in Hac (Fig. 4(b)). This behaviour depends
weakly on the frequency (Fig. 5(a)). In mechanical models that do not
consider thermal fluctuation, a hysteresis loop appeared when Hac
was higher than Hsw. Because Hsw of ferromagnetic nanoparticles
with randomly oriented easy axes ranges from HK/2 5 29 kA/m to
HK 5 57 kA/m, and is often close to 0.5 HK, that PH/(Hac?f ) is almost
independent of frequency at Hac . 30 kA/m in the non-rotatable

Figure 2 | Efficiency of heat dissipation in the nearly spherical

nanoparticles (typical SPIONs) that are (a) non-rotatable and (b)
rotatable, where PH is the specific energy dissipation rate. Dashed lines
represent the Neel relaxation time (2ptN)21, dotted lines show the
Brownian relaxation time (2ptB)21, and solid lines indicate typical angular
velocity, vH(H 5 Hac, y 5 p/4)/2p, of the rotation caused by magnetic
torque. White lines show the thresholds for biomedical safety. Diamonds A
and B on the white lines denote the conditions for maximum PH/(Hac?f ) in
the rotatable nanoparticles.
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Figure 4 | Magnetic response of elongated spheroidal nanoparticles

(typical ferromagnetic nanoparticles) in high-frequency AC fields with
f 5 10 000 kHz and various values of Hac. (a) Steady magnetisation curves
in the non-rotatable case; the corresponding curves for rotatable
nanoparticles are presented in Fig. 6(a) and (b). Solid lines indicate
StonerWohlfarth model curves. (b) Hac2dependence of the efficiency of
heat dissipation. The open and solid symbols show the values of the nonrotatable and rotatable nanoparticles, respectively. The arrows indicate the
peak maxima of PH/(Hac?f ) in both cases, and the broken line shows half of
the anisotropic field, HK/2. The inset shows an enlarged view.
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Figure 5 | Efficiency of heat dissipation of elongated spheroidal

nanoparticles (typical ferromagnetic nanoparticles) that are (a) nonrotatable and (b) rotatable. Dashed lines represent the Neel relaxation
time (2ptN)21 and the solid line indicates fp, which was calculated using
equation (5). White lines show the thresholds for biomedical safety.
Diamonds C and D on the white lines denote the conditions for maximum
PH/(Hac?f ) in the rotatable nanoparticles.

ferromagnetic nanoparticles is consistent with the properties

expected for the hysteresis loss.
Figure 6 shows the magnetisation curves for rotatable elongated
spheroidal nanoparticles at f 5 10,000 kHz. Because the magnetic
response slowly changed after the AC magnetic field was applied at
t 5 0, transient variations of the hysteresis loops are observed. The
shape of the major hysteresis loop at Hac 5 60 kA/m was initially
consistent with that predicted by the StonerWohlfarth model with
randomly oriented easy axes. However, the remanence of the major
loop gradually increased from 0.5 Ms to Ms. In other words, the
major loop became squarer, and the area inside the loop increased
with time. In comparison, the remanence of the minor loop at
Hac 5 26 kA/m gradually decreased and the area became smaller
over time. As shown in Fig. 6(c) and (d), the long (easy) axes of the
nanoparticles gradually turned when the variations of the loops proceeded (see the next section for details). Consequently, the increased
area of the major hysteresis loops and decreased area of the minor
loops caused the maximum of PH/(Hac?f ) to shift towards higher Hac
compared with the non-rotatable case (see arrows in Fig. 4(b)). Note
that reversals occurred every hundred nanoseconds (,1/f ), while
rotations took several microseconds (Fig. 6(c)). Thus, the assumption that the amount of hysteresis loss is unaffected by the rotation
of nanoparticles when reversal is significantly faster is invalid
for ferromagnetic nanoparticles in large AC magnetic fields at high
frequencies.
Before discussing this novel phenomenon observed at high
frequencies, the other important variation in the contour plot of
PH/(Hac?f ) (Fig. 5) that occurred because of the ability of the ferromagnetic nanoparticles to rotate at lower frequencies shall be
examined. The maximum of PH/(Hac?f ) shifted toward lower Hac
below 100 kHz for the rotatable elongated spheroidal nanoparticles,
while it stayed between HK/2 and HK in the non-rotatable case.
Figure 7(a) shows the magnetisation curve obtained when Hac 5
16 kA/m and f 5 30 kHz. The curve in the rotatable case had an
obvious hysteresis loop with a large remanence in the steady state,
but there was no hysteresis observed for the non-rotatable situation.
Because Hac 5 16 kA/m is much smaller than HK/2, no reversals of m
occur at any orientation of the easy axis so hysteresis is not observed for
the latter case. Figure 7(b) shows the variation of ,cosh. in the
rotatable case, where ,cosh. (0 , h , p/2) is the mean angle between
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Figure 6 | Magnetic response of elongated spheroidal nanoparticles

(typical ferromagnetic nanoparticles) in high-frequency AC fields with
f 5 10 000 kHz and various values of Hac. (a) Transient major hysteresis
loops of the rotatable nanoparticles after application of a field with Hac 5
60 kA/m at t 5 0. (b) Transient minor loops of the rotatable nanoparticles
after application of a field with Hac 5 26 kA/m at t 5 0. Solid lines indicate
StonerWohlfarth model curves. (c) Relaxation of the mean orientation of
the long axis, ,cos h., (d) steady values of ,cos h. and relaxation time
trot. Dashed lines in (d) show HK/2 and HK; and the solid line in (d)
indicates the reciprocal, [vH(H5Hac siny50.43)]21, of the typical angular
velocity of rotation caused by magnetic torque. Orientations are indicated
in the inset images.

the magnetic field and the long axes of the spheroidal nanoparticles.
Note that ,cosh. is synchronised with jM/Msj 5 jcosyj, where y is
the angle between m and H. This fact indicates that the hysteresis in the
rotatable case (Fig 7(a)) is mainly caused by the rotation of the easy axis
where the direction of m is fixed. Consequently, heat equivalent to the
hysteresis loss dissipates even at Hac , HK/2.
For Brownian relaxation, tB can be expressed as follows:
4
tB ~3gVH:0:8z0:2k=kB T ,
where g is the viscosity of the surrounding medium, and VH is the
hydrodynamic volume. In equation (4), the frictional torque for
spheroids, described in the Methods section, is considered. For the
elongated spheroidal nanoparticle, (2ptB)21 is calculated to be
8 kHz. This value is too low to cause the nanoparticle to rotate at
30 kHz. Therefore, Yoshida et al.13 also took into account the rotation caused by magnetic torque, m(t) 3G(t). They concluded that the
area of the hysteresis loop was maximised as follows:

2 0:5
:
5
2pfp ~t1
B 1z0:07mHac =kB T
The location of the peak in PH/(Hac?f ) below 100 kHz can be
explained by this equation, as shown in Fig. 5(b). An expression that
describes all of the variation in the position of the primary peak of
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Figure 7 | Magnetic response of elongated spheroidal nanoparticles

(typical ferromagnetic nanoparticles) in a low-frequency AC field with
f 5 30 kHz and Hac 5 16 kA/m. (a) Steady magnetisation curves, where
the open and solid symbols show the values of the non-rotatable and
rotatable nanoparticles, respectively. Solid lines are StonerWohlfarth
model curves. (b) Mean orientation of the long (easy) axis of nanoparticles,
,cosh..

PH/(Hac?f ) is desirable, and equation (5) can be rewritten as follows:


2 0:5
:
6
2pfp ~ tN Hac {1 zt1
B 1z0:07mHac =kB T
This equation is an extended relationship of t21 5 tN21 1 tB21 for
a large AC magnetic field. This expression is for the primary
maximum; the secondary maximum is discussed later. The second
term of equation (6) can be approximated to 0.1mHac/(gVH) for
mHac/kBT (0.07)20.5 and k , 1. On the other hand, tN(Hac) of
ferromagnetic nanoparticles becomes extremely short only when
the energy barrier disappears between HK/2 and HK. Therefore, the
changeover between the two terms in the equation (6) generally
occurs at Hac < HK/2 and 2pf < 0.1mHK/(2gVH)50.1 KdV/(gVH).
For the elongated spheroidal particles (k 5 1.4, Kd516 kJ/m3, and
V/VH 5 0.3) in a liquid phase with g 5 1 mPa?s, the values of Hac
and f are 29 kA/m and 76 kHz. Such a changeover around 100 kHz
occurs for ferromagnetic nanoparticles of any size, as long as the
conditions, Kd, V/VH, and g, are constant. We must keep in mind
that, even when ferromagnetic nanoparticles are large enough for
their Brownian relaxation to be negligible, the magnetic torque
caused by the large AC magnetic field can easily rotate such nanoparticles in the liquid phase at a time scale of microseconds. This
knowledge is helpful when considering the frequency for hyperthermia treatment, even if it is obtained for a simplified system.
In summary, most of the simulated results, including significant variations for ferromagnetic nanoparticles exposed to a lowfrequency AC magnetic field, can be explained using the existing
models. The two essential exceptions are as follows:
(a) a secondary maximum in the relaxation loss for SPIONs exposed
to a low-frequency AC magnetic field, and
(b) a shift of the maximum hysteresis loss caused by the ability of
typical ferromagnetic nanoparticles exposed to a high-frequency AC
magnetic field to rotate.
These novel phenomena are discussed in detail in the following
section.

Discussion
The two novel phenomena of rotatable nanoparticles in a large AC
magnetic field described above cannot be explained by simple models
that consider a linear response of thermodynamic equilibrium states
or magnetic field-driven reversals. In this section, we shall further
SCIENTIFIC REPORTS | 1 : 157 | DOI: 10.1038/srep00157

discuss these atypical responses from the viewpoint of the orientation

of the long (easy) axis. First, we begin with the appearance of a
secondary maximum of PH/(Hac?f ) near Hac 5 8 kA/m and f 5
30 kHz for the nearly spherical nanoparticles (typical SPIONs)
where an S-shaped hysteresis loop without remanence was obtained
(Fig. 3). We must recall that the variation in ,cosh. showed
butterfly-shaped hysteresis under these conditions. This behaviour
explains the atypical magnetic response in the period f21 (33 ms)
(Fig. 3(b)). Initially (at t 5 0), no magnetisation exists because the
occupation probabilities of m in the two stable directions parallel to
the long (easy) axis are equalised in a zero magnetic field. As H
increases, the occupation probability in the more stabilised direction
immediately increases because of reversals on a time scale of tN
(# 20 ns). The reversed m in the stabilised direction is not completely
parallel to H, y ? 0, and the magnetic torque mHsiny turns the long
(easy) axis towards the direction of the field. If we neglect Brownian
torque l(t) (see equation (11) in the Methods section), the angular
velocity of the rotation due to magnetic torque can be expressed as
vH H t , yt ~mH t sinyt =6gVH :0:8z0:2k: 7
Hence, vH(H(t), y(t)) increases in proportion to the field amplitude
H 5 Hacsin(2pf?t). For example, vH(H, y 5 p/4) is 0.153106 rad/s
when H (t 5 1/4f < 8 ms) is 8 kA/m. Therefore, rotation is not
negligible in the peak period of the oscillations of H. Subsequently,
H decreases to zero at t 5 1/2f < 17 ms, and the occupation probabilities are again equalised because reversal is rapid, so the magnetic
torque disappears. Alternatively, the Brownian torque randomises
the orientation of the long axis on a time scale of tB (5 8 ms).
Therefore, competition between the magnetic and Brownian torques
can cause the butterfly-shaped hysteresis of ,cosh.. Because the
equilibrium magnetisation of SPIONs with easy axes parallel to H is
higher than that of randomly oriented SPIONs14, the magnetisation
curve shows hysteresis without remanence. Consequently, a secondary maximum appears for the rotatable SPIONs even though tN tB.
Next, we investigate the influence of the ability of elongated spheroidal nanoparticles to rotate under a high-frequency AC magnetic
field on the shift of the maximum PH/(Hac?f ). As shown in Fig. 6(a)
and (b), the magnetisation curves varied after an AC magnetic field
was applied at t 5 0. At the same time, transient variations also
occurred in ,cosh., as shown in Fig. 6(c). In the case of the major
loop at Hac 5 60 kA/m, ,cosh. gradually increased from 0.5 to
0.95. In other words, the long (easy) axis became oriented towards
the direction parallel to H. The characteristic time, trot, was estimated
to be 1.3 ms using the approximation of exponential decay. Note that
the direction of m is not completely parallel to H even for H $ HK,
even though m is already reversed for all of the nanoparticles. Because
sin y is 0.43 when cos y is 0.9, a large magnetic torque can turn the
long axis even if the magnetisation is almost saturated after reversals
at H , HK. Indeed, trot at Hac $ HK is comparable to the reciprocal of
typical values of vH(H 5 Hac, sin y 5 0.43) (Fig. 6(d)). Therefore,
these transient variations can be attributed to the longitudinal orientation being adopted preferentially because of the magnetic torque.
In the minor loops at Hac 526 kA/m, the remanence of the rotatable nanoparticles decreased gradually with time (Fig. 6(b)) and
,cosh. simultaneously decreased from 0.5 (Fig. 6(c)). The long axis
was oriented perpendicular to H during this period, although the
longitudinal orientation is preferred when the Zeeman energy is
considered. It should be noted that the angle y for m in a stable
direction more parallel to H is smaller than that in a metastable
direction less parallel to H (Fig. 6(d)). In other words, the magnitude
of the magnetic torque toward the longitudinal orientation in the
former is weaker than that toward the perpendicular orientation in
the latter. This difference makes the orientation of the long axis
planar on average, because the stable and metastable states alternate
every half period when the reversal of m is blocked in the minor loop.
These arguments suggest that the slowing of the rotation for
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0.5 HK # Hac # HK (Fig. 6(d)) can be attributed to compensation
between two magnetic torques in the intermediate range. Briefly, in
ferromagnetic nanoparticles in the aqueous phase, longitudinal or
planar orientations are adopted, irrespective of the free energy, as
dissipative structures under a high-frequency AC magnetic field.
Consequently, PH/(Hac?f ) increases gradually in major hysteresis
loops and decreases in minor loops. These variations cause the maximum of PH/(Hac?f ) to shift towards higher Hac.
Finally, we return to the contour plots of PH/(Hac?f ) in Figs. 2 and
5, and discuss the effect of rotation on the design for maximising PH/
(Hac?f ). If a safety limit of Hac?f , 4.853108 Am21s21 is applied9,
then maximum values of PH/(Hac?f ) for rotatable SPIONs and ferromagnetic nanoparticles are obtained at the conditions shown by
diamonds A and C in Figs. 2(b) and 5(b), respectively. However, no
heat dissipation occurs under the same conditions (A and C) if the
rotation of these nanoparticles is blocked (Figs. 2(a) and 5(a)). If a
highly amplified AC magnetic field Hac?f of 1.7431010 Am21s21 is
allowed15, a maximum PH/(Hac?f ) of 3.031024 m23s22A21
(5.2 MW/kg) for the rotatable ferromagnetic nanoparticles can be
obtained (diamond D in Fig. 5(b)). However, PH/(Hac?f ) halves when
the rotation of these nanoparticles is blocked (Fig. 5(a)) because
oriented structures are not formed. In contrast, condition B for the
primary maximum of PH/(Hac?f ) in the rotatable SPIONs remains
the optimum condition when these nanoparticles cannot rotate
(Fig. 2(a) and (b)). This is because the long (easy) axes of SPIONs
are randomly oriented in rotatable SPIONs as Brownian torque has
more effect than magnetic torque in a weak magnetic field. As
demonstrated here, rotation generated by the magnetic torque
caused by a large alternating magnetic field greatly affects the conditions for maximising heat dissipation in magnetic nanoparticles.
In this study, we simulated the magnetic responses of superparamagnetic and ferromagnetic magnetite nanoparticles in a large
alternating magnetic field. The results show that both the relaxation
loss for tN tB and the hysteresis loss at Hac < Hsw are affected by the
formation of dissipative structures because of the ability of nanoparticles to rotate. Consequently, the conditions for maximising heat
dissipation depend strongly on the inhomogeneous microviscosity of
the surrounding medium.
Compared with the simplified model used for our simulation,
actual magnetic nanoparticles used for targeted magnetic hyperthermia treatment are not ideal. For this reason, the factors affecting
more realistic situations need to be evaluated. First, the effects of
crystalline and surface anisotropy energy are considered. In this case,
the potential energy with respect to the direction of m is complicated.
Even if multiple valleys appear in the energy surface, the easy axes are
not parallel to H, because the orientations of the nanoparticles are
randomised by Brownian torque in the liquid phase. For this reason,
slow rotations inevitably occur after fast reversals because of the
magnetic torque in an AC magnetic field. These rotations lead to
secondary relaxation loss in SPIONs in a low frequency AC magnetic
field and shift the hysteresis loss in ferromagnetic nanoparticles in a
high frequency AC magnetic field. Next, the variation in the size and
shape of actual nanomagnets must be considered. In this case, Neel
relaxation times, tN, differ significantly because they depend exponentially on the volume of each nanoparticle and the shape anisotropy constant. In contrast, the dependence of frictional torque on
the size and shape of nanoparticles is weak. Because the S-shaped
hysteresis loop of SPIONs appears in the frequency range of rotation,
the secondary loss peak becomes less diffuse compared with the
primary relaxation loss peak. For ferromagnetic nanoparticles, the
shift of the hysteresis loss at high frequencies should still be significant even if the size of nanoparticles is not uniform, because the
anisotropy field is independent of nanoparticle size. Finally, the effect
of dipoledipole interactions is considered, because the density of
nanoparticles accumulated in cancer cells might be inhomogeneous
if they are trapped at specific sites. In such a case, chain structures of
SCIENTIFIC REPORTS | 1 : 157 | DOI: 10.1038/srep00157

longitudinally aligned nanoparticles have been conventionally discussed in a magnetic field, although their details are still controversial16. Our findings illuminate this conventional view, because, in
some cases, formation of structures with a planar orientation is predicted even for individual ferromagnetic nanoparticles. In future
studies, we will clarify a variety of dissipative structures, which
are different from ordinary chains, for interacting nanoparticles.
As discussed here, knowledge of the heat dissipation in the nonequilibrium steady states of rotatable nanoparticles is essential for
the design of targeted magnetic hyperthermia treatments using large
AC magnetic fields.

Methods
Model for the simulation. The magnetic response to an AC magnetic field
Hacsin(2pf?t) was simulated for individual superparamagnetic/ferromagnetic
magnetite nanoparticles in two extreme cases: non-rotatable nanoparticles strongly
anchored to structures resembling organelles and rotatable nanoparticles in an
aqueous phase resembling the cytoplasm. We considered the nanoparticles to be
monodisperse prolate spheroids with equatorial diameters, 2RM, from 12 to 24 nm,
and aspect ratios, k, between 1.1 and 1.4. Because these dimensions are smaller than
the typical exchange length of magnetite, 27 nm,17 all of the spins are parallel to one
another in each nanoparticle. In other words, we can assume that each nanoparticle
has a single magnetic moment m 5 MsV (coherent rotation/ macro-spin
approximations14), where V is the volume of each nanoparticle, [(4/3)p?kRM3]. The
magnitude of spontaneous magnetisation Ms 5 jMsj was set to the value of bulk
magnetite6, 450 kA/m, because the dependence of Ms on particle size has not been
well established18.
The magnitude of m is important; for example, m of a nanoparticle with 2RM 5
24 nm and k 5 1.4 is 1.53105 mB. Hence, such nanoparticles aggregate because of the
large dipoledipole interactions between m unless a sufficient non-magnetic surfactant layer exists. The required thickness of this layer is approximately 6 nm for
nanoparticles with 2RM 5 24 nm19. Therefore, in our model, we used non-magnetic
layers with a thickness dR of 0.5 RM. Consequently, we can assume that the nanoparticles are uniformly dispersed and do not aggregate. In this case, the typical
distance between nanoparticles is n1/3, where n is the number density of nanoparticles. Because the actual mass fraction of nanoparticles accumulated in cancer cells
does not exceed 1% (approximately 10 mg/mL), the magnitude of the interaction
between nanoparticles with 2RM 5 24 nm, n?m2/kB, is estimated to be less than
13102 K. Consequently, we did not consider minor effects caused by dipoledipole
interactions in our simulations.
In such an individual nanoparticle, the potential energy with respect to the direction of m, U(V), is given by the following equation:
U V~Ud VzUc VzUs V{m_H

where Ud(V), Uc(V), Us(V) and 2m?H are the shape, crystalline, and surface
anisotropy energies, and Zeeman energy, respectively, and V is the solid angle of m.
For spheroidal particles, the first term, Ud(V), can be described as KdVsin2w and has
two minima separated by the energy barrier DU5KdV, where Kd is the shape
anisotropy constant and w is the angle between the long (easy) axis and m. The
magnitudes of Kd, given by (NeasyNhard)m0?Ms2, are 5 and 16 kJ/m3 for spheroidal
particles with k of 1.1 and 1.4, respectively. Neasy and Nhard are the demagnetising
factors for the long and short axes, respectively. In comparison, magnetite has cubic
crystalline anisotropy20 and an anisotropy constant K15211 kJ/m3. The energy
landscape of cubic anisotropy (K1,0) is gentle and DU is (1/12)K1V < (1 kJ/m3)?V19.
Additionally, the effects of surface anisotropy are generally insignificant if the particles are larger than 10 nm18, although the rationale for this is still unknown. For these
reasons, we assumed that the uniaxial shape anisotropy dominated. Consequently,
equation (8) can be simplified as follows:
U Q,y ~ Kd V sin2 Q{mHac sin2pf :t cos y,
9
where y is the angle between m and H (see Fig. 3).
Little is known about the local environments of magnetic nanoparticles accumulated in tumour tissue. For example, nanoparticles coated with dextran are completely
immobilised in tissues21, whereas dextran nanoparticles appear to be mobile in cells5.
For this reason, we simulated the magnetic response of the monodisperse spheroidal
nanoparticles in the following two extreme cases: non-rotatable nanoparticles with
randomly oriented easy axes, and rotatable nanoparticles in a Newtonian fluid with a
viscosity g of 1 mPa?s.4
Simulation of the reversal. The detailed trajectories of m in a magnetic field applied at
an oblique angle h to the long easy axis of a spheroidal particle can be precisely
simulated by solving the stochastic LandauLifshitzGilbert equations. However, we
are only interested in the reversal of m once every microsecond because the frequency
used for hyperthermia is limited. Therefore, we can use a well-known coarse-grained
approach, or two-level approximation14, that considers thermally activated
reversals between the meta-stable directions, (w1, y1) and (w2, y2), via the midway
saddle point at (w3, y3) in Uh(w,y). The reversal probability from (w1, y1) to (w2, y2),
u12, is given by f01?exp[(Uh(w3, y3) 2 Uh(w1, y1))/kBT ], while the backward reversal

www.nature.com/scientificreports
probability u21 is f01?exp[(Uh(w3, y3) 2 Uh(w2, y2))/kBT ], where f0 is the attempt
frequency of 109 s1.
In the simulation, the time evolution of the occupation probabilities, p1(h), p2(h) 5
1 2 p1(h), at the two stable directions of a nanoparticle tilted at h was computed using
the following relationship:
Lp1 =Lt~u21 p2 h{u12 p1 h:

10

p1(h) was simply set to either zero or one when there was only one minimum in
Uh(w,y). This calculation was continued until the transient factors depending on the
initial conditions disappeared. The time step Dt was typically 1024/f s but was shorter
when u12Dt (or u21Dt) became large compared with one. At each step, magnetisation
was obtained as #(p1(h)mcosy1 1 p2(h)mcosy2)sinhdh. Test simulations were performed to check the validity of this method using the same parameters as in an earlier
study14 to calculate the reversals of magnetic nanoparticles in large AC magnetic
fields. As detailed in the Supplementary Information, our results agree with the
reported behaviour14.
Simulation of reversal and rotation. The rotation of spheroidal nanoparticles was
simulated in synchronisation with the reversal of m. In Newtonian fluids, the frictional
torque for rotation can be expressed as 6gVH?(0.8 1 0.2k)?v (t),22 where VH 5 [(4/
3)p?k(RM 1 dR)3] is the hydrodynamic volume and v (t) is the angular velocity of
rotation; de/dt 5 v (t) 3e (t), where e (t) is the unit vector along the long axis of the
spheroid; and m (t)?e (t) 5 mcosw. Under typical conditions, where g 5 1 mPa?s, VH
< 103 nm3, and v(t) < 13105 rad/s, the inertia of the nanoparticle can be neglected
(Brownian dynamics simulation). In this inertia-less limit23, the frictional torque
balances with magnetic torque m (t)3H(t) and Brownian torque l(t) as follows:
11
6gVH :0:8z0:2k:vt ~mt |H t zlt

vli t w~0,

12

vli t1 li t2 w~2kB T :6gVH :0:8z0:2k:dt1 {t2 ,

13

where d(t12t2) is the Dirac delta function.

At the beginning of the simulation for the rotatable nanoparticles, an assembly of
randomly oriented nanoparticles was generated, where their number ensures an
optimal compromise between calculation time and precision. Then, the time evolution of the direction of m and the orientation of the long easy axis were computed by
the following steps. (i) Using equation (9), reversible variations of the meta-stable
directions (wi(t), yi(t)) caused by the latest changes in the field strength and direction
of the easy axis were calculated, (ii) m (t) at (w1(t), y1(t)) was reversed if x , u12Dt, but
otherwise not. In this case, x g [0, 1] is a pseudorandom number generated by the
Xorshift algorithm24. The backward reversal was computed in a similar manner. (iii)
Substituting the reversed (or held) m (t) into equation (11), v (t) was calculated. (iv)
e(t) was finally computed using the relationship de/dt 5 v (t)3e (t). This calculation
was continued until transient factors depending on the initial conditions disappeared.
In this simulation, Dt was typically 1024/f s but was shorter unless u12Dt, or the
changes in e (t) were sufficiently small compared to one. Magnetisation was obtained
as S(nimcosyi) at each step. Test simulations were performed to check the validity of
this method. There have been no prior theoretical studies on systems where both
reversal and rotation occur simultaneously in a large AC magnetic field.
Consequently, comparisons with prior studies were performed under two extreme
conditions. In the first case, high viscosities were assumed. Because reversal dominates rotation under these conditions, the results were compared with those reported
by Carrey et al.14. In the second case, a high anisotropic field was assumed. Because
rotation dominates reversal in this situation, the results were compared with the
numerical simulations of Yoshida et al., where nonlinear Brownian rotational
relaxation of magnetic fluids with a large excitation field was studied using the
FokkerPlanck equation13. The results obtained from our simulation of reversal and
rotation were consistent with those of earlier studies (Supplementary Figs. S1S4).
Therefore, we can now take a first step toward understanding the roles that rotation of
a nanoparticle and reversal of its magnetic moment play together in large AC magnetic fields.
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Acknowledgements
This study was partly supported by a Grant-in-Aid for Scientific Research (21241023 and
21681014).

Author contributions
H. M. performed the simulation. H. M. and B. J. wrote the manuscript.

Additional information
Supplementary information accompanies this paper at http://www.nature.com/
scientificreports
Competing financial interests: The authors declare that they have no competing financial
interests.
License: This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivative Works 3.0 Unported License. To view a copy
of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
How to cite this article: Mamiya, H. & Jeyadevan, B. Hyperthermic effects of dissipative
structures of magnetic nanoparticles in large alternating magnetic fields. Sci. Rep. 1, 157;
DOI:10.1038/srep00157 (2011).