Journal of the Korean Physical Society, Vol. 74, No. 12, June 2019, pp. 1151∼1159

Characterization of Zinc-Doped Cobalt Ferrite Nanoparticles for Applicationas Heat Generators in Magnetic Hyperthermia and MRI Contrast Agents

Ashfaq Ahmad

Department of Physics, Kyungpook National University, Daegu 41566, Korea andDepartment of Physics, Women University Swabi, Swabi, Khyber Pakhtunkhwa, Pakistan

Hongsub Bae, Chan Kim and Ilsu Rhee∗

Department of Physics, Kyungpook National University, Daegu 41566, Korea

(Received 20 February 2019, in final form 25 April 2019)

Co0.6Zn0.4Fe2O4 nanoparticles were synthesized using a one-step hydrothermal technique. Then,the particles were encapsulated with a silica shell to obtain a highly stable and nontoxic aqueoussuspension. The average diameter of the particles was 90 nm, with a core-shell structure in whichmultiple particles constitute the core. We characterized the particles to check whether they couldbe used as both heat generators in magnetic hyperthermia and enhancers of the relaxation processin magnetic resonance imaging (MRI). The particles’ heat-generating capability was confirmed bymeasuring the saturation temperature of a dispersion of particles in an alternating magnetic fieldwith an intensity of 4.4 kA/m at 260 kHz. The saturation temperature of a dispersion with a particleconcentration as low as 6 mg/mL was larger than 42◦C, which is the therapeutic temperatureof magnetic hyperthermia. An enhancement of the hydrogen proton’s relaxation process in theaqueous solution of particles was observed using a 4.7 T MRI scanner. The T2 relaxivity was foundto be 126.86 mM−1·s−1, much higher than that reported for corresponding particles. From thesemeasurements, we can conclude that our particles are suitable for application to both magnetichyperthermia and MRI.

PACS numbers: 76.60.Es, 61.46.Df, 87.61.−cKeywords: Zinc-doped cobalt ferrite nanoparticles, Magnetic hyperthermia, MRI contrast agentsDOI: 10.3938/jkps.74.1151

I. INTRODUCTION

Nanoparticles exhibit their own unique chemical, opti-cal, electrical, mechanical, and magnetic characteristicsdistinct from those of their corresponding bulk systems[1,2]. The main reason for this is that the reactivity ofnanoparticles with other materials is enhanced by theirlarge surface-to-volume ratio; they also exhibit quantumsize effects because of their small size [3–6]. The high re-activity of nanoparticles is used in nanoparticle catalysts,nano drug delivery, enhancement of durability againstabrasion, and corrosion resistance by coating nanoparti-cles on material surfaces.

Ferrite nanoparticles have especially attracted greatattention for their biomedical applications [7] becauseof their ease of synthesis, high chemical stability, andlarge saturation magnetization [8]. They have the chem-ical structure MFe2O4, where M represents the divalentmetal ions of Mn2+, Fe2+, Co2+, Ni2+, etc. Ferrites havean inverse spinel structure in which the unit cell con-

∗E-mail: ilrhee@knu.ac.kr

sists of 8 divalent ions (Mn2+, Fe2+, Co2+, Ni2+, etc.),16 trivalent ions (Fe3+), and 32 oxygen atoms, forminga closed packed cubic structure. Ferrite nanoparticleshave been extensively studied for their potential appli-cations in a variety of areas such as information stor-age systems [9], gas sensors [10], environmental applica-tions [11], magnetic resonance imaging (MRI) contrastagents [12], medical diagnostics [13], drug delivery [14],and magnetic hyperthermia [15].In medical applications, magnetic nanoparticles are

used as heat generators in magnetic hyperthermia, con-trast agents in MRI, and carriers in nano drug deliv-ery. Magnetic hyperthermia relies on the therapeuticconcept of eliminating cancerous tissue with heat gener-ated by magnetic nanoparticles in an alternating mag-netic field. Magnetic nanoparticles in a radio-frequency(RF) field generate heat through certain loss mechanismsthat depend on their magnetic properties. In ferromag-netic and superparamagnetic nanoparticles, the domi-nant heat-generating mechanisms are hysteresis and Neelrelaxation along with Brownian relaxation. The heat lossresulting from the reversal of the magnetic moment in the

pISSN:0374-4884/eISSN:1976-8524 -1151- c©2019 The Korean Physical Society

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field is known as Neel loss [16], and the heat generatedby the friction induced by physical rotation of nanoparti-cles in aqueous media is called Brownian relaxation loss[17]. The heating efficiency of the magnetic nanoparticlesdepends upon intrinsic properties such as the saturationmagnetization, coercive force, and applied magnetic fieldintensity. High heating efficiency minimizes dosage andincreases the specific absorption rate (SAR). The SARis used to quantify the heating ability of nanoparticles,and it depends on the chemical composition, anisotropicenergy, density, particle size, and magnetic properties ofthe particles.

Magnetic nanoparticles are also used to enhance theimage contrast in MRI. MRI contrast agents are classi-fied as T1 and T2 agents, depending on which effect (T1

or T2) is dominant. The T1 contrast agent absorbed by acertain tissue accelerates the T1 relaxation process of thehydrogen protons at that site, giving a larger magneticresonance (MR) signal than that of other tissues, result-ing in a well-contrasted image. The T2 contrast agentaccelerates the T2 relaxation process to reduce the MRsignal at that site. The tissue-dependent uptake of thenanoparticles is used for image contrast. The blood ves-sels of cancer cells have leaky and incomplete structuresas well as incomplete lymphatic drainage owing to theirrapid angiogenesis. Therefore, nanoparticle systems canpenetrate into the cancer tissues with high permeabil-ity and have a long retention time in the cancer sites.This enhanced permeability and retention (EPR) effectenables nanoparticles to accumulate at the cancer sites.The magnetic nanoparticles absorbed by cancer tissuesquicken the T1 relaxation at those sites. This increasesthe intensity of the signal from a cancer tissue site in aT1-weighted image; hence, it provides a brighter intensityat a cancer tissue site compared with that at a normaltissue site. In addition, the particles absorbed by cancertissues increase the T2 relaxation at those sites, whichleads to a decrease of the MR signal at the cancer tissuesites in a T2-weighted image, providing a well-contrastedimage, as the MR signals at normal sites remain unal-tered [18,19].

Magnetic nanoparticles are used in magnetic nanodrug delivery [20, 21]. The nano drug delivery systemin which a drug is attached to the magnetic nanoparti-cles is moved to the cancer site by an external magneticfield, and the drug is released to that site. In this sce-nario, the nanoparticles are used as carriers in the drugdelivery system. In targeted drug delivery with varioustargeting processes, the nanoparticles are also used ascontrast agents in MRI to observe whether the nano drugdelivery system is well absorbed by the targeted tissuesite.

As discussed above, magnetic nanoparticles can beapplied to various medical applications. For medicalapplications of magnetic nanoparticles, the surfaces ofthe nanoparticles should be coated with biocompati-ble materials to negate the toxicity of the magneticmaterials. In gadolinium contrast agents such as Gd-

diethylenetriaminepentacetate (DTPA), the gadoliniumis chelated with DTPA to reduce the toxicity of gadolin-ium. Various coating materials such as dextran (Reso-vist, Feraheme, Sinerem, and Feridex), polyethylene gly-col (PEG; Clariscan), and silica (GastroMARK) areused in commercial nanoparticle contrast agents. Inlaboratory-based research on the medical applicationsof magnetic nanoparticles, various biocompatible mate-rials, including carbon [22], gold [23, 24], chitosan [12,25], and oleic acid, have been tested [26,27]. This coat-ing of biocompatible materials onto the surfaces of theparticles also makes the particles’ surfaces neutral andhydrophilic to prevent them from being captured by thereticuloendothelial system [28].Cobalt ferrite has an inverse spinel cubic structure

with high magnetocrystalline anisotropy and relativelyhigh saturation magnetization [8, 29, 30]. Also, cobaltferrite nanoparticles are highly stable with good chemi-cal and physical properties. The magnetization of cobaltzinc ferrite (Co1−xZnxFe2O4) has been reported to in-crease with increasing zinc doping up to x < 0.5 andthen to decrease [31,32]. The preference of the zinc ionfor the tetrahedral position results in an increase in mag-netization owing to its ferrimagnetic moment and, at thesame time, a reduction in coercivity. This makes thecobalt zinc ferrite system a useful platform for alteringand tuning magnetic properties by changing the chemicalcomposition, particle size, coating material, and synthe-sis technique.In this study, cobalt zinc ferrite nanoparticles with a

zinc composition of x = 0.4 were synthesized using ahydrothermal technique, after which their surfaces werecoated with silica [33,34]. The chemical composition ofCo0.6Zn0.4Fe2O4 was selected for obtaining low coerciv-ity and high saturation magnetization [31,32], which aredesirable for applications of particles as heat generatingagents in magnetic hyperthermia and as MRI contrastagents. The characterization of nanoparticles was per-formed to observe the suitability of the particles for ap-plications to both magnetic hyperthermia and MRI.

II. EXPERIMENTAL

CoCl2·6H2O, ZnCl2·6H2O, FeCl3·6H2O, and sodiumhydroxide from Sigma Aldrich were used without furthermodification. As the dissolving agent of the chemicals,de-ionized water was used. The one-step hydrothermaltechnique with a 100-mL stainless-steel autoclave wasused to synthesize the zinc-doped cobalt ferrite nanopar-ticles with a chemical composition of Co0.6Zn0.4Fe2O4.In brief, for the synthesis of Co0.6Zn0.4Fe2O4 nanopar-ticles, 142 mg of CoCl2·6H2O, 54 mg of ZnCl2·6H2O,and 540 mg of FeCl3·6H2O were mixed with 20 mL ofdeionized water in a 100-mL beaker under magnetic stir-ring. Then, a 1-M NaOH solution was added to the so-lution to adjust the pH to 11. The mixture turned black

Characterization of Zinc-Doped Cobalt Ferrite Nanoparticles for Application as· · · – Ashfaq Ahmad et al. -1153-

Fig. 1. (Color online) XRD patterns of the bare and thesilica-coated Co0.6Zn0.4Fe2O4 nanoparticles. The indices ofthe crystal planes in the figure match well with those of aninverse spinel ferrite. The silica peaks can be seen in thecoated particles, indicating a firm coating of the silica on theparticles. The intensities of the peaks in the coated particleswere also reduced.

brown upon adding the NaOH solution. The mixturewas continuously stirred at ambient temperature by us-ing a magnetic stirrer under an argon atmosphere, withargon bubbles being introduced into the solution. Then,the obtained homogeneous mixture was transferred intoa Teflon-lined stainless-steel autoclave with a 40% fillingdegree and put into a vacuum oven at 160◦C for 12 h.Then, the solution was naturally cooled to room temper-ature. Nanoparticles were separated from the solutionby using a magnet to discard the unreacted precursorresidue left in the solution after synthesis. This processwas performed several times until the unreacted productshad been completely removed.

Zinc-doped cobalt ferrite nanoparticles were coatedwith silica by using the same method as reported in ourprevious paper [35]. First, 40 mg of the nanoparticles wasdissolved in water and sonicated in an ultrasonic cleaneruntil a homogeneous mixture of particles had been ob-tained. Then, the nanoparticle solution was put into ice-cold nitric acid, followed by separation using a centrifuge;the particles were subsequently redispersed in ice-cold 1-M citric acid. The nanoparticles were separated using acentrifuge again and then alkalized by introducing a fewdrops of ammonia. Then, the particles were put into amixture of water (35 mL), ethanol (150 mL), and am-monia (20 mL). Then, 0.4 mL of tetra-orthosilicate wasadded into a large beaker while stirring, and the mix-ture was maintained at 40◦C for 4 h. Then, the coatednanoparticles were separated from the solution using acentrifuge and washed several times using water. Finally,the obtained silica-coated nanoparticles were dissolevd inwater for further characterization.

X-ray diffraction (XRD; X’pert PRO from PANalyti-cal) was used to confirm the crystallinity and the inversespinel structure of the particles. Transmission electronmicroscopy (TEM; HT 7700, Hitachi, Ltd.) was used tocheck the shape and the size distribution of the parti-cles. The stoichiometry of the particles was determinedwith inductively coupled plasma spectroscopy (ICP; IR-SAP Thermo Jarrell Ash). The hysteresis curves of theparticles at room temperature were measured with a vi-brating sample magnetometer (VSM; MPMS, QuantumDesign). The coating status of the silica on the nanopar-ticles was checked with Fourier-transform infrared (FT-IR) spectra obtained from a Nicolet 380 system. Mag-netic hyperthermia measurements were taken using aninduction heating system (Osung High Tech, OSH-120-B). The temperature of the aqueous solution of nanopar-ticles was measured with a CALEX thermometer (Py-roUSB CF, Calex Electronics, Ltd.). The particle con-centration in the solution was determined by using ICP.The relaxivities of the hydrogen protons in the solutionwere obtained with a 4.7 T MRI scanner (Bruker Biospec47/40).

III. RESULTS AND DISCUSSION

The XRD patterns for the bare and the silica-coatedCo0.6Zn0.4Fe2O4 nanoparticles are shown in Fig. 1. Allpeaks in the XRD patterns confirmed the phase purityand the crystallinity of the nanoparticles, indicating theformation of an inverse spinel crystalline structure. Noevidence of any residue peak was found in the patterns,which was confirmed by ICP data corresponding to theinitial ratio of the precursors used during synthesis (Co:384 ppm, Zn: 296 ppm, Fe: 1192.5 ppm). The presenceof an amorphous silica shell was reflected in the broadpeak at approximately 22◦ in the XRD patterns of thecoated particles. The peaks observed at 30◦, 35◦, 43◦,56◦, and 62◦, corresponding to the characteristic crystal-lographic (2 2 0), (3 1 1), (4 0 0), (5 1 1), and (4 4 0)planes, indicated the inverse spinel crystalline structureof the particles.TEM images of the silica-coated Co0.6Zn0.4Fe2O4

nanoparticles are shown in Fig. 2. The histogram for thesize distribution of the particles was obtained by measur-ing the diameters of one hundred particles in the TEMimage. The mean diameter of the nanoparticles was de-termined to be 90 nm. The representative TEM imagesin Fig. 2 indicate encapsulation of the nanoparticles bysilica. The silica shell contains multiple magnetic cores,forming clusters inside a shell.The surface chemical structure of the silica-coated

Co0.6Zn0.4Fe2O4 nanoparticles was analyzed by usingFT-IR spectra recorded in the range of 400–4000 cm−1,as shown in Fig. 3. The ferrite nanoparticles are char-acterized by four characteristic vibrational modes below600 cm−1. These are divided into two bands. The lower

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Fig. 2. (Color online) TEM images on (a) 100-nm and (b)50-nm scales. The inset in (a) presents the histogram of onehundred particles.

frequency bands below 400 cm−1 arise from the oscilla-tions of the metallic ions in the force field of octahedraland tetrahedral lattice sites while the higher frequencymodes above 400 cm−1 arise from the metallic-oxygenbond (M-O, where M = Co, Zn, Fe) stretching vibra-tions of octahedral and tetrahedral lattice sites [36]. Thesmall absorption band at 576 cm−1 is attributed to theFe-O stretching vibrations in Fe-O-Si bonds. The largeabsorption bands at 1095 and 795 cm−1 are attributed tothe formation of a silica shell on the nanoparticles’ sur-faces [37]. Si-O-H and Si-O-M vibrations are representedby the faint absorption bands at 943 and 470 cm−1, re-spectively. The band at 1629 cm−1 is associated withthe bending vibrations of the water molecule. The faintpeak at 2912 cm−1 represents the symmetric vibration ofCH2 molecules. The large band at 3432 cm−1 is ascribedto the stretching vibrations of the O-H group. The TEMimages and the FT-IR spectrum show that the nanopar-ticles are well encapsulated by silica [38,39].

Fig. 3. (Color online) FTIR spectra of the coatedCo0.6Zn0.4Fe2O4 nanoparticles. The absorption bands in thefigure represent the stretching and the vibration of specificchemical bonds, indicating the presence of silica on the sur-faces of the nanoparticles.

Fig. 4. (Color online) Magnetization as a function of mag-netic field at room temperature for both bare and silica-coated particles. The saturation magnetization of the coatedparticles was reduced compared with that of the bare parti-cles, which is due to the silica coating. The inset shows anenlarged curve near zero field for the silica-coated particles.The particles show superparamagnetic behavior with negligi-ble coercive force.

The hysteresis curves at room temperature for thebare and the silica-coated Co0.6Zn0.4Fe2O4 nanoparti-cles are shown in Fig. 4. The saturation magnetiza-tion of the coated particles was reduced comparing withthat of the bare particles, which is the effect of the sil-ica coating. The saturation magnetization and the co-ercive force of the coated particles were 55 emu/g and35 Oe, respectively. These values are lower than thoseof bulk cobalt ferrites [37]. Nanoparticles have a surfacedead layer and bond with silica on their surfaces, which

Characterization of Zinc-Doped Cobalt Ferrite Nanoparticles for Application as· · · – Ashfaq Ahmad et al. -1155-

Fig. 5. (Color online) Heating curves for an aqueous sus-pension of Co0.6Zn0.4Fe2O4 nanoparticles for various particleconcentration.

leads to an unpaired magnetic moment, resulting in areduction of saturation magnetization. Also, this couldbe explained on the basis of surface spin and zinc ionsin lattice sites. Zinc’s preference for occupying tetrahe-dral lattice sites pushes iron ions into octahedral sites,which results in an increase in net magnetization untilx < 0.4 in Co1−xZnxFe2O4; however, a further increaseof zinc ions weakens the A-B superexchange interactionin ferrite, leading to spin canting and thereby decreas-ing the saturation magnetization [40–42]. The coercivityof the zinc-doped cobalt ferrite nanoparticles is reducedcompared with that of cobalt ferrite nanoparticles. Thisbehavior could be attributed to the decrease in magne-tocrystalline anisotropy with increasing Zn content. Zincions with zero angular momentum incorporated into thecobalt ferrite decrease the coercivity owing to a reductionin the number of highly anisotropic cobalt ions. Similarresults have been reported in previous studies [32]. Thesilica coating has also been reported to decrease the sat-uration magnetization but increases the coercivity as aresult of surface bonding. However, the saturation mag-netization of our particles is higher than those previouslyreported [40]. The lower coercive force and moderate sat-uration magnetization make our nanoparticles suitablefor hyperthermia applications.

Aqueous suspensions of various particle concentrationsranging from 3 to 15 mg/mL were prepared to investigatethe magneto-thermal effects of the particles. The calori-metric measurements were performed in an inductionheating system with an IR thermometer sensor to eval-uate the magneto-thermal potential of the silica-coatedCo0.6Zn0.4Fe2O4 nanoparticles for magnetic hyperther-mia applications. The heating curves for aqueous sam-ples with various particle concentrations in a 4.4-kA/mAC field at a frequency of 216 kHz are shown in Fig. 5.The temperature rises sharply at first for all samples,followed by stabilization; this stabilization is achieved

at a point where the generation of heat is balanced bythe heat loss to the environment. The therapeutic tar-get temperature of 42◦C for magnetic hyperthermia wasachieved for all samples except for the 3.3-mg/mL sam-ple.The generated heat by magnetic particles in the pres-

ence of an AC magnetic field increases the temperatureof the sample constituents. The generated heat and thetemperature increase are related as

ΔQ = mW cWΔT +mNcNΔT , (1)

where ΔT is the temperature increase of the sample, cWand cN are the specific heats of water and nanoparticles,respectively, and mW and mN are the masses of water(1 mL) and nanoparticles, respectively. The SAR is de-fined as the heat generated per unit mass of the magneticcomponents in the particles [14]:

SAR =ΔQ/Δt

mm=

ΔT/Δt

mm[mW cW +mNcN ]

∼= mW cWmm

(ΔT

Δt

), (2)

where mm and ΔT/Δt are the mass of the magneticcomponents in the particles and the initial rate of thetemperature increase, respectively. In the last step ofEq. (2), we used the facts that the mass of water (1 g)is much larger than that of particles (10 mg) and thatthe specific heat of water is also larger than that of par-ticles. Therefore, the amount of heat to increase thetemperature of the nanoparticles is much less than theheat needed to increase the temperature of the water inthe sample.Several factors, such as the magnetization, particle

size, and magnetic materials of particles, determine theheat capability of magnetic particles in an AC mag-netic field [14,43]. The heating mechanism in magneticnanoparticles is governed by two types of loss mech-anisms: hysteresis losses in multidomain nanoparticlesand relaxational losses in superparamagnetic nanoparti-cles. Our particles exhibited superparamagnetic behav-ior with negligible coercivity; therefore, we can ignore thecontribution of hysteresis losses. The relaxational lossescan be further catagorized into Neel losses arising fromthe reversal of the magnetic moment in the AC mag-netic field and Brownian losses arising from the physicalrotation of the particles in the aqueous medium [44].The relationship between the SAR and particle con-

centration is shown in Fig. 6. The value of the SAR de-creases with increasing particle concentration. The max-imum SAR value of 52 W/g was recorded for the samplewith the lowest particle concentration, 3 mg/mL. Thedecrease in the SAR with increasing particle concentra-tion, as shown in Fig. 6, was explained by several reportson the basis of dipolar interactions between particles [45].The decrease in the interparticle distance with increasingparticle concentration enhances the dipolar interactions

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Fig. 6. (Color online) SAR as a function of the magneticcomponents of particles in an aqueous suspension.

Fig. 7. (Color online) Heating curves for aqueous suspen-sions of particles at a fixed particle concentration (15 mg/mL)as a function of the magnetic field intensity.

between particles, which leads to reduced heat genera-tion by particles. However, multiple conflicting modelshave been introduced by several groups to explain the ef-fects of particle concentration on the dipolar interactionsand relaxation time. Dormann et al. predicted that anincrease in the particle concentration would result in anincreased anisotropy energy barrier, which would lead toan increase in the Neel relaxation time [46]. However,Mørup and Tronc predicted the opposite [47]. Nonethe-less, a behavior similar to ours was observed in previousreports for iron oxide and other ferrite-based systems [48,49].

The heating curves as a function of the magnetic fieldintensity were obtained for the 15-mg/mL sample bychanging the field intensity from 3.57 to 4.6 kA/m at216 kHz. These data are shown in Fig. 7. The SAR asa function of the square of the field intensity is depicted

Fig. 8. (Color online) SAR as a function of the square ofthe field intensity.

in Fig. 8. The power loss in the magnetic nanoparticlesas a function of field intensity is given as [50]

P =1

2μ0χ

′′ωH20 , (3)

where H0 is the field intensity, ω is the field’s angular fre-quency, and χ′′ is the particles’ magnetic susceptibility,which depends on the Neel and the Brownian relaxationtimes of the particles. Our data depicted in Fig. 8 provedthe relationship in Eq. (3).Ten aqueous samples containing differing particle con-

centrations in the range of 0.1–1 mM were prepared toreveal the potentials of the particles as MRI contrastagents. The concentration of the particles in the aque-ous solution was determined using ICP. MR images ofthe ten samples were simultaneously obtained using anMR scanner.An inversion-recovery pulse sequence was applied to

determine the T1 relaxation time of the hydrogen protonsin the aqueous solutions of the particles. In this pulsesequence, the signal intensity can be expressed as

I ∼ M0(1− 2e−t

T1 ). (4)

The T1 relaxation time was determined by fitting theMR intensities using Eq. (4). The MR intensities as afunction of time for the T1 measurements are shown inFig. 9(a) for the samples with three different particleconcentrations. The figure shows that the T1 relaxationfor the sample with the higher particle concentrationsis faster than that for the samples with lower particleconcentrations.The Carr-Purcell-Meiboon-Gill (CPMG) pulse se-

quence with a multiple spin echo was used for the T2

measurements. The dependence of the signal intensityas a function of the T2 relaxation time is given as

I ∼ M0e− t

T2 . (5)

Characterization of Zinc-Doped Cobalt Ferrite Nanoparticles for Application as· · · – Ashfaq Ahmad et al. -1157-

Fig. 9. (Color online) (a) T1 and (b) T2 relaxations ofnuclear spins in aqueous samples with three different particleconcentrations.

The T2 relaxation time was determined by fitting theMR intensities using Eq. (5). The MR intensities as afunction of time in the T2 measurements are shown inFig. 9(b) for the samples with three different particleconcentrations. The figure shows that the T2 relaxationfor the sample with the higher particle concentrationsis faster than that for the samples with lower particleconcentrations.

The concentration dependence of the MR images forboth T1 and T2 measurements are shown in Fig. 10. Forthe T1 relaxation, the MR images for the samples withhigher particle concentrations are brighter than those forthe samples of lower particle concentrations. On theother hand, the MR images for the T2 relaxation becomedarker as the particle concentration is increased.

The relaxivity is a measure of the ability of an MRIcontrast agent to enhance the relaxation of the surround-ing hydrogen protons, which can be used to increase thecontrast of MR images. The relaxivity is expressed inunits of mM−1·s−1 (of nanoparticles). The relaxivities(1/Tim) of the nuclear spins in an aqueous solution of

Fig. 10. MR images of aqueous samples ofCo0.6Zn0.4Fe2O4 nanoparticles with increasing particleconcentration. For the T1 relaxation process, the MR signalincreases with increasing particle concentration while forthe T2 relaxation process, the MR signal decreases withincreasing particle concentration.

Fig. 11. (Color online) 1/T1 and 1/T2 versus concentra-tion of the magnetic components in aqueous solutions of par-ticles. The slopes in the figure determine the T1 and the T2

relaxivities. The inset shows an enlarged plot of 1/T1 versusconcentration of the magnetic components.

magnetic nanoparticles can be expressed as [51]

1

Tim=

1

Ti+ riC, (6)

where i = 1 or 2, 1/Ti are the relaxivities of the hydro-gen protons without particle contrast agents, ri are therelaxivities in the presence of contrast agents, and C isthe concentration of the particles in the solution. 1/T1

and 1/T2 versus particle concentration in the sample areplotted in Fig. 11. The slopes of these lines representthe T1 and the T2 relaxivities. The T1 and the T2 relax-ivities denoted by r1 and r2 were determined to be 0.07and 126.86 mM−1·s−1, respectively. The value of r1 wasvery small compared with that of r2, which is a typicalcharacteristic of a spherical magnetic nanoparticle con-trast agent. In Fig. 11, the plot of 1/T1 versus particleconcentration is enlarged in the inset.The inner and the outer sphere processes are impor-

tant to determine the effect of the magnetic contrast

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Table 1. Comparison of contrast agents for magnetic resonance imaging.

Agent material Coating Particle size r1 r2 r2/r1 Company(Agent name) material [nm] [mM−1·s−1] [mM−1·s−1]

Co0.6Zn0.4Fe2O4 Silica 90 0.07 (4.7 T) 126.86 (4.7 T) 1812.29 This work

Co0.5Zn0.5Fe2O4 Dextrin 3.9 8.5 (1.5 T), 79 (r∗2) [43]

Co0.5Zn0.5Fe2O4Dimercaptos- 16 (bare) 1.49 (bare, 1.5 T) 88.46 (bare) 59.3

[44]uccinic acid 40 (coated) 0.58 (coated) 28.80 (coated) 50

Gd-DTPA Gd-chelated 4.8 (4.7 T) 5.3 (4.7 T) 1.10 Bayer Schering [45]

Mn-DPDP Mn-chelated 2.3 (1.5 T) 4.0 (1.5 T) 1.74 GE Healthcare

FeridexDextran 80–150 7 (1.5 T) 66 (1.5 T) 9.43

AMAG Pharm.

(iron oxide) (no longer available)

Resovist (iron oxide) Carboxy- dextran 45–60 8.7 (1.5 T) 61 (1.5 T) 7.01 Bayer Schering

agents on the relaxation of the nuclear spins (hydrogenprotons) [29]. The inner sphere process is generated bythe chemical interchange interaction between the boundwater of the magnetic agents and the surrounding freewater. This chemical interchange enhances the T1 re-laxation of the nuclear spins. On the other hand, theouter sphere process occurs while the magnetic agentsdiffuse through the free water. During this process, therandom fluctuations of the magnetic agents generate aninhomogeneity in the local magnetic field. This increasesthe T2 relaxation of the nuclear spins [52]. In commer-cial gadolinium contrast agents, the gadolinium ions arechelated using DTPA. Therefore, the bound water of thecontrast agent can continuously interact with the sur-rounding free water to increase the T1 relaxation of thenuclear spins. Most chelated agents exhibit a much largerinner sphere effect than outer sphere effect. Therefore,they are used as T1 contrast agents. However, the mag-netic nanoparticle agents are completely surrounded bytheir coating material. Thus, the inner sphere processdoes not occur. Furthermore, the superparamagneticnanoparticles have a significantly larger magnetic mo-ment than the gadolinium ions do. Consequently, theyproduce a larger inhomogeneity of the magnetic field,which is the main reason for the T2 relaxation. Owing tothis property of the magnetic nanoparticles, they are con-sidered as an ideal T2 contrast agent. In the above MRresults, our silica-coated cobalt zinc ferrite nanoparticlesalso showed a significantly larger T2 relaxivity, comparedwith the T1 relaxivity, which indicates that our nanopar-ticles are suitable as T2 contrast agents.

Compared to a small-relaxivity contrast agent, a large-relaxivity contrast agent can give the same contrast ef-fect at a lower dose. Furthermore, the ratio of r2/r1shows the efficiency of the T2 contrast agents. A higherratio indicates better T2 contrast efficacy. Our par-ticles exhibited a very large ratio of r2/r1, 1812.29.The reason for this is that the particles have an espe-cially large value of T2 relaxivity while the T1 effect wasnegligible. Ghasemian et al. [53] reported that theirCo0.5Zn0.5Fe2O4 particles showed the behavior of a T2

contrast agent, but that the T2 relaxivity of their parti-cles decreased after the particles had been coated. Com-mercial Gd-DTPA and Mn-DPDP have nearly the sameeffects on T1 and T2. Their ratios of r2/r1 were 1.10and 1.74, respectively. However, commercial iron-oxidenanoparticle contrast agents such as Feridex and Reso-vist are T2 contrast agents. Their T2 relaxivities aremuch larger than their T1 relaxivities. A comparisonof T1 and T2 relaxivities of various contrast agents isgiven in Table 1. We can conclude that our particles aresuitable for use as highly efficient T2 agents.

IV. CONCLUSION

Silica-encapsulated Co0.6Zn0.4Fe2O4 nanoparticleswith high chemical stability were synthesized using ahydrothermal technique. This method ensures thatparticles with good crystallinity, high magnetization,and small size are obtained. The mean diameter ofthe particles was 90 nm, with a core-shell structure inwhich the core has multiple particles surrounded by asilica shell. The adhesion status of the silica shell on theparticles’ surface was confirmed by using FT-IR spectra.The particles exhibited superparamagnetic behaviorwith negligible coercive force. The magneto-thermalproperties of an aqueous solution of the particles wereinvestigated as functions of the particle concentrationin the solution and the magnetic field intensity. Theparticles showed sufficient heat-generating capabilitysuitable for applying them to magnetic hyperthermia.The properties of enhancing the relaxation processes ofthe nuclear spins was checked to apply these particlesas MRI contrast agents. The particles exhibited amuch higher T2 relaxivity than the value reported forother corresponding particles. From the results of thesemeasurements, we can conclude that our particles canbe used as T2 agents with high efficacy.

Characterization of Zinc-Doped Cobalt Ferrite Nanoparticles for Application as· · · – Ashfaq Ahmad et al. -1159-

ACKNOWLEDGMENTS

This research was supported by the Basic Science Re-search Program through the National Research Founda-tion of Korea (NRF) funded by the Ministry of Educa-tion (2016R1A2B1006449, 2017R1A6A3A11036426).

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