Heat generation of coreshell particles composed of
biodegradable polymer and iron oxide
C. Oka, K. Ushimaru, N. Horiishi*, T. Tsuge, and Y. Kitamoto
Interdisciplinary Graduate School of Science and Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,

Yokohama 226-8503, Japan*Bengala Techno Lab., 1-19 Kodai, Miyamae-ku, Kawasaki 216-0007, Japan

A suspension of coreshell particles composed of a biodegradable polymer core and iron oxide nanoparticles(IONPs) exhibits higher heat generation under an alternating magnetic field compared with a suspension of IONPs
at the same IONP concentration. The improvement of the heat generation will be attributed to the change of thestrength of dipolar interactions between adjacent IONPs. The IONPs in the coreshell particles were relatively
isolated, in contrast with that in IONP suspension before the formation of the coreshell particles. Therefore, in thecoreshell particles, the dipolar interaction is reduced, and the heat-generating capability is increased. This
explanation is brought through investigating the influence of the agglomerate size of IONPs on the heat-generating
capability.
Key words: magnetic hyperthermia, coreshell particle, iron oxide nanoparticle, dipolar interaction, hydrodynamic
diameter, delta M plots

1. Introduction
Magnetic hyperthermia (thermotherapy), whichkills cancer cells by heat generated from magnetic
nanoparticles under alternating magnetic fields, is a
type of cancer treatment under study in clinical
trials1)4). In the magnetic hyperthermia, tumor tissues
are exclusively affected by selective accumulation of themagnetic nanoparticles, which are heat agents, in thetissues. Hence, the magnetic hyperthermia has been
attracting significant attentions as a more effective
treatment than conventional hyperthermia methods; alot of researchers have been investigating magnetic
nanoparticles and an apparatus generating themagnetic field for the treatment to improve theefficiency5)11).
In our previous study, a coreshell particle
composed of a core of a biodegradable polymer particle
and a shell of assembly of magnetic iron oxide
nanoparticles (IONPs) has been prepared as a
candidate for a drug carrier for magnetically guided
drug delivery system (MGDDS)12). It can loadhydrophobic drugs into its polymer core. We havealready confirmed that the coreshell particles werestrongly attracted to a NdFeB magnet, and will havemagnetic properties enough for MGDDS.
In the present study, heat generation of thecoreshell particles in the alternating magnetic field isinvestigated. The coreshell particle can act as a heat
agent for magnetic hyperthermia as well as a MGDDS
carrier because its structure includes magnetic
nanoparticles. Therefore, the coreshell particle isexpected to be a promising carrier having hybrid
function of a drug carrier and a heat agent. The heat
agent is an assembly of IONPs as a shell; the assembled
structure of the IONP-shell is controlled by theFig. 1 Schematic illustration of coreshell particle
composed of biodegradable polymer and iron oxide
nanoparticles.
preparation conditions. The heat generation is induced
by relaxation losses of IONPs, which are Néel and
Brownian relaxation losses, and the relaxation
dynamics is greatly affected by their agglomerate state
due to dipolar interactions between IONPs13),14). To
discuss the heat-generating capability of the coreshellparticles in view of the agglomerate status in theirsuspension, the capability was compared with that of
IONP suspensions with various agglomerate sizes
manipulated by adding a flocculant and by changing
IONP concentrations.
2. Experimental
Two types of IONPs, whose sizes were 8 nm and 11
nm, were synthesized by a coprecipitation method using
FeCl2, FeCl3 and NaOH. Blocking temperatures of the
IONPs were about 240 K for the 8 nm IONPs, andhigher than room temperature for the 11 nm IONPs at
a powder state. Although the temperature of the 11 nm
IONPs indicates being ferromagnetic, both of the IONPs
seem to be superparamagnetic in these suspensions at
the room temperature. The coreshell particles wereprepared as reported in our previous report with the 8
nm IONPs12). To evaluate the heat-generatingcapability, suspensions of the coreshell particles, the 8
nm IONPs, and the 11 nm IONPs were prepared at
IONP concentrations of 0.1, 0.3, 0.5, 1, 1.5, and 2.0 mg
Fe/mL. The IONP concentrations were determined by aconcentration of Fe in the suspension. The agglomerate
status, in particular, the size of the 11 nm IONPs was
manipulated by adding polyvinyl alcohol (PVA) as aflocculant to the IONP suspension.
The heating curves of the suspensions were measured
by a system with a coil generating the magnetic field ata frequency of 2 MHz and a field strength of 3.4 kA/mrms,
and temperature was measured with a fiber-optic
thermometer. Since the frequency is considerably high,
it is presumed that the Néel relaxation is dominantrather than the Brownian relaxation in the condition.
The heat-generating capability was evaluated by the
Box-Lucas equation15):

T(t) = T(0) + A(1  eBt)(1)where T is temperature, t is time, and A and B are
parameters related to the saturation temperature andthe curvature of the heating curve. At t = 0, the productAB represents an initial rate of temperature rise ΔT/Δt. The specific absorption rate (SAR) is proportional tothe product, expressed as

SAR = (ΔT / Δt ) (C / mFe)  AB

(2)

Table 1 Hydrodynamic diameter and the productAB of fitting parameters for suspensions of 8 nm
IONPs, and coreshell particles prepared using the
8 nm IONPs.

8 nm IONPs
Core-shell particles

Hydrodynamic
diameter( nm )79-

AB
per Fe mass
( K/(sg Fe))
37
64

Fig. 2 Heating curves of 0.3 mg Fe/mL ofsuspensions of 8 nm IONPs, and coreshell particles
prepared using the 8 nm IONPs.

where C is the heat capacity per unit mass of a
specimen and mFe is the Fe mass per unit mass of a
specimen. Therefore, the values of AB were calculated
from the heating curves of the suspensions of thecoreshell particles and the IONPs as a substitute for
SAR.
To elucidate the difference in magnetic interaction
between IONPs and the core-shell particles, zero-fieldcooled (ZFC) and field cooled (FC) magnetization,
isothermal remanent magnetization (IRM) and direct
current demagnetization (DCD) of the 8 nm IONPs andthe core-shell particles using the IONPs were measured.
The ZFC and FC measurements were conducted at 8.0
kA/m from 5 K to 320 K. The IRM and DCD were
measured at 5 K for delta M plots16). The IRM was
obtained by the following protocol; 1) starting from astate of zero remanence, 2) applying a field, and 3)
measuring magnetization (Mr) after decreasing the fieldto zero. For the DCD, the protocol was 1) saturating thespecimen in a positive field, 2) applying a negative field,
and 3) measuring magnetization (Md) after increasing
the field to zero. Mrs and Mds were obtained bychanging the applying field in each process. The
magnitude of the applying fields was from 12.0 kA/m to638 kA/m, and the field for the saturation was 798 kA/m.
The delta M (M) plots can be obtained by the following
equation16);M = Md  (1  2Mr)

(3)The M expresses the degree of a deviation from asystem without any magnetic interaction between
magnetic nanoparticles. Generally, negative M
represents dipolar-like (demagnetizing) interactions,and positive M indicates exchange-like (magnetizing)
interactions.
3. Results and discussion
The capability of a suspension of the coreshellparticles was superior to that of the 8 nm IONPs
prepared at the same IONP concentration, which was
0.3 mg Fe/mL. Figure 2 shows heating curves of thesuspensions, and Table 1 lists the product AB
calculated from the fitting parameters of these curves.
The product was approximately doubled by theformation of the coreshell particles. We speculated thisimprovement would be induced by the change of theagglomerate state of IONPs. Indeed, the agglomeratestate of IONPs in its suspension seemed considerably
different from that in the coreshell particles. In the
IONP suspension, IONPs agglomerate, resulting in theformation of a secondary particle; the hydrodynamic
diameter measured by dynamic laser scattering (DLS)
was 79 nm. On the other hand, the IONPs on thecoreshell particles relatively exist with a gap and theassembled size is equal to the size of the coreshellparticle as apparently observed in a TEM image of Fig.
3.

Therefore, we focus on agglomerate state, inparticular, on the agglomerate size of IONPs as aparameter to strongly influence the heat generation inorder to discuss the above-mentioned improvement of
the capability in the coreshell particles. The 11 nm
IONPs were employed for this experiment instead of the
8 nm IONPs to obtain larger amount of the heatgenerated from IONPs. The agglomerate size wasmanipulated by adding PVA. We selected ahydrodynamic diameter in the suspensions measured
by DLS as a parameter strongly correlated with theagglomerate size. Open circles in Fig. 4 represent thehydrodynamic diameter of the 11 nm IONPs at PVA
concentration of 0, 0.1, 0.2, 0.5, and 1.0 wt%. The
diameter was increased with the increase of PVA
concentration. The IONP concentration was 0.3 mg
Fe/mL.
Figure 5(a) shows heating curves of the IONP
suspensions with different concentrations of PVA. The
curves were changed by an amount of PVA. However, it
was found that the heat generation under thealternating magnetic field was observed even in PVA

aqueous solutions (aq.) without the IONPs as shown in
Fig. 5(b). The heating of the PVA aq. would be causedby an eddy current loss17),18). The temperature risedepends on the PVA concentration. Therefore, we drew
new curves subtracting the temperature rise of PVA aq.
from heating curves of IONP suspensions, so as toestimate the heat generation induced only by IONPs.
Figure 5(c) shows the recalculated curves, and filled
circles in Fig. 4 indicate the products AB of these
fitting parameters. The product was decreased with theFig. 3 TEM image of coreshell particle preparedusing 8 nm IONPs.

Fig. 4 Dependences of the product AB (filled
circles) and hydrodynamic diameter (open circles) of
11 nm IONPs on PVA concentration of the IONP
suspension.

Fig. 5 Heating curves of (a) IONP suspensions
prepared at different PVA concentrations, (b) PVA
aqueous solutions at different concentrations
without IONPs, and (c) curves recalculated bysubtracting (b) from (a).

increase of the PVA concentration. This result suggeststhat the heat-generating capability is reduced by the
agglomeration.
To corroborate the results about the negative
influence of the agglomeration of IONPs on the heating
capability, the heating capability of IONP suspensions
with different IONP concentrations were evaluated. The
agglomerate size of IONPs can be regulated not only byadding the flocculant such as PVA but also by changing
the concentration of IONPs in the suspension based on
DLVO theory. Hence, the IONP suspensions wereprepared at different IONP concentrations. The
hydrodynamic diameter was increased with the increaseof the concentration as shown in Fig. 6 (open circles).
These heating curves after removing the heating effectof the solvent are shown in Fig. 7. The curves weredrawn by subtracting the heating of water, which is thesame as the result of 0 wt% PVA aq. in Fig. 5(b). The
product of the fitting parameters of the recalculated
curves is indicated in Fig. 6 (filled circles). The productdecreased exponentially with the IONP concentration.
The product AB is proportional to SAR. Therefore, thisresult indicates that the heat-generating capability of
IONPs is reduced by the agglomeration induced byincreasing the concentration of IONPs. The decrease ofSAR at high concentrations has also been demonstrated
in other papers13),19),20).
Figure 8 represents the relationship between thehydrodynamic diameter of IONPs and the product of thefitting parameters; the relationship was obtained fromthe dependences of the hydrodynamic diameter and the
product on the PVA concentration and IONP
concentration seen in Figs. 4 and 6. The productobviously exhibits a linear decrease against the increaseof the diameter, indicating the reduction of the heating
capability with the increase of the agglomerate size.
The tendency has also been reported by otherresearchers although the reason has been unclear21). In
addition, the relationship from the PVA-concentration
dependence (open circles) emerged above that from the
IONP-concentration dependence (filled circles). Because
the hydrodynamic diameter of IONPs with PVA wasevaluated to be larger than that without PVA due to theexistence of PVA, which was a hydrophilic polymer.
The reduction of the capability was probably related
to dipolar interactions between adjacent IONPs in the
agglomerate. Some researchers have reported that thedipolar interaction has a negative influence on SAR,
and three dimensional cluster of magnetic nanoparticles
exhibited the reduction of the heat generation22),23). We
speculate the reason why the interaction will become
greater with the increment of the agglomerate size of
IONPs in the following. One IONP in a larger
agglomerate interacts magnetically with more other
IONPs than that in a smaller agglomerate, resulting in
the increase of dipolar interactions. Therefore, the heatgeneration was reduced with the increase of theagglomerate size of IONPs leading to the increase of

Fig. 6 Dependences of the product AB (filled
circles) and hydrodynamic diameter (open circles) of
11 nm IONPs on IONP concentration of its
suspension.

Fig. 7 Heating curves of IONP suspensions ofdifferent IONP concentrations after removing theheating effect of the solvent, that is the curves
subtracting temperature rise of water.

Fig. 8 The product AB as a function ofhydrodynamic diameter of IONPs in its suspensionschanging PVA concentrations (open circles) and
IONP concentrations (filled circles).

number of IONPs which one IONP interacted with.
We speculate that the improvement of theheat-generating capability by the formation of thecoreshell particles seen in Fig. 2 and Table 1 was
induced by a change of their agglomerate state of
IONPs. The IONPs were deposited on the biodegradable
polymer core with a gap between each IONP in thecoreshell particles. Whereas the assembly of IONPs isa two-dimensional cluster in the coreshell particles,
the agglomerate of IONPs is a three-dimensional
cluster in the IONP suspension, because the IONPs
spontaneously agglomerate in order to reduce surface
energy. The number of IONPs interacting with one
IONP in the coreshell particles is less than that in the
agglomerate of IONPs, which is the three-dimensional
cluster of IONPs. Thus, dipolar interactions in thecoreshell particles are weaker than in the agglomerateof IONPs, resulting in the improvement of theheat-generating capability. Figure 9 shows ZFC-FC
curves of the core-shell particles and the 8 nm IONPs. It
indicates that magnetic property of the core-shellparticles is obviously different from the 8 nm IONPs.

An energy barrier to magnetization reversal in the 8nm
IONPs seems to be larger in consequence of strong
agglomeration. Figure 10 exhibits delta M plotsobtained from IRM and DCD measurements16). The
magnitude of M represents the degree of the magnetic
interaction, and it is always zero in a system of
non-interacting particles according to the Wohlfarth
relationship. The maximum of the deviation from zeroin M was 0.33 for the core-shell particles, which was
smaller than 0.38 for the 8 nm IONPs. The magnetic
interaction, that is probably the dipolar interaction, wasrestrained by the formation of the shell assembly of the
IONPs.
4. Conclusion
The heat-generating capability of the coreshellparticles composed of the biodegradable polymer core
and the iron oxide nanoparticles was discussed in thepresent paper. The capability of the coreshell particles
was superior to that of the original IONPs used for theformation of the coreshell particles. The improvementby the formation of the coreshell particles wereexplained in view of the agglomerate state of magnetic
IONPs correlating to dipolar interaction. We
demonstrated that the heat-generating capability isinversely proportional to the hydrodynamic diameter, inother words, the agglomerate size of IONPs in thesuspension. The dependence on the agglomerate size isprobably explained by the number of IONPs interacting
in the agglomerate. Finally, we concluded the higher
capability of the coreshell particles was brought fromthe difference in the agglomerate state of IONPs
between the coreshell particles and the original IONP
suspension.
Acknowledgement The present work was partially
supported by Kobayashi International ScholarshipFoundation.

Fig. 9 ZFC (solid line)-FC (dotted line) curves ofcore-shell particles and 8 nm IONPs.

Fig. 10 Delta M plots for core-shell particles and 8
nm IONPs. Hc is coercivity at 5 K.

References
1) Q. A. Pankhurst, J. Connolly, S. K. Jones, and J. Dobson: J.
Phys D, 36, R167 (2003).
2) R. Hergt, R. Hiergeist, I. Hilger, W. A. kaiser, Y. Lapatnikov,
S. Margel, and U. Richter: J. Magn. Magn. Mat., 270, 345(2004).
3) B. Thiesen, and A. Jordan: Int. J. Hyperthermia, 24, 467(2008).
4) A. Jordan, R. Scholz, P. Wust, H. Fahling, and R. Felix: J.
Magn. Magn. Mat., 201, 413 (1999).
5) C. P. Gooneratne, M. Kakikawa, T. Ueno, and S. Yamada: J.
Magn. Soc. Jpn,. 34, 119 (2010).
6) S. Vasseur, E. Duguet, J. Portier, G. Goglio, S. Mornet, E.
Hadova, K. knizek, M. Marysko, P. Veverka, and E. Pollert:
J. Magn. Magn. Mat., 302, 315 (2006).
7) S. Maenosono, and S. Saita: IEEE Trans. Magn., 42, 1638
(2006).
8) B. Mehdaoui, A. Meffre, J. Carrey, S. Lachaize, L. M.
Lacroix, M. Gougeon, B. Chaoudret, and M. Respaud: Adv.
Funct. Mat., 21, 4573 (2011).

9) S. Balivada, R. S. Rachakatla, H. Wang, T. N. Samarakoon,
R. K. Dani, M. Pyle, F. O. Kroh, B. Walker, X. Leaym, O. B.
Koper, M. Tamura, V. Chikan, S. H. Bossmann, and D. L.
Troyer: BMC cancer, 10, 119 (2010).
10) L. M. Lacroix, R. B. Malaki, J. Carrey, S. Lachaize, M.
Reapaud, G. F. Goya, and B. Chaudret: J. Appl. Phys., 105,
023911 (2009).
11) C. C. Berry, and A. S. G. Curtis: J. Phys. D, 36, 198 (2003).
12) C. Oka, K. Ushimaru, N. Horiishi, T. Tsuge, and Y.
Kitamoto: J. Magn. Magn. Mat., 381, 278 (2015).
13) E. Lima, E. D. Biasi, M. V. Mansilla, M. E. Saleta, M.
Granada, H. E. Troiani, F. B. Effenberger, L. M. Rossi, H. R.
Rechenberg, and R. D. Zysler: J. Phys. D, 46, 045002(2013).
14) A. Roch, Y. Gossuin, R. N. Muller, and P. Gillis: J. Magn.
Magn. Mat., 293, 532 (2005).
15) M. Kallumadil, M. Tada, T. Nakagawa, M. Abe, P.
Southern, and Q. A. Pankhurst: J. Magn. Magn. Mat., 321,
1509 (2009).
16) C. B. Andujar, D. Ortega, P. Southern, Q. A. Pankhurst,
and N. T. K. Thanh, Nanoscale, 7, 1768 (2015).

17) S. A. Theron, E. Zussman, and A. L. Yarin, Polymer, 45,2017 (2004).
18) F. Liu, S. Crozier, H. Zhao, and B. Lawrence, Concept.
Magnetic Res., 15, 26 (2002).
19) C. M. Boubeta, K. Simeonidis, A. Makridis, M. Angelakeris,
O. Iglesias, P. Guardia, A. Cabot, L. Yedra, S. Estrade, F.
Peiro, Z. Saghi, P. A. Midgley, I. C. Leboran, D. Serantes,
and D. Baldomir: Sci. Rep., 3, 1652 (2013).
20) A. Urtizberea, E. natividad, A. Arizaga, M. Castro, and A.
Mediano: J. Phys. Chem., 114, 4916 (2010).
21) X. Wang, H. Gu, and Z. Yang: J. Magn. Magn. Mat., 293,
334 (2005).
22) L. C. Branquinho, M. S. Carriao, A. S. Costa, N. Zufelato,
M. H. Sousa, R. Miotto, R. Ivkov, and A. F. Bakuzis: Sci.
Rep., 3, 2887 (2013).
23) D. Serantes, K. Simeonidis, M. Angelakeris, O. C. Fesenko,
M. Marciello, M. P. Morales, D. Baldomir, and C. M.
Boubeta: J. Phys Chem., 118, 5927 (2014).
Received Oct. 20, 2015; Revised Feb. 19, 2016; Accepted Mar.
30, 2016