Materials Science and Engineering C 46 (2015) 394–399

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Materials Science and Engineering C

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ZnFe2O4 nanoparticles as radiosensitizers in radiotherapy of humanprostate cancer cells

AlirezaMeidanchi a,b, Omid Akhavan b,c,⁎, Samideh Khoei d, Ali A. Shokri a,e, Zahra Hajikarimi d, Nakisa Khansari f

a Department of Physics, Payame Noor University (PNU), P.O. Box 19395-3697, Tehran, Iranb Department of Physics, Sharif University of Technology, P.O. Box 11155-9161, Tehran, Iranc Institute for Nanoscience and Nanotechnology, Sharif University of Technology, P.O. Box 14588-89694, Tehran, Irand Department of Medical Physics, Iran University of Medical Sciences, Tehran, Irane Computational Physical Sciences Research Laboratory, School of Nano-Science, Institute for Studies in Theoretical Physics and Mathematics (IPM), PO Box 19395-5531, Tehran, Iranf Department of Cardiology, Hamadan University of Medical Sciences, Hamadan, Iran

⁎ Corresponding author.E-mail address: oakhavan@sharif.edu (O. Akhavan).

http://dx.doi.org/10.1016/j.msec.2014.10.0620928-4931/© 2014 Elsevier B.V. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history:Received 11 May 2014Received in revised form 10 August 2014Accepted 21 October 2014Available online 24 October 2014

Keywords:Zinc ferrite spinelsNanoparticlesRadiosensitizersRadioresistant cancer cellsRadiotherapy

Nanoparticles of high-Z elements exhibit stronger photoelectric effects than soft tissues under gamma irradia-tion. Hence, they can be used as effective radiosensitizers for increasing the efficiency of current radiotherapy.In this work, superparamagnetic zinc ferrite spinel (ZnFe2O4) nanoparticles were synthesized by a hydrothermalreactionmethod and used as radiosensitizers in cancer therapy. Themagnetic nanoparticles showed fast separa-tion from solutions (e.g., ~1min for 2mgmL−1 of the nanoparticles in ethanol) by applying an externalmagneticfield (~1 T). The ZnFe2O4 nanoparticleswere applied in an in vitro radiotherapy of lymphnode carcinoma of pros-tate cells (as high radioresistant cells) under gamma irradiation of 60Co source. The nanoparticles exhibited nosignificant effects on the cancer cells up to the high concentration of 100 μgmL−1, in the absence of gamma irra-diation. The gamma irradiation alone (2 Gy dose) also showed no significant effects on the cells. However,gamma irradiation in the presence of 100 μg mL−1 ZnFe2O4 nanoparticles resulted in ~53% inactivation of thecells (~17 times higher than the inactivation that occurred under gamma irradiation alone) after 24 h. The highercell inactivation was assigned to interaction of gamma radiation with nanoparticles (photoelectric effect),resulting in a high level electron release in the media of the radioresistant cells. Our results indicated thatZnFe2O4 nanoparticles not only can be applied in increasing the efficiency of radiotherapy, but also can be easilyseparated from the cell environment by using an external magnetic field after the radiotherapy.

© 2014 Elsevier B.V. All rights reserved.

1. Introduction

In all over the world, cancer is known as one of the major causes ofdeath. For example, the first cause of death in Iran is due to cancer,after coronary heart disease and accidents [1]. Among the cancers, pros-tate cancer is one of themain causes of death inmen [2]. Surgery (open,laparoscopic or robotic-assisted), external beam radiation, or radioac-tive seed implants (brachytherapy) may be used to treat early stagesof disease. Combination of hormonal therapy, chemotherapy, radiation,or one of them alone can be used to treatmore advanced disease. Radio-therapy was often used as an effective treatment for clinically localizedcancer cells. However, radioresistance of cancer cells is one of themajorcauses of ineffective treatments [3].

In recent years, nanostructures with unique physico-chemical prop-erties, such as small particle size, high effective surface area, and capa-bility of functionalization, are promisingly used in cancer therapeutic

researches and applications (see, for example, [4–9]). Meantime, theuse of magnetic nanoparticles not only provides imaging of the cancercells, but also can lead to more effective localized treatments of tumorsby targeted drug delivery [10,11].

On the other hand, radiotherapy is one of the most current and im-portant cancer therapeutic methods. Using radiotherapy cancer cellscan be destructed through direct and indirectmechanisms. In direct de-struction, the gamma radiation directly affects the DNA through ioniza-tion and/or excitation of target atoms. Based on the indirectmechanism,gamma radiation interacts with other atoms or molecules around DNA(i.e., water and/or nanoparticles) to produce free radicals or Auger elec-trons which can destruct the cells. The interaction of gamma radiationwith nanoparticles having high Z-elements (as radiosensitizers) canfurther excite the photoelectric effects and/or Auger electron ejections.Hence, somenanoparticles with high Z-elements (such as gold and gad-olinium) have been used as effective radiosensitizers in cancer therapy[12–14]. Moreover, Choi et al. [15] investigated the potential of sensitiz-ing effect of iron oxide nanoparticles for photon activated therapy. Theyobserved a more significant reduction in viability of the FeO-treated ir-radiated cells, compared to the radiation alone group.

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Recently, spinel ferrite nanoparticles with superparamagnetic prop-erty are utilized in many areas including magnetic storage media [16],ferrofluids [17,18], biosensors [19], catalysts [20], environmental reme-diation [21,22], and water purification [23,24]. In addition, spinel ferritenanoparticles with low toxicity have been used in some nanomedicineapplication such as hyperthermia treatments [25,26], magnetic reso-nance imaging [27,28], drug delivery [29] and DNA separation [30].Among the various spinel ferrites, zinc ferrite (as a normal spinel struc-ture with (Zn)[Fe2]O4 representation in which square brackets containthe octahedral or B sites and parenthesis shows the cations in tetrahe-dral or A sites) has attractedmuch interest, due to its low ordering tem-perature and antiferromagnetic ground statewith aNéel temperature at~10 K, paramagnetic behavior at room temperature and narrow bandgap of 1.9 eV [31].

Concerning the application of ZnFe2O4-based composites in cancertherapy, Tomitaka et al. [32] found that ZnFe2O4 and NiFe2O4 nanopar-ticles exhibited cytotoxic effects on HeLa cells when exposed to100 μg mL−1 of the nanoparticles. Then, Shah et al. [33] reported mag-netic and bioactivity evaluation of ferromagnetic ZnFe2O4-containingglass ceramics for the hyperthermia treatment of cancer. Very recently,Liu et al. [34] suggested ZnFe2O4 nanoparticles with good magneticproperty and neuro-cytocompatibility for potential applications inmag-netic resonance imaging of cells. Since nanoparticles with high Z-elements (such as gold [12,13], iron oxide [15] and gadolinium-based[14] nanoparticles) have been used as radiosensitizing agents in radio-therapy of cancer, the ZnFe2O4 nanoparticles (including high Z-elements) can also be proposed as a suitable magnetic radiosensitizerin cancer treatments. However, no investigation concerning applicationof ZnFe2O4 nanoparticles as radiosensitizers in radiotherapy of cancercells has been reported, yet.

In this work, ZnFe2O4 nanoparticles were synthesized by using aone-step hydrothermal process. The morphological, structural, optical,and magnetic properties of the nanoparticles were investigated. Theconcentration-dependent cytotoxicity of the nanoparticles on humanprostate cancer cells was studied. Moreover, the nanoparticles were ap-plied as radiosensitizers in an in vitro radiotherapy of human prostatecancer cells (as high radioresistant cells), under gamma irradiation.

2. Experimental

2.1. Materials

LNCaP human prostate cancer cells derived from ametastatic lymphnode were prepared from the Pasteur Institute of Iran. Fetal bovineserum (FBS), Trypan blue dye, RPMI 1640 and penicillin/streptomycin(Invitrogen), 96-well microplates (JET BIOFIL) and ethanol (Merck,99.9%) were prepared for the experiments. Other products such asMTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide),dimethyl sulfoxide (DMSO, ≥99%), trypsin-ethylenediaminetetraaceticacid, Zn(NO3)2·6H2O (≥98%), and Fe(NO3)3·9H2O (≥98%) were ob-tained from Sigma-Aldrich.

2.2. Hydrothermal synthesis of ZnFe2O4 nanoparticles

ZnFe2O4 nanoparticles were synthesized through the coprecipitationof Zn(NO3)2·6H2O and Fe(NO3)3·9H2O in the presence of the ethanol[35], To do this, 298 mg Zn(NO3)2·6H2O and 808 mg Fe(NO3)3·9H2Owere added to 80 mL ethanol and the mixture was stirred at 400 rpmfor 30 min. After that, the mixture was sealed in a Teflon-lined stainlesssteel autoclave at 180 °C for 12 h. Then, themixture was cooled down atroom temperature. The obtained ZnFe2O4 powder was rinsed bydistillated water (with purity of ≥98%) several times, and dried in anoven at 60 °C for 24 h. In the material characterization stage, ZnFe2O4

nanoparticles were dispersed in ethanol and distilled water, while forthe biological tests (see the following) the desired amount of the

nanoparticles was dispersed in culture media to obtain the desiredconcentrations.

2.3. Material characterizations

The optical absorption spectra of the samples were recorded byusing a UV–visible spectrophotometer (UV–vis. CARY 300 Conc) in thewavelength range of 200–800 nm. The band gap energy (Ebg) ofthe prepared sample was estimated by the following formula: Ebg(eV) ≤ 1240 / λ (nm) where λ is the wavelength (~550 nm) of the ab-sorption peak of the ZnFe2O4 nanoparticles. Fourier transform infrared(FTIR) spectra were recorded by using a FTIR-4200, JASCO equippedwith a pressed KBr pellets in wavenumber range of 400 to 4000 cm−1.Themorphology of the nanoparticleswas characterized byfield emissionscanning electronmicroscopy (FE-SEM, Hitachi S4160) and transmissionelectron microscopy (TEM, Zeiss-EM10C) at accelerating voltages of 15and 80 kV, respectively. The TEM samples were prepared by dispersingthe desired powder in acetone, and then, dipping carbon coated coppergrids into the suspension. Raman spectroscopy (BRUKER ModelSENTERRA) was performed at room temperature using a high-energydiode excitation source operating atwavelength of 785 nm. Themagnet-ic property of the ZnFe2O4 nanoparticle was studied by a vibration sam-ple magnetometer (VSM/AGFM-Meghnatis Kavir Kashan Co.) with amaximum applied magnetic field of 10 kOe, at room temperature.

2.4. Cell culture, gamma ray irradiation and MTT assay

The human prostate cancer cell line LNCaP was selected, becauseLNCaP cells show higher radioresistance than parental cell lines [36].The cells were cultured in RPMI-1640 medium supplemented with10% FBS and 1% penicillin–streptomycin, in T-25 tissue culture flasksin a 5% CO2 atmosphere at 37 °C. The medium was changed every2–3 days. After three passages, approximately 8 × 103 LNCaP cells/well were seeded in two similar 96well plates (180 μL of cell suspensionwas added to the wells) and incubated to adhere overnight. After 24 h,20 μL suspension containing medium and ZnFe2O4 nanoparticles (soni-cated at frequency of 40 kHz and power of 100 W for 10 min) added tothe plates until wells reach to various concentrations (0.01, 0.1, 1, 10,100 μgmL−1, 4 wells for each nanoparticle concentration) and incubat-ed in a 5% CO2 atmosphere at 37 °C for 24 h. Cell proliferation mediumwithout the ZnFe2O4 nanoparticles was set as a control. Then, one ofthe plates was irradiated by a gamma ray of 60Co source (2 Gy dose)of a cobalt therapy system (Shohada-e-Tajrish Hospital, Tehran, Iran).After irradiation, MTT dye was added to each well (two plates) and in-cubated at 37 °C for 4 h. Then, theMTT containingmediumwas then re-moved and replaced with DMSO (100 μL/well) to dissolve the formazincrystals. The absorbance at 590 nmwasmeasured by ELISA micro platereader (DYNEX MRX, USA) using a reference wavelength of 620 nm.The cell viability percentage was calculated by the following formula:cell viability (%) = [(optical density (OD) of the sample − OD of themedium) / (OD of the cell control − OD of the medium] × 100. All bio-logical assays were repeated at least three times. To statistically analyzethedata, Tukey's post-hoc testwas utilized using SPSS software (version16.0). The differences were considered significant for the P-valuesb0.05. It should be noted that, although investigation about the proba-ble toxicity of the ZnFe2O4 nanoparticles on normal human cells is im-portant, the ethical laws and institutional guidelines of the IranUniversity of Medical Sciences prevented us to test the effects of thenanoparticles on the human normal cells.

3. Results and discussion

3.1. Morphological study

The morphological structures of the ZnFe2O4 nanoparticles were in-vestigated by SEM and TEM, as presented in Fig. 1. Using SEM (Fig. 1a

a)

c)

b)

d)

Fig. 1. SEM (a and b) and TEM (c and d) images of the ZnFe2O4 nanoparticles at different magnifications.

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and b), it was found that the prepared powders were spherical clusters(with ~0.5–2 μm sizes) containing nanoparticles (with ~10–50 nmsizes). The clusters were disassociated by sonication, before any biolog-ical test. The TEM images (shown in Fig. 1c and d) also confirmed thepresence of the nanoparticles (with sizes in the range of ~5–15 nm) inthe cluster structures.

3.2. Optical properties

To have a preliminary understanding from the structure of theZnFe2O4, the chemical structure of the zinc ferrite is shown in Fig. 2a.Then, Fig. 2b shows the optical absorption spectrum of the ZnFe2O4 sus-pension. The hydrothermal synthesis of ZnFe2O4 nanoparticles resultedin a color change of their suspensions from pellucid red for solution thatinvolved Zn(NO3)2·6H2O and Fe(NO3)3·9H2O in the presence of theethanol into dark orange for ZnFe2O4 nanoparticles, as shown in theinset of Fig. 2b. The optical absorption spectrum of the ZnFe2O4

suspension shows a broad absorption peak around 550 nm. A relativelynarrow band gap energy (~2.25 eV) was calculated for the ZnFe2O4

nanoparticles.

3.3. FTIR spectroscopy

FTIR spectrum of the ZnFe2O4 nanoparticles is presented in Fig. 2c.The absorption bands were located at 3420 cm−1 (O–H stretchingband), 1635 cm−1 (skeletal vibrations of aromatic domains),1418 cm−1 (bending absorption of carboxyl group O = C–O) and1048 cm−1 (C–O stretching vibrations). Furthermore, the vibrations ofions in the crystalline lattice are usually observed in the range of1000–400 cm−1 [37]. Here, the bands observed at ~564 and436 cm−1 can be assigned to the tetrahedral Zn2+ (Zn–O mode) andthe octahedral Fe3+ (Fe–O mode) stretching vibrations, respectively[38,39].

3.4. Raman spectroscopy

Fig. 3 presents Raman spectrum of the ZnFe2O4 nanoparticles. In therange of 100–1000 cm−1, the Raman spectrum shows the spinel struc-ture of ZnFe2O4with Fd3m space group havingfive active Ramanmodes(A1g + Eg + 3F2g) [40]. These five Ramanmodes are observable at 221,286, 347, 487 and 645 cm−1. Since motion of oxygen in tetrahedral AO4

groups occurred at the modes above 600 cm−1, hence the mode at645 cm−1 can be assigned to the A1g symmetry and the other low fre-quency modes correspond to both Eg (mode at 286 cm−1) and F2g(modes at 221, 347 and 487 cm−1) which represent the characteristicsof the octahedral sites (BO6) [34]. Because the Zn and Fe cations havevery close wavelengths and take place in the tetrahedral and octahedralsites, so the first-order Raman modes at 347, 487 and 645 cm−1 causethe vibrations relating to these two types of cations. Hence, thesepeaks can be assigned to ZnFe2O4 spinel [34].

3.5. Magnetic properties

By using VSM, the magnetic property of the ZnFe2O4 nanoparticleswas studied, as presented in Fig. 4. The magnetization hysteresis loopof the nanoparticles shows a superparamagnetic property with a satu-rated magnetization at about 10.2 emu/g at room temperature. Thesuperparamagnetic property of the ZnFe2O4 nanoparticles resulted intheir fast separation (~1 min) from the solution (here, 2 mg mL−1 ofthe nanoparticles in ethanol) by applying an external magnetic field(with the field strength of ~1 T), and then, redispersing the nanoparti-cles in the solution after removing the magnetic field.

3.6. Biological applications

The synthesized ZnFe2O4 nanoparticles were utilized for the de-struction of LNCaP prostate cancer cells by using radiotherapy. Fig. 5

c)

b)

a)

Fig. 2. a) A diagram from the chemical structure of ZnFe2O4, b) UV–vis. absorption of theZnFe2O4 suspension (1 mg mL−1 in ethanol). The inset of (b) shows digital picture ofthe suspensions. And c) FTIR spectrum of the ZnFe2O4 nanoparticles.

Fig. 3. Raman spectrum of the ZnFe2O4 nanoparticles.

Fig. 4.Magnetization hysteresis loop of the ZnFe2O4 nanoparticles. The inset shows digitalpicture of the ZnFe2O4 nanoparticle suspension (in ethanol) in the absence (left) and inthe presence (right) of amagnet. Themagneticfield resulted in separation of the nanopar-ticles from the solution through their aggregation on the wall of the container.

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shows optical images of LNCaP cells after exposure to the ZnFe2O4 nano-particles (100 μg mL−1) in the absence and presence of gamma ray of60Co source with 2 Gy dose. Fig. 5a shows LNCaP cells with ~13 ± 5cells per clusters after 24 h incubation in the absence of the nanoparti-cles and gamma irradiation (control cells). No considerable dead cellswere observed after 24 h. The effects of gamma irradiation on the cancercells in the absence and in the presence of the nanoparticles are shownin Fig. 5b and c. In the absence of the nanoparticles only a slight decreasein destruction of the cancer cells was observed, while in the presence ofthe nanoparticles a majority of the cancer cells were destructed. Themorphology of the cells was deformed and wrinkled after the effectiveradiotherapy. In addition, the number of cell per cluster (as a quantifica-tion of the changes) reduced to ~9±5 and 7±3 for the cells exposed tothe gamma irradiation alone and gamma irradiation in the presence ofthe nanoparticles, respectively. The higher cell destruction obtained inthe radiotherapy using the nanoparticles can be assigned to cytotoxicity

of the ZnFe2O4 nanoparticles against the LNCaP cells, especially undergamma irradiation, as studied in more details in the following. Our pre-liminary study showed that the same trends can be expected for themedia containing denser cancer cells. Of course, denser cells requiredmore period of gamma irradiation to yield the same cell inactivation.

Because a portion of the cell destruction could be assigned to cyto-toxicity of the nanoparticles, we also checked MTT cytotoxicity of ournanoparticles, as shown in Fig. 6. No significant cytotoxicity was ob-served for the various concentrations (up to 100 μg mL−1) of theZnFe2O4 nanoparticles. Therefore, the nanoparticles alone were not re-sponsible for the cancer cell destructions. MTT cell viability of LNCaPcells exposed to the gamma irradiation in the presence of the ZnFe2O4

nanoparticles with various concentrations is also shown in Fig. 6. Inthe absence of the nanoparticles (as another benchmark), once again,no significant cell destruction was found by 2 Gy gamma irradiation.This also confirmed the radioresistance of LNCaP cells against thegamma irradiation. By increasing the concentration of the nanoparticlesfrom 0.01 to 100 μg mL−1, only about 10% of the cells could beinactivated. A sharp decrease in the cell viability (~53%) was observedfor the nanoparticle concentration of 100 μg mL−1 under 2 Gy gammairradiation. In fact, Fig. 6 also shows synergic effects of the nanoparticlesand gamma irradiation on the cancer cell destruction. In fact, based onthe statistical analysis, it is seen that a significant synergistic effect(with the P-values b0.05) was found at the high concentration of100 μg/mL. In this regard, the efficiency in the cancer cell destructionby using the nanoparticles under the gamma irradiation was ~17

b)

a)

Live cells

c)

Cluster of nanoparticles

Deformed cells

Fig. 5.Optical images of LNcAP cells incubated in a culturemedium for 24h a)without anytreatment (control), b) under gamma irradiation of 60Co, and c) under the gamma irradi-ation in the presence of the ZnFe2O4 nanoparticles (100 μg mL−1).

Fig. 6.Cell viability of LNCaP cells exposed to the ZnFe2O4 nanoparticles in the absence andpresence of gamma irradiation of 60Co, as compared to the viability of the control cells. Sig-nificant results are marked by asterisks (*) for P-values b0.05 (n = 3).

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times higher than the efficiency obtained through only gamma irradia-tion. Such increase in the cell destruction efficiency can be assigned tophotoelectric effect and generation of low energy Auger electrons bythe ZnFe2O4 nanoparticles as sensitizers under gamma irradiation.

To present one of the in vivo potential applications of the ZnFe2O4

nanoparticles, it should be noted that, recently, in a preliminarystudy, our group applied the ZnFe2O4 nanoparticles in magneto-photothermal therapy of the mice bearing U87MG tumor [41]. In fact,by using ZnFe2O4–graphene (20 wt.%), a substantial reduction in thetumor volume (N90%) was obtained after ~1 min NIR irradiation with

laser power of 7.5 W/cm2 in the presence of an external magneticfiled (~1 T, which was utilized for localizing the nanoparticles aroundthe tumor area). It should be noted that in the absence of the magneticfield only b50% reduction in the tumor volume was found.

4. Conclusions

The superparamagnetic ZnFe2O4 nanoparticles synthesized by a hy-drothermal reaction showed a fast separation property from solutions(here, ~1 min for 2 mgmL−1 of the nanoparticles in ethanol) by apply-ing an external magnetic field (~1 T). The biocompatible ZnFe2O4 nano-particles were successfully used in radiotherapy of human prostatecancer cells as radiosensitizers of gamma irradiation of 60Co. Thegamma irradiation alone showed no significant influence on cell de-struction, as expected for such radio resistant cells. Moreover, the nano-particles (up to concentration of 100 μg mL−1) indicated a very lowcytotoxicity on the cancer cells. The use of the ZnFe2O4 nanoparticles(with concentration of 100 μg mL−1) in radiotherapy caused a synergiceffect resulting in ~17 times higher cell destruction efficiency than theefficiency obtained by the radiotherapy for high radioresistant cancercells. This improvement was attributed to further degradation of thecells by the low energy electrons generated in the nanoparticles(which acted as radiosensitizers) under gamma irradiation. These re-sults can promote more investigations on the application of magneticnanoparticles as radiosensitizers in radiotherapeutic methods in orderto improve their efficiencies.

Acknowledgments

The authors would like to thank the Research Council of Sharif Uni-versity of Technology and also the Iran Nanotechnology Initiative Coun-cil for the financial support of the work. We would like also thankHamadan Payame Noor University for providing a chemistry Lab. Thevaluable help of Mr. S. Homayounfar in analyzing some data is greatlyacknowledged.

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