3460 IEEE TRANSACTIONS ON MAGNETICS, VOL. 49, NO. 7, JULY 2013

New -Tuned Manganese Ferrite-Based Magnetic Implant forHyperthermia Therapy Application

Mohammad Reza Barati , Kiyonori Suzuki , Cordelia Selomulya , and José S. Garitaonandia

Department of Materials Engineering, Monash University, Victoria 3800, AustraliaDepartment of Chemical Engineering, Monash University, Victoria 3800, Australia

Zientzia eta TeknologiaFakultatea, EuskalHerrikoUnibertsitatea, UPV/EHU, E-48080 Bilbao, Spain

The aim of this work is to develop a new low- magnetic implant material with high heat generation and self-controlled capability forhyperthermia treatments based on a new class of spinel ferrite. Magnetic ferrites weresuccessfully prepared by a coprecipitation technique. The structural and magnetic properties were characterized using X-ray diffrac-tion (XRD), thermomagneto-gravimetric analysis (TMGA), and vibrating sample magnetometer (VSM). The heat generation ability ofthese magnetic materials was evaluated by calorimetric measurements of specific absorption rate (SAR). XRD results demonstrated anincrease in the lattice constant of Mn-ferrites with increasing Ti content, whereas showed a tendency to decrease linearly with in-creasing Ti content in the Mn-ferrite. was confirmed to be tunable within the therapeutic temperature range by adjusting thecontent near . These behaviors could be explained by considering the lattice expansion in the spinel structure of Mn-ferrites,which was accompanied by a decrease in the overlap of orbital and the superexchange interaction. The SAR value obtained wasabout 17.5 W/g with a maximum self-controlled temperature within the safe therapeutic range (42–46 ). MTT (3-[4,5-dimethylthi-azol-2-yl]-2, 5-diphenyltetrazolium bromide) assay results confirmed that the toxicity of bare ferrite particles was related to the particleconcentration. The cell viability showed a decrease from 93% to 66% with increasing particle concentration from 0.05 to 10 mg/ml. Thehigh saturation magnetization and SAR of along with tunability of its Curie temperature in the therapeutic tem-perature range, and its relatively low cytotoxicity rendered this new magnetic material attractive for hyperthermia therapy applicationsin comparison with other -tuned spinel ferrites.

Index Terms—Biomagnetics, cytotoxicity, hyperthermia, in vivo, magnetic nanoparticles.

I. INTRODUCTION

M AGNETIC hyperthermia therapy (MHT) is a localizedheat treatment to increase the temperature in a range

of 42–46 to destroy cancerous cells [1]. All the magnetichyperthermia methods are based on the heat generation due tothe energy losses during dynamic magnetization processes inmagnetic materials.Among the magnetic hyperthermia treatments with insertion

of a heating source, the application of injectable magneticnanoparticles has the great capability to selectively targetcancerous cells. It may be possible to reduce the dose of theseparticles without reducing the heating effect with a more uni-form temperature distribution around the tumor site. Moreover,applying this type of heating source will eliminate the need forsurgical removals after treatment. Magnetic nanoparticles canbe directly injected into the tumor tissue or through the arterialsupply of the tumor, which can act as the pathway of transferto the tumor site. Hence, it offers the possibility of a reductionof the chemo- or radiotherapy doses despite optimizing thetherapeutic effect and reducing the toxic side effects from othertherapeutic modalities [1].However, the main concern in magnetic hyperthermia

therapy (MHT) is controlling the overheating near the tumorcells without damaging normal cells. Since the primary originof heat generation in magnetically ordered materials is thecore losses, the heat generation should be safely regulated

Manuscript received November 05, 2012; revised January 09, 2013; acceptedJanuary 30, 2013. Date of current version July 15, 2013. Corresponding author:M. R. Barati (e-mail: Mohammad.barati@monash.edu).Color versions of one or more of the figures in this paper are available online

at http://ieeexplore.ieee.org.Digital Object Identifier 10.1109/TMAG.2013.2246860

at the Curie point where the core losses diminish, i.e.,self-controlled heating. Among magnetic ferrite nanoparticles,

ferrite nanoparticles have attracted interest becauseof its high biocompatibility and high heat generation [2]. Moreimportantly, ferrite has a lower Curie point (573K) than that of other ferrimagnetic ferrites, such as(713 K), (793 K), and (858 K) ferrites[3]. Hence, ferrite can be a potential candidate forMHT application. However, while the application offerrite for magnetic hyperthermia therapy has been reported,the temperature rise is controlled rather through adjusting theamplitude and frequency of the external magnetic field [4] andlittle has been studied on the self-regulating heating ability in

ferrite nanoparticles. Thus, ferrite withadjusted to the therapeutic temperature can potentially act

as a smart implant for a self-controlled hyperthermia treatment.Shimizu et al. [5] synthesized Ti-substituted Mg-ferrite as a

self-controlled heating magnetic implant. They reported a lineardecrease in with increasing nonmagnetic titanium content inthe ferrite system. They also proposed a possible de-crease of the Curie temperature by reducing the superexchangeinteraction between the magnetic ions in the ferrite system bypartial replacement of magnetic ions with nonmagnetic ions.Thus, this implies that the Curie temperature of fer-rite can be fine tuned by doping nonmagnetic ions such asions.

II. EXPERIMENTAL PROCEDURES

ferrite nanoparticles were prepared usingthe coprecipitation method through reaction of metal salts( , and ) with NaOH [6]. The washed pre-cipitates were sealed in an evacuated quartz tube with a pressureless than mmHg and then were heated in a box furnace at1273 K for 2h. The aqueous magnetic suspension was prepared

0018-9464/$31.00 © 2013 IEEE

BARATI et al.: NEW -TUNED MANGANESE FERRITE-BASED MAGNETIC IMPLANT FOR HYPERTHERMIA THERAPY APPLICATION 3461

Fig. 1. XRD patterns of ( –0.6) ferrites.

in DI water by dispersing magnetic nanoparticles using ultra-sonic disruption to break up any aggregates. The concentrationof magnetic nanoparticles aqueous suspension was then ad-justed to 10 mg/ml. After concentration adjustment, 1 ml of thefinal suspension was pipetted into a double-wall vacuum flask.X-ray powder diffraction (XRD) measurements were con-ducted on a Philips PW 1140/90 diffractometer usingradiation. Specific values of the saturation magnetization (Ms)were obtained using a vibrating sample magnetometer (VSM)at 300 K and 15 kOe. Thermo-magneto gravimetric analyzer(TGMA) was also utilized to measure the Curie temperature.The heat generation ability was investigated using an inductionheating system (EASYHEAT 0224—Ambrell, Australia) witha heating coil consisting of 8 turns (N) with 2.5 cm diameter(D) and 4 cm length (L). The cytotoxicity of bare nanopar-ticles was assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay in COS-7 cells (SV-40transformed African Green Monkey kidney fibroblast cells).

III. RESULTS AND DISCUSSIONS

Fig. 1 shows XRD patterns for ferrite pow-ders with different titanium contents (x). The high intensity re-flection peaks from the ferrites were seen onthe pattern without traces of impurity phases, confirming that thecoprecipitation process and subsequent thermal annealing led tohigh crystallinity structures in all samples. Both the peak posi-tion and relative intensity of reflection peaks observed for the

ferrite in Fig. 1(a) matched the standardpowder diffraction data (ICSD 01-073-3820) of crys-tallite phase. Moreover, the reflection peaks are shifted towardsthe smaller angles with increasing contents (x), as shownin Fig. 1(a) to Fig. 1(h). Although the change in d-spacing uponTi-doping is evident, these reflection peaks from arealso seen on the patterns of Ti-substituted Mn-ferrite. This in-dicates that the crystal symmetry was unaffected by Ti-dopingin spite of the enhanced d-spacing value. The lattice parameterswere estimated from the XRD patterns in Fig. 1 and the resultsare plotted in Fig. 2(a) as a function of Ti content. The latticeparameter increases linearly with Ti content, reflecting a latticeexpansion by the dissolution of ions. Fig. 2(b) shows therelationship between the saturation magnetization (Ms) and the

content for Ti-substituted Mn-ferrites.

Fig. 2. Changes of (a) the lattice parameter; (b) saturation magnetization at300 K and 15 kOe; (c) Curie temperature for Mn-ferrite with different titaniumcontent (x). The shaded area shows the safe temperature range for MHT.

The saturation magnetization was obtained from the hys-teresis loops of (Mn,Ti)-ferrite nanoparticles with ferrimagneticbehavior at 300 K and 15 kOe. It is evident from the plot thatthe room-temperature Ms value of (Mn,Ti)-ferrites is reducedsignificantly by the increase in the content. The increaseof lattice constant with increasing content could be at-tributed to the possible expansion of A- and B-sites induced byoccupation of the (0.91 ) and (0.68 ) ions withlarger ion radii compared with ions (0.67 ) with smallerion radius [7]–[10]. Moreover, the net magnetic moment ofspinel structures depends on the difference of magneticmoments in A and B sublattices, and , respectively,

[7], [10]. Thus, the drop in Ms due to theincrease in the density of ions in the Mn-ferrite can berelated to the replacement of the ions with a high mag-netic moment (5 ) by the nonmagnetic ions in B-sites.As a result, Ti-substitution could result in a reduction in themagnetic moment at B-sites , so that the total magneticmoment decreases. Fig. 2(c) shows the dependence of the Curietemperature on the Ti content for the Mn-ferrites with different

3462 IEEE TRANSACTIONS ON MAGNETICS, VOL. 49, NO. 7, JULY 2013

Fig. 3. (a) Time-dependent temperature curves and (b) maximum tempera-ture increase of under different magnetic fieldstrengths at frequency of 279 kHz. The solid line is the function of the fit. Errorbar represent the standard deviation from three experiments.

Ti contents (x). shows a tendency to decrease linearly withincreasing the Ti content and the near therapeutic temper-ature range can be achieved by substituting the ions at

. This relationship between and concentration ofions can be explained based on the molecular field theory

as , where is the exchange integral,is the Boltzman constant, z is the number of nearest neighborsand S is the spin value [11]. According to this theory, theCurie temperature is proportional to exchange interaction .Moreover, the strength of exchange interaction between mag-netic moments depends on the density of magnetic ions, theirdistance, and the angle between them [10], [11]. Therefore, thedecrease in could be attributed to the decrease in the overlapof orbital and the superexchange interaction due to latticeexpansion induced by ions. In addition, the decrease inthe density of ions by additions of nonmagneticions also reduces the magnetic exchange interaction. Since thespontaneous magnetization is lost at the Curie temperature inMn-ferrites, the Ti-substituted Mn-ferrite with couldpotentially be used as a magnetic implant with a self-controlledheating characteristic for MHT. The temperature rise of the

nanoparticles dispersed in water wastherefore measured under various magnetic fields rangingfrom 3.4 to 22 using an IR Thermacams(FLIR Thermacam SC2000) at the frequency of 279 kHz.Fig. 3(a) shows the change in temperature as a function ofheating time for a range of applied magnetic field values. Each

Fig. 4. Dependence of the SAR on applied magnetic field at frequency of279 kHz. The inset shows the dependence of the SAR on the square of themagnetic field amplitude .

curve shows a sign of saturation after heating for 30 min andthe maximum temperature change was obtained bytaking the difference in temperature between the initial stateand after heating for 30 min. The values are plotted inFig. 3(b) as a function of the square of applied magnetic field.It can be seen that the maximum temperatures that could beachieved under applied magnetic field of 3, 13 and 16were less than 42 , which is insufficient for hyperthermiatherapy application. However, the maximum temperature wasraised close to 44 by increasing the magnetic field to 20

, and up to 46 at 22 . Thus, to reach thetherapeutic temperature range (42–46 ) as the optimumtemperature range for MHT, the magnetic field intensity shouldbe selected as . The time-dependenttemperature curves of the samples exposed to 22 alsoshow a faster temperature rise than at 20 . This showsthat the exposure time could also be minimized for patient’sconvenience by applying a slightly higher magnetic field of22 . The effect of magnetic field strength on the heatgeneration or specific absorption rate (SAR) was evaluatedfrom the time-dependent temperature curves. The SAR value isdefined as the heat released per unit mass of magnetic ferrite perunit time. SAR values were estimated by the well-establishedequation, i.e., , where is thespecific heat capacity of suspension ( 4.18 J/gK),is the initial slope of the temperature versus time curve at thetime of zero , and are the specific masses of thesuspension and magnetic material, respectively [1]–[4].Fig. 4 shows the magnetic field dependence of the heat

generation for the water dispersednanoparticles. The versus SAR plots are also included inthe inset. Least-squares fitting of the experimental results showsthat the SAR value is proportional to where ,indicating that the heat generation scales approximately as thesquare of the applied field strength. This is consistent withthe established relationship, i.e., , where isa constant which depends on the permeability, conductivity,particle shape and size [12]. Furthermore, although the appliedmagnetic field (22 at 279 kHz) was higher than the

-restriction range for safeMHT [1], the resultant SAR value of 17.5 W/g was signifi-cantly higher than the heat generation of

BARATI et al.: NEW -TUNED MANGANESE FERRITE-BASED MAGNETIC IMPLANT FOR HYPERTHERMIA THERAPY APPLICATION 3463

Fig. 5. Cell viability of COS-7 cells incubated with medium containing bareferrite nanoparticles with different concentration. The

cell viability results are the mean of at least three experiments SD (standarddeviation).

( 3 W/g) in Shimizu et al. [5] who obtained this SAR valueat 16 and 230 kHz. Interestingly, the value forwater-dispersed suspension was foundto be . The resultant value of was higher thanthe value of reported by Chen et al. [12] from theinduction heating of nanoparticle suspension as the mostcommon magnetic fluid for MHT. The higher value can bedue to their higher magnetic permeability that directly induceslarger heat generation ability where the magnetic hysteresisloss is dominant part of heat generation mechanism.The influence of concentrations on

COS-7 cells viability after 72 h incubation is shown in Fig. 5.These results indicated that the cell viability is reduced slightlyby the increase in the nanoparticles concentration. Hence, the

suspension in the concentration rangeconsidered in present study could be considered to be relativelynoncytotoxic. The nanoparticles at a concentration of 10 mg/mlexhibited a slightly lower cell viability of 66%. A possibleexplanation for this slight reduction in the cell viability could bedue to the fact that the mean interparticle distance of nanopar-ticles at high concentrations is reduced and the electrostaticand/or magnetic dipolar interaction will become relevant. Thehigher concentrations with larger aggregated nanoparticleshave more tendency for particle penetration of cell membranes.Thus, high concentrations exert a stronger stimulus on the cellsurface and generated more pronounced damages to the cellmembrane structure over a period of time, causing cell lysis[13].In comparison with cell viability data reported by Yao et al.

[14] and Prasad et al. [15] for bare -tuned(less than 20% at 4 mg/ml) and (less than25% at 1.02 mg/ml) nanoparticles, respectively, the re-sults obtained here show a very lower toxicity profile of

nanoparticles on COS-7 cells, showingtheir biocompatibility for possible in vivo applications.

IV. CONCLUSION

In summary, nanoparticles were suc-cessfully synthesized with tunable within the therapeutictemperature range. The SAR value obtained was about 17.5W/gwith a self-controlled temperature in a safety range 42–46 ,depending on the strength of the external magnetic field. Thein vitro cell viability studies of nanopar-ticles for MHT showed that they were relatively biocompatiblein the concentration range observed, with highest cell viabilitycompared with those reported so far for other bare -tunedmagnetic nanoparticles implant. The high heat generation witha self-controlled heating ability, and low cytotoxicity renderedthese nanoparticles a promising candidate for in vivo hyper-thermia agent.

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