exchange-coupled magnetic nano particles for

Exchange-coupled magnetic nanoparticles forefficient heat inductionJae-Hyun Lee1, Jung-tak Jang1, Jin-sil Choi1, Seung Ho Moon1, Seung-hyun Noh1, Ji-wook Kim1,

Jin-Gyu Kim2, Il-Sun Kim3, Kook In Park3 and Jinwoo Cheon1*

The conversion of electromagnetic energy into heat by nano-particles has the potential to be a powerful, non-invasive tech-nique for biotechnology applications such as drug release1–3,disease treatment4–6 and remote control of single cellfunctions7–9, but poor conversion efficiencies have hinderedpractical applications so far10,11. In this Letter, we demonstratea significant increase in the efficiency of magnetic thermalinduction by nanoparticles. We take advantage of the exchangecoupling between a magnetically hard core and magneticallysoft shell to tune the magnetic properties of the nanoparticleand maximize the specific loss power, which is a gauge of theconversion efficiency. The optimized core–shell magnetic nano-particles have specific loss power values that are an order ofmagnitude larger than conventional iron-oxide nanoparticles.We also perform an antitumour study in mice, and find thatthe therapeutic efficacy of these nanoparticles is superior tothat of a common anticancer drug.

Thermal energy is emerging as an important means of triggeringfunctions for various applications in biomedical systems. Forexample, gold nanoparticles can successfully convert photons intothermal energy in drug release systems and for photothermalcancer therapy12–16. However, limited penetration depth and inter-ferences of photons with tissues and surrounding media couldhamper the effectiveness of these materials17. Magnetic nanopar-ticles are also attracting considerable interest for their ability tomediate heat induction. When an external alternating current(a.c.) magnetic field is applied, a magnetization reversal processoccurs18. Thermal energy is produced continuously as these par-ticles return to their relaxed states19,20. Because this magnetic heatinduction makes use of radiofrequency electromagnetic waves,tissue penetration is not limited. Theoretically, at 400 kHz forexample, 99% of energy can be transferred to magnetic nanopar-ticles located 15 cm inside the body21. In addition to its non-invasivecharacter, this thermal energy generation technique via magneticnanoparticle mediators can be controlled remotely and actuatedon-command. Such applications include the release of drugs frommesoporous nanoparticles and thermosensitive polymer-coatedcarriers3,22, treatment of diseases with hyperthermia6,9, thermalimaging of target lesions23 and the development of thermallydriven ion channel controls for cell signalling7. However, for mostof these exciting new imaging and therapeutic applications ofthermal actuation, the relatively poor energy transfer efficiency ofthe nanoparticle mediators presents a challenging obstacle, whicheither hinders full functionality or leads to a requirement forrelatively large amounts of nanoparticles10, with the concomitantpotential for side effects.

In an attempt to develop new nanoparticles with high thermalenergy transfer capability, we first examined the effects of size and

composition on the magnetic heating power of ferrite magneticnanoparticles (MFe2O4, M¼Mn, Fe, Co) (Fig. 1a,b). The specificloss powers (SLPs) of nanoparticles can depend on nanoparticlesize, composition and magnetic field (Fig. 1b)19. (Note that syn-thesized nanoparticles are highly uniform in size (s¼ 0.05;Supplementary Fig. S1.) When SLPs were measured (seeMethods), it was found that Fe3O4 nanoparticles had values of152, 349 and 333 W g21 for diameters of 9, 12 and 15 nm, respect-ively. Similarly, MnFe2O4 had a SLP maximum of 411 W g21 at15 nm and CoFe2O4 had its SLP maximum of 443 W g21 at9 nm. Unfortunately, these values do not significantly exceedthose reported for conventional magnetic nanoparticles19,24, indicat-ing that size and compositional effects are marginal.

To investigate other means for obtaining higher heat inductionpower, we simulated SLP as a function of magnetocrystalline aniso-tropy K, diameter of the nanoparticle D, and magnetization M(Fig. 1c,d). We adopted a theoretical model consolidated byRosensweig in which the SLP of superparamagnetic nanoparticlesprimarily depends on magnetic spin relaxation processes20. The plotof SLP shows a sharp maximum: the marked dependency on Kchiefly results from the internal magnetic spin fluctuation (Neelrelaxation), and the dependency on D is due to both Neel andBrownian relaxation (Fig. 1). This plot indicates the optimal rangeof K and D for nanoparticles with high SLP values: values between0.5 × 104 and 4.0 × 104 J m23 for K and between 10 and 30 nm forD exhibit SLP values from 1,000 to 4,000 W g21 (Fig. 1c). Highmagnetization M is also beneficial, and there have been studiesaimed at increasing SLP25,26. Figure 1d clearly shows the proportionalrelationship between M and SLP. For maghemite (g-Fe2O3), thelow SLP primarily originates from the relatively small value of M(�40–60 emu g21), although its K (1.6 × 104 J m23) is withinoptimal range (Fig. 1d)19.

Because the magnetocrystalline anisotropy K is an intrinsicmaterials property for each of the metal ferrite nanoparticles, it isa challenging task to tune K values of nanoparticles as desired.However, an exchange-coupled magnet, by means of the interfacialexchange interaction between hard and soft magnetic phases, hasthe potential to exhibit tunable magnetism27–29. Here, we usenanoparticles with a core–shell structure, with mutual coupling ofmagnetically hard and soft components. This coupling can allowoptimal tuning of K values in particular. Because of the facilesynthetic controls that result in nanoparticles with uniform coresize and shell thickness, excellent crystallinity and size mono-dispersity, spherical core–shell-type nanoparticles are a desirablestructure. To examine the tunability of K and its magnetic heatingpower, a representative magnetically hard material (CoFe2O4,K¼ 2.0 × 105 J m23; Supplementary Table S1) was coupled toa representative soft material (MnFe2O4, K¼ 3.0 × 103 J m23;

1Department of Chemistry, Yonsei University, Seoul, 120-749, Korea, 2Division of Electron Microscopic Research, Korea Basic Science Institute, Daejeon,305-333, Korea, 3Department of Pediatrics and BK 21, Yonsei University College of Medicine, Seoul, 120-752, Korea. *e-mail: [email protected]

LETTERSPUBLISHED ONLINE: 26 JUNE 2011 | DOI: 10.1038/NNANO.2011.95

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Supplementary Table S1). For the synthesis, we modified a seed-mediatedparticle growth method (see Methods)30. Figure 2a presents atransmission electron microscopy (TEM) image of core–shellnanoparticles with CoFe2O4 in the core and MnFe2O4 in the shell(CoFe2O4@MnFe2O4), showing their homogeneity in size(s ¼ 0.05). The core–shell structure was confirmed by electronenergy-loss spectrum (EELS) mapping analysis. Figure 2c–f showsEELS mapped images of CoFe2O4@MnFe2O4 nanoparticles, inwhich Co, Fe and Mn are colour-coded green, red and blue,respectively. Co is present only in the core region of each nanoparticle(Fig. 2c), but Fe is distributed throughout the nanoparticle (Fig. 2d)and Mn only on the shell (Fig. 2e). A composite image (Fig. 2f)reveals a homogeneous coating of 3 nm MnFe2O4 on the initial9 nm CoFe2O4 nanoparticles to give a 15 nm core–shell structure.The core–shell structure showing Co inside, Mn outside and Fedistributed throughout the nanoparticle is confirmed by theline-scanned EELS data of a single nanoparticle shown in Fig. 2g.

To investigate the coupled magnetism of these nanoparticles, wemeasured a M–H curve with a superconducting quantum interferencedevice (SQUID). The M–H curve of CoFe2O4@MnFe2O4 demonstratescoupled magnetism, exhibiting a smooth hysteresis M–H loop at bothlow and ambient temperatures (Fig. 2h). The coercivity value (Hc) at5 K falls between the values for CoFe2O4 and MnFe2O4 nanoparticles:Hc (CoFe2O4@MnFe2O4)¼ 2,530 Oe; Hc (CoFe2O4)¼ 11,600 Oe;Hc (MnFe2O4)¼ 0 Oe. This clearly indicates that the obtainedCoFe2O4@MnFe2O4 nanoparticles are magnetically exchange-coupled. The K value of 1.5× 104 J m23 for CoFe2O4@MnFe2O4was obtained by measuring the effective anisotropy field(Supplementary Table S1)31. We then extended this magneticallycoupled binary system to various core and shell combinations includ-ing CoFe2O4@Fe3O4, MnFe2O4@CoFe2O4 and Fe3O4@CoFe2O4(Supplementary Figs S2 and S3). In addition to the appropriate Kand M values, the uniformity of nanoparticles is another importantfactor for high SLP19,20. For example, a size deviation s of 0.05 canresult in an 8–15% decrease in SLP value from perfect monodisper-sity (Supplementary Table S2).

The SLP values of core–shell nanoparticles were compared withsingle-component magnetic nanoparticles (Fig. 3). Although theSLPs of single-component nanoparticles range from 100 to

450 W g21 (Fig. 3b), the SLPs of core–shell nanoparticles exhibitvalues approximately one order of magnitude higher (Fig. 3c). Inaddition, SLPs of core–shell nanoparticles can be tuned to someextent by varying the combination of the core and shell components(CoFe2O4@MnFe2O4, 2,280 W g21; CoFe2O4@Fe3O4, 1,120 W g21;MnFe2O4@CoFe2O4, 3,034 W g21; Fe3O4@CoFe2O4, 2,795 W g21)(Fig. 3c). The magnetic coupling of core and shell components pro-vides K values of �1.5 × 104 to 2.0 × 104 J m23, which fit in theoptimal K range (Fig. 1c).

The key advantage of our nanoparticle system lies in the fact thatversatile combinations of core–shell components can bring faciletuning of K, as well as M, to achieve high SLP while maintainingthe superparamagnetism. For example, when core–shell nano-particles ([email protected]) with high M(150 emu g21) were used32, SLP was 3,886 W g21

. This is 1.7times higher than that for CoFe2O4@MnFe2O4 and 34 timeslarger than for Feridex, a conventional iron-oxide magnetic nano-particle (115 W g21). Our core–shell nanoparticles typically showSLP values that are superior to those of superparamagnetic nano-particles and comparable to those of ferromagnetic nanoparticles(Supplementary Table S3)19,33,34. These nanoparticles demonstratesuperparamagnetism at room temperature (Fig. 2h, inset), animportant property for biomedical applications. In contrast to ferro-magnetic nanoparticles, superparamagnetism can prevent nanopar-ticle aggregation or cluster formation, because the spin relaxesquickly and demagnetizes at room temperature35.

Magnetic nanoparticles with high SLP values can be used formany applications. Because core–shell nanoparticles have adequatebiocompatibility without noticeable cytotoxicity (SupplementaryFig. S4), we decided to test the efficacy of CoFe2O4@MnFe2O4in antitumour hyperthermia therapy. U87MG human braincancer cells were xenografted to the abdomen of nude mice inseveral experimental groups (n¼ 3). CoFe2O4@MnFe2O4 nano-particles (75 mg), dispersed in normal saline (50 ml), were injectedsubcutaneously into the tumour (100 mm3). The mouse wasplaced in a water-cooled magnetic induction coil with a diameterof 5 cm (Fig. 4a). An a.c. magnetic field of 500 kHz at37.3 kA m21 was applied for 10 min. Following treatment, thetumour burden was monitored for up to one month. For the

Water-cooled coil

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Figure 1 | Experimental setup, measurements and simulations of SLP of magnetic nanoparticles. a, Samples are placed in the water-cooled magnetic

induction coil with a heat insulator (Styrofoam). b, Experimentally observed SLP values of MFe2O4 (M¼Mn, Fe, Co) nanoparticles of different sizes

( f¼ 500 kHz, H0¼ 37.3 kA m21). The maximum peak of SLP changes with the size and composition of nanoparticles. Error bars indicate standard deviation

(n¼ 5). c, Simulated plot of SLP based on nanoparticle size D and magnetic anisotropy constant K at a magnetization value M of 100 emu g21. d, Simulated

plot of SLP based on K and M for 12 nm nanoparticle. SLP of maghemite is indicated by the blue line. Simulations are based on the superparamagnetic

characteristics of nanoparticles.

NATURE NANOTECHNOLOGY DOI: 10.1038/NNANO.2011.95 LETTERS

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EELS

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Figure 2 | TEM analyses and magnetic measurements of core–shell nanoparticles. a,b, TEM image (a) and high-resolution TEM image (b) of 15 nm

CoFe2O4@MnFe2O4, showing the narrow size distribution and single crystallinity. c–f, EELS mapped images: Co mapped image (c), Fe mapped image (d), Mn

mapped image (e) and overlay image of c–e (f). g, Co, Fe and Mn line-scanned EELS profiles of a nanoparticle. EELS images and line-scan profiles confirm

the CoFe2O4 core and MnFe2O4 shell. h, Schematic drawing of core–shell nanoparticle with an exchange-coupled magnetism, and M–H curve of 15 nm

CoFe2O4@MnFe2O4, 15 nm MnFe2O4 and 9 nm CoFe2O4 nanoparticles measured at 5 K using a SQUID magnetometer. The magnetization curve of the

core–shell nanoparticle (red curve) shows the hard–soft exchange-coupled magnetism with a smooth hysteresis curve. Inset: M–H curve of

CoFe2O4@MnFe2O4 at 300 K, showing its superparamagnetic nature with zero coercivity.

0

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Figure 3 | SLP comparison of magnetic nanoparticles. a, Schematic of 15 nm CoFe2O4@MnFe2O4 nanoparticle and its SLP value in comparison with the

values for its components (9 nm CoFe2O4 and 15 nm MnFe2O4). b,c, SLP values of single-component magnetic nanoparticles (Feridex and MFe2O4; M¼Mn,

Fe and Co) (b) and various combinations of core–shell nanoparticles (CoFe2O4@MnFe2O4, CoFe2O4@Fe3O4, MnFe2O4@CoFe2O4, Fe3O4@CoFe2O4,

[email protected]) (c). SLP values range from 100 to 450 W g21 for single-component magnetic nanoparticles, and values for core–shell

nanoparticles range from 1,000 to 4,000 W g21 ( f¼ 500 kHz, H0¼ 37.3 kA m21). Error bars indicate standard deviation (n¼ 5).

LETTERS NATURE NANOTECHNOLOGY DOI: 10.1038/NNANO.2011.95





untreated control group of mice, tumour size increased ninefold byday 18 (Fig. 4b,c). However, for the group that received thehyperthermia treatment with core–shell nanoparticles, the tumourwas eliminated during the same period (Fig. 4b,c). For comparison,another group of mice underwent hyperthermia treatment withFeridex, and the other group was treated with the chemotherapeuticdrug doxorubicin (75 mg) with an identical dosage of core–shellnanoparticles. Both groups were monitored in the same way.Although the tumours initially regressed in the mice treated withdoxorubicin, by day 26 the tumour had regrown to four times itsoriginal size (Fig. 4b,c). The mice treated with Feridex hyperthermia(Fig. 4b,c) and mice from the other control groups (treated witheither an a.c. magnetic field only or core–shell nanoparticles onlyshowed growth behaviours similar to the untreated control (Fig. 4c).

We then analysed the tissue subjected to hyperthermia treatmentwith core–shell nanoparticles using immunofluorescence histology.The absence of fluorescence confirmed the elimination of tumour ina treated mouse (Fig. 4d, upper image), in contrast with the brightfluorescence observed in tissue from an untreated control mouse(Fig. 4d, lower image). We also conducted a dosage study tocompare the effects of core–shell nanoparticle hyperthermia, doxor-ubicin, and Feridex hyperthermia for the treatment of a same-sizedtumour (100 mm3) (Fig. 4e). For treatment with hyperthermia andcore–shell nanoparticles, a dose of 75 mg of nanoparticles wasneeded to completely eliminate the tumour; achieving the same

result with doxorubicin required a dose of 300 mg (Fig. 4e). Forthe Feridex hyperthermia treatment, even a dose in excess of1,200 mg did not produce any significant reduction in tumour size(Fig. 4e). The a.c. magnetic field used here was safe for micewithout physical injuries or weight loss (Supplementary Fig. S5)and the heat transport profile of nanoparticles was consistentwith the Pennes model (Supplementary Fig. S6). As a note, theimplementation of ‘self-regulated heating’ near body temperaturewas not applicable due to high spin transition temperatures (Tc)of �600 K for ferrite nanoparticles (Supplementary Fig. S6)36–38.

In summary, we have developed exchange-coupled magneticnanoparticles as a new means of modulating magnetism, resultingin a significant enhancement of magnetic heat induction;however, conventional approaches of altering the size and compo-sition of the nanoparticles had comparatively marginal effects onmagnetic heating power. These magnetically coupled nanoparticlescan be a highly effective new nanoscale tool useful for a variety ofsystems that rely on heat induction, including magnetic hyperther-mia therapy and other advanced nanobiotechnology applicationssuch as on-demand drug release and thermal activation of metabolicpathways within a single cell.

MethodsSynthesis of core–shell nanoparticles. For the synthesis of 15 nm CoFe2O4@MnFe2O4nanoparticles, a 9 nm CoFe2O4 nanoparticle was used as a seed and MnFe2O4 was

Tumour

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Figure 4 | In vivo hyperthermia treatment of cancer. a, Schematics of magnetic in vivo hyperthermia treatment in a mouse. Magnetic nanoparticles were

directly injected into the tumour of a mouse and an a.c. magnetic field was applied. b, Nude mice xenografted with cancer cells (U87MG) before treatment

(upper row, dotted circle) and 18 days after treatment (lower row) with untreated control, CoFe2O4@MnFe2O4 hyperthermia, Feridex hyperthermia and

doxorubicin, respectively. The same amounts (75 mg) of nanoparticles and doxorubicin were injected into the tumour (tumour volume, 100 mm3, n¼ 3).

c, Plot of tumour volume (V/Vinitial) versus days after treatment with core–shell nanoparticle hyperthermia, doxorubicin, Feridex hyperthermia, a.c. field only,

core–shell nanoparticles only and untreated control. In the doxorubicin-treated group, tumour growth slowed initially, but then regrew after 18 days. In the

group treated with core–shell nanoparticles hyperthermia, the tumour was clearly eliminated in 18 days. The suppression of tumour growth was not observed

for the groups of Feridex hyperthermia, a.c. field only, core–shell nanoparticles only and the untreated control. d, Immunofluorescence histological images of

the tumour region after hyperthermia treatment with core–shell nanoparticles (upper image) and the control tumour region (lower image). e, Plot of dose

dependency on tumour volume measured 18 days after the treatment. For core–shell nanoparticle hyperthermia and doxorubicin treatments, doses of 75 mg

and 300 mg, respectively, were needed to completely eliminate a tumour with a volume of 100 mm3. For Feridex hyperthermia, even a 1,200mg nanoparticle

dose did not adequately suppress tumour growth. Error bars in c,e, indicate standard deviation (n¼ 5).

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over-grown by thermal decomposition onto the surface of the seed particle.(See Supplementary Section 1 for details of the synthesis of a seed nanoparticle).MnCl2 (3.25 mmol) and Fe(acac)3 (5 mmol) were placed in a 250 ml three-neckround-bottom flask in the presence of oleic acid, oleylamine and trioctylamine. Afterinjection of 9 nm CoFe2O4 nanoparticles suspended in hexane, the reaction mixturewas heated at 365 8C for 1 h. After removing the heat source, the reaction productswere cooled to room temperature and 15 nm core–shell CoFe2O4@MnFe2O4nanoparticles were isolated using procedures described previously32. Different kindsof core–shell nanoparticles were synthesized using the appropriate reactants (CoCl2,FeCl2 and MnCl2) and similar reaction conditions. As-synthesized nanoparticleswere transferred to the aqueous phase by modification of the surface using2,3-dimercaptosuccinic acid32.

Measurement of SLP value. Measurement of heat generation of the nanoparticleswas carried out using a high-radiofrequency heating machine (HF 10K, TaeyangSystem Co. Korea) that radiated an a.c. magnetic field at a frequency f of 500 kHzand strength H0 of 37.3 kA m21. The a.c. magnetic field generated sinusoidalmagnetic field H as a function of time t, frequency f and maximum field strength H0:

H = H0 sin(2pft) (1)

The sample vial was thermally insulated using Styrofoam and inserted in awater-cooled magnetic induction coil (diameter, 5 cm) where the nanoparticleconcentration in toluene was 5 mg ml21. The SLP was calculated using equation (2),

SLP = CVs

mdTdt

(2)

where dT/dt is the initial slope of the graph of the change in temperature versus time,C is the volumetric specific heat capacity of the sample solution, Vs is the samplevolume and m is the mass of magnetic material in the sample. See SupplementarySection 10 for the complete parameters and detailed simulation procedure.

In vivo mouse experiments. We maintained six-week-old female BALB/c nudemice under the approval of and in accordance with the guidelines of the AnimalCare Committee of Yonsei University, Korea. U87MG cells (7 × 106) in 100 mlHanks’ balanced salt solution were xenografted into the abdomen of each mouse.When the size of the tumour reached 100 mm3, a solution of 75 mg nanoparticles ordoxorubicin dissolved in normal saline (50 ml) were injected intratumorally. Micewere treated with an a.c. magnetic field for 10 min (frequency, 500 kHz; strength,37.3 kA m21). For the dosage comparison study, same-sized tumours (100 mm3) weretreated by either nanoparticles or doxorubicin of different amounts in saline (50 ml).

Received 7 April 2011; accepted 19 May 2011;published online 26 June 2011

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30. Sun, S. H. et al. Monodisperse MFe2O4 (M¼Fe, Co, Mn) nanoparticles. J. Am.Chem. Soc. 126, 273–279 (2004).

31. Cullity, B. D. Introduction to Magnetic Materials (Addison-Wesley, 1972).32. Jang, J-t. et al. Critical enhancements of MRI contrast and hyperthermic effects

by dopant-controlled magnetic nanoparticles. Angew. Chem. Int. Ed. 48,1234–1238 (2009).

33. Hergt, R. et al. Magnetic properties of bacterial magnetosomes as potentialdiagnostic and therapeutic tools. J. Magn. Magn. Mater. 293, 80–86 (2005).

34. Gonzales-Weimuller, G., Zeisberger, M. & Krishnan, K. M. Size-dependentheating rates of iron oxide nanoparticles for magnetic fluid hyperthermia.J. Magn. Magn. Mater. 321, 1947–1950 (2009).

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AcknowledgementsThis work was supported by Creative Research Initiative (2010-0018286), WCU Program(R32-2009-10217) and BK21 Project. The authors thank H. Nah for preliminary SLPmeasurements and Y. Jo at KBSI for magnetism measurements. K.I.P. was supported by theStem Cell Research Center and Korea Healthcare Technology R&D Project (A091159).

Author contributionsJ.C. conceived and designed the experiment. J-H.L, J-t.J., S.H.M., J-G.K. and S-h.N. performedsyntheses, characterizations and property measurements of the nanoparticles. J-s.C., I-S.K. andK.I.P. performed in vivo experiments. J-H.L., J-w.K. and J.C. wrote the manuscript.

Additional informationThe authors declare no competing financial interests. Supplementary informationaccompanies this paper at www.nature.com/naturenanotechnology. Reprints andpermission information is available online at http://www.nature.com/reprints/.Correspondence and requests for materials should be addressed to J.C.

LETTERS NATURE NANOTECHNOLOGY DOI: 10.1038/NNANO.2011.95




http://www.nature.com/reprints/

mailto:[email protected]



SUPPLEMENTARY INFORMATIONDOI: 10.1038/NNANO.2011.95

NATURE NANOTECHNOLOGY | www.nature.com/naturenanotechnology 1

1

Supplementary Information

Exchange-Coupled Magnetic Nanoparticles

for Efficient Heat Induction

Jae-Hyun Lee, Jung-tak Jang, Jin-sil Choi, Seung Ho Moon, Seung-hyun Noh,

Ji-wook Kim, Jin-Gyu Kim, Il-Sun Kim, Kook In Park, and Jinwoo Cheon*

* To whom correspondence should be addressed.

E-mail: [email protected], Phone: (+82) 2-2123-5631, Fax: (+82) 2-364-7050.


2

Supplementary Section 1: Synthesis of single component ferrite nanoparticles (MFe2O4,

M = Mn, Fe, Co)

Prior to compare the specific loss power (SLP), various ferrite nanoparticles with different sizes

were synthesized according to the method previously described1. Briefly, in order to synthesize 9 nm

CoFe2O4 nanoparticles, the following method was used. CoCl2 (3.25 mmol) and Fe(acac)3 (5 mmol)

were placed in a 250 mL three-neck round-bottom flask in the presence of oleic acid, oleylamine and

octyl ether. The reaction mixture was heated at 300oC for 1 h and, after removing the heat source, the

reaction products were cooled to room temperature. Upon the addition of ethanol, a black powder

precipitated and was isolated by centrifugation. The isolated nanoparticles were dispersed in a solvent

such as hexane.

The as-synthesized nanoparticles are shown in Figure S1, of which size distribution (σ) was ~0.05.

Figure S1. Transmission electron microscope (TEM) images of various metal ferrite nanoparticles

(MFe2O4, M = Mn, Fe, Co). All the scale bars are 20 nm.


3

Supplementary Section 2: Electron energy-loss spectrum (EELS) analysis of

MnFe2O4@CoFe2O4

As another example, MnFe2O4@CoFe2O4 nanoparticle was analyzed by EELS. For the analysis,

standard three-window method was used with the energy window of 25 eV, entrance aperture of 3 mm

and exposure time of 45 sec. The analysis shows that Mn atoms are distributed in core and Co atoms

in shell, clearly indicating the core-shell structure.

Figure S2. EELS mapping analysis of MnFe2O4@CoFe2O4 nanoparticle. (a) Mn atom is mapped as

green color. (b) Co atom is mapped as red color. (c) Merged image of Mn and Co, which clearly

shows the core-shell structure.


4

Supplementary Section 3: Exchange magnetism of various core-shell nanoparticles

Exchange-coupled properties of various core-shell nanoparticles (CoFe2O4@MnFe2O4,

CoFe2O4@Fe3O4, MnFe2O4@CoFe2O4, Fe3O4@CoFe2O4) were investigated by using M-H curve

measurements with SQUID (superconducting quantum interference device) magnetometer (Quantum

Design MPMS7). All the measurements were performed from –5 T to +5 T at 5 K. All of the M-H

curves show single magnetic phase, not showing any phase separation or kinks in the graphs. Also, the

results show the characteristics of exchange-coupled magnetism of hard-soft magnet that core-shell

nanoparticles with CoFe2O4 in core exhibit reduced coercivity (Hc) and enhanced saturation

magnetization (Ms) than initial core nanoparticle (9 nm CoFe2O4), whereas core-shell nanoparticles

with CoFe2O4 in shell exhibit broad Hc and increased Ms than initial core nanoparticle (9 nm MnFe2O4

and Fe3O4).

Figure S3. M-H curves of various core-shell nanoparticles measured with SQUID at 5K. (a,b) core-

shell nanoparticle with CoFe2O4 in core and (c,d) core-shell nanoparticle with CoFe2O4 in shell. In

(a,b), coercivity (Hc) is reduced and saturation magnetization (Ms) is increased when the nanoparticle

is shelled and thus magnetically coupled , whereas in (c,d) Hc and Ms are increased.


5

Supplementary Section 4: In vitro cytotoxicity study of core-shell nanoparticles

Two kinds of core-shell nanoparticles (CoFe2O4@MnFe2O4 and MnFe2O4@CoFe2O4) were treated

to the representative cancer cell lines (U87MG brain cancer and HeLa cervical cancer) in order to

assess the cytotoxicity. 12.5 – 200 µg/ml concentrations of nanoparticles were treated to 106 number

of cells for 24 hrs. Then, the cells were assayed by using CCK-8 (cell counting kit-8, Dojindo

Molecular Technology). Our results indicate the cells are not interfered by nanoparticles and healthy.

Figure S4. In vitro cytotoxicity results of core-shell nanoparticles on U87MG and HeLa cancer cell

lines. (a) CoFe2O4@MnFe2O4 nanoparticles and, (b) MnFe2O4@CoFe2O4 nanoparticles treated cell

lines.


6

Supplementary Section 5: In vivo safety study of AC magnetic field

We investigated the effect of AC magnetic field on mice. AC magnetic field of f = 500 kHz with H0

= 37.3 kA m-1 was applied to the mice (n = 5) for 10 min. After the treatment, the weights of mice

were measured for 16 days. If eddy current induced by AC magnetic field was harmful enough to

mouse, the overall weight of mouse would not be maintained and weight loss might occur. As shown

in Figure S5, the weight loss did not occur in experimental group and the slight weight increase was

identical to the control group. In addition, the mice did not show any physical wounds after the

application of magnetic field throughout the experiment and all mice were healthy.

Figure S5. The weights change profile of mice (n = 5) (Black dot: mice with AC magnetic field (f =

500 kHz, H0 = 37.3 kA m-1), red dot: control mice). Gradual increase of weight was observed for both

AC magnetic field applied group and control group.


7

Supplementary Section 6: Heat transport analysis of core-shell nanoparticles

We measured heat transport of core-shell nanoparticles by using agarose gel matrix as cancer tissue

analog following a known process2. 30 µg of CoFe2O4@MnFe2O4 nanoparticles were embedded in the

agarose gel, and then exposed to AC magnetic field (500 kHz, 37.3 kA m-1). The temperature of

nanoparticle embedded agarose gel rose to 43 oC in 300 sec and the temperature was maintained

around 50 oC (Figure S6a). The effective heating was observed only in the vicinity of nanoparticles

and the temperature decreased drastically as the distance grew apart (Figure S6b). Our observation is

consistent with the well-known bioheat transfer model by Pennes3.

Figure S6. Heat transfer profiles of CoFe2O4@MnFe2O4 nanoparticles to the surrounding agarose

gel which is used as pseudo-cancer tissue. (a) Graph on temperature vs. time where nanoparticles are

embedded. (b) Graph on temperature vs. distance from the nanoparticle site.


8

Supplementary Section 7: Temperature dependent magnetization of core-shell

nanoparticles

The temperature dependent magnetizations were measured for 15 nm CoFe2O4@MnFe2O4 and

MnFe2O4@CoFe2O4 nanoparticles. After the nanoparticles were placed in a gelatin capsule,

magnetization was measured while changing the temperature from 300 K to 700 K. The spin

transition temperatures (Tc = Curie temperature) were observed near 590 K and 600 K for

CoFe2O4@MnFe2O4 and MnFe2O4@CoFe2O4, respectively.

Figure S7. Magnetization curves of core-shell nanoparticles as a function of temperature. (a)

CoFe2O4@MnFe2O4, and (b) MnFe2O4@CoFe2O4.


9

Supplementary Section 8: Summary of magnetic properties

The K values were measured at room temperature (300 K). In order to measure the K values, we

adopted the method described by B. D. Cullity4. Briefly, a measured M-H curve was fitted with a

calculated magnetization curve with appropriate K and M value.

Table S1. Size, saturation magnetization (Ms) and magnetocrystalline anisotropy constant (K) of

MFe2O4 (M = Mn, Fe, Co) nanoparticles and core-shell nanoparticles

MnFe2O4 Fe3O4 CoFe2O4 CoFe2O4

@ MnFe2O4

MnFe2O4@

CoFe2O4

CoFe2O4@

Fe3O4

Fe3O4 @

CoFe2O4

Size (nm) 12 15 18 9 12 15 6 9 12 15 15 15 15

Ms (emu g-1) 110 125 133 85 101 110 66 77 96 110 108 105 104

Measured K

(J m-3) 3.0 (±0.3) × 103 1.3 (±0.2) × 104 2.0 (±0.3) × 105 1.5 (±0.2)

× 104 1.7 (±0.3)

× 104 2.0 (±0.2)

×104 1.8 (±0.3)

×104

reference K values

4.0 × 103 (ref 5) 1.2 × 104 (ref 7) 2.0 × 105 (ref 9)

4.0× 103 (ref 6) 1.1 × 104 (ref 8) 1.6 × 105 (ref 10)


10

Supplementary Section 9: The effect of size distribution on SLP

We analyzed size distribution effect on SLP using the method previously described by Rosensweig11.

When setting the size deviation σ = 0.05, SLP value decreased by 8–15% from that of perfect

monodispersity.

Table S2. The effect of size distribution of nanoparticles on SLP (f = 500 kHz, H0 = 37.3 kA m-1)

Nanoparticle Calculated SLP (W g-1) Size distribution effect on SLP

(σ = 0.05) (W g-1) SLP decrease (%)

9 nm CoFe2O4 160 148 7.5

15 nm MnFe2O4 414 369 10.8

15 nm CoFe2O4 @MnFe2O4

1710 1453 15.0


11

Supplementary Section 10: SLP comparison of core-shell nanoparticles with other

reported values

Table S3 summarizes SLP values of core-shell nanoparticles and other representative magnetic

nanoparticles.

Table S3. Reported SLP values of various magnetic nanoparticles.*

Material Size (nm)

Frequency f (kHz)

Amplitude, H0

(kA m-1) f·H0

(A m-1 s-1)

Reported SLP

(W g-1) Magnetism Reference

γ-Fe2O3 16.5 700 24.8 17.36 x 109 1650 superpara 12

CoFe2O4 9.1 700 24.8 17.36 x 109 360 superpara 12

CoFe2O4 3.9 700 24.8 17.36 x 109 40 superpara 12

Fe3O4 10 300 15 4.1 x 109 168 superpara 13

MnFe2O4 10 300 15 4.1 x 109 136 superpara 13

CoFe2O4 10 300 15 4.1 x 109 52 superpara 13

Fe3O4 14 400 24.5 9.8 x 109 447 superpara 14

Fe3O4 40 410 10 4.1 x 109 960 ferro 15

CoFe2O4@ MnFe2O4

15 500 37.3 18.7 x 109 2280 superpara this study

MnFe2O4@ CoFe2O4


Fe3O4@ CoFe2O4


Zn0.4Co0.6Fe2O4

@ Zn0.4Mn0.6Fe2O4


* This comparison cannot absolutely be perfect and should be rather regarded as an approximate guideline because the dimensions of inductive coil, which also affect the SLP, are not incorporated due to their unavailability from literatures.


12

Supplementary Section 11: Detailed Calculation of SLP

The principal equations on SLP and the power dissipation (P) are as follows.

ρφPSLP =

(1)

200 fHP χπµ ′′=

(2)

In equation (2), χ″ is out-phase-component of susceptibility which is expressed as follows.

02)(1χ

ωτωτχ

+=′′

(3)

In equation (3), χ0 is the actual susceptibility and τ is the effective relaxation time which can be

expressed as equation (4) and (6), respectively.

−=ξ

ξξ

χχ 1coth30 i

(4)

In equation (4), χi is the susceptibility calculation parameter and is Langevin parameter which can

be expressed as equation (5) and (9), respectively.

TkVM

B

mdi 3

20φµχ =

(5)

Equation (6) represents effective relaxation time which is consisted of Néel (equation 7) and

Brownian (equation 8) relaxation time.

BN

BN

τττττ+

=

(6)

mKVN e0ττ =

(7)

TkV

B

hB

ητ 3=

(8)

TkVHM

B

md 00µξ =

(9)


13

The values of the variables: µ0: permeability in free space (4π x 10-7 T m A-1)

f: frequency of magnetic field (500 kHz) H0: magnetic field intensity (37.4 kA m-1) ω: angular frequency (= 2πf = 3.14 x 10-6 s) φ: nanoparticle volume fraction (0.13%) ρ: particle density (5.3 x 103 kg m-3) Md: domain magnetization of suspended particle (6.36 x 105 A m-1) Vm: nanoparticle volume (m3) Vh: hydrodynamic volume of nanoparticle (m3): 2 nm diameter increase to Vm K: magnetic anisotropy constant (J m-3) η: viscosity of solution (toluene 550 µPa s; water 894 µPa s) kBT: Boltzman constant product (4.14 x 10-21)

This calculation successfully reproduces the other ones reported. Below are the SLP graphs

excerpted from the other’s report and the reproduced graph by using our calculation.

Figure S8. SLP graphs excerpted from the other report and the reproduced graphs by using our

calculation. (a) Original SLP graphs from Fortin et al and (b) reproduced graph by our

calculation12.


14

Supplementary Section 12: Transmission electron microscope (TEM) and electron

energy loss spectrum (EELS) analysis

The morphology and size distribution of metal ferrite and core-shell nanoparticles were

investigated by TEM with JEOL-2100 at 200 kV and ARM1300S (JEOL, Korea Basic Science

Institute) at 1,250 kV with a point resolution of 1.2 Å. The EELS mapping analysis was performed

using a standard three-windows method with an energy window of 25 eV, an entrance aperture of 3

mm and exposure time of 45 sec.


15

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