Synthesis and characterization of Zinc (II)-loaded ZeoliteGraphene

Synthesis and characterization of Zinc (II)-loaded Zeolite/Graphene oxide nanocomposite as a new drug carrier

M.Khatamian a ,B.Divband b ,a ,?,F.Farahmand-zahed a

a Inorganic Chemistry Department,Faculty of Chemistry,University of Tabriz,C.P.51664Tabriz,Iran b

Research Center for Pharmaceutical Nanotechnology,Tabriz University of Medical Sciences,Tabriz,Iran

a b s t r a c t

a r t i c l e i n f o Article history:

Received 15January 2016

Received in revised form 5April 2016Accepted 22April 2016

Available online 26April 2016Current research has focused on the preparation of Zinc-clinoptilolite/Graphene Oxide (Zn-Clin/GO)hybrid nanostructure and investigating its biocompatibility for the ?rst time.As prepared samples were characterized by X-ray diffraction (XRD),Scanning electron microscopy (SEM),Thermo gravimetric analysis (TGA)and Fourier transform infrared (FT-IR).In order to use it as a drug carrier two important factors were investigated:cytocompatibility of nanocomposites and their drug loading capacity.The results showed that the prepared nanocomposite is cytocompatible and its high loading capacity and slow release performance for Doxorubicin (DOX),as a cancer drug,proved that it can be used as a drug carrier.At last in-vitro toxicity of DOX loaded nano-composite was compared with pure DOX.

?2016Elsevier B.V.All rights reserved.

Keywords:

Drug carrier system Biocompatibility Doxorubicin

In vitro cytotoxicity Clinoptilolite

1.Introduction

Graphene,the thinnest known material,is a sheet of two-dimensional (2D)sp 2-hybridized carbon atoms [1].It has special prop-erties which make it suitable for many applications.Its high speci ?c sur-face area,exceptional electrical and thermal conductivity,97.7%light transmittance,high strength and tunable mechanical properties makes it suitable respectively in absorbents for organic molecules [2],electric devices and biosensors [3,4],Magnetic Resonance Imaging (MRI)and biomedical imaging [5,6]and medical implants and scaffolds used in tissue engineering [7].Graphene oxide (GO)is oxidized form of graphene that has carboxylic,hydroxide and epoxy groups.It is used more than graphene in biomedical applications.But there are some con-cerns about toxicity of graphene and its derivatives.Recent researches have shown that different forms of graphene will affect differently on cells.A lot of factors are important,some of them are rigidity,lateral di-mensions and etc [8,9].Additionally,large surface area of graphene,π–πstacking and electrostatic or hydrophobic interactions of graphene,hy-drophilic interaction of graphene oxide allows it to achieve high drug loading capacity.Polyethylene glycol (PEG)–functionalized nanoscale graphene oxide (NGO)sheets loaded with a camptothecin (CPT)analog,SN38was synthesized [10],which showed high cytotoxicity in HCT-116cells,1000times more than CPT.In the other study PEG-NGO was used to load DOX [11].This led to a series of studies on using of graphene

based materials for loading of drugs such as DOX [11–21].For example Wu et al.[22]proposed a strategy to reverse cancer drug resistance in DOX-resistant MCF-7/ADR cells by loading DOX on graphene oxide sur-face via physical mixing.GO enhanced DOX accumulations in MCF-7/ADR cells causing higher cytotoxicity than free f53f5ed78ad63186bceb19e8b8f67c1cfbd6ee5cposites of GO maybe divided to two main groups:pH sensitive [21,23–25]and ther-mal sensitive [26].Graphene-based materials have been conjugated with a number of natural organic biopolymers like gelatin and chitosan as functionalizing agents for drug delivery applications [17,27,28].Nat-ural biopolymers are biocompatible,biodegradable and have low im-munogenicity which can greatly reduce the toxic effects of graphene.So preparing safe composites has got a lot of interest.Here we use nat-ural inorganic polymer such as zeolites.

Zeolites,porous aluminosilicates,have found many uses because of their special architecture.They have been used widely as absorbents,cat-alysts,and detergent builders [29,30].Recently their uses in biomedical applications have attracted a lot of attention.For example they have been used in biosensors [31],magnetic resonance imaging [32]and drug delivery systems [33].Clinoptilolite (Clin)is known as the most prevalent natural zeolite all over the world,which is biocompatible and has been used as substrate in controlled drug delivery.Jevtic et al.[34]used surfactant-modi ?ed Clin as a salicylate carrier.This composite displayed antibacterial activity against Escherichia coli and Staphylococcus aureus .Rahimi et al.[35]reported that Clin can absorb fat-soluble vitamins and because of its buffer property can protect vita-mins against acidic pH.Recently Tonder et al.[36]suggested Clin as a car-rier for pH-controlled oral delivery aspirin.To the best of our knowledge,there are few studies carried out on zeolite/GO nanocomposites [37–39].

Materials Science and Engineering C 66(2016)251–258

?Corresponding author at:Research Center for Pharmaceutical Nanotechnology,Tabriz University of Medical Sciences,Tabriz,Iran.

E-mail address:baharakdivband@f53f5ed78ad63186bceb19e8b8f67c1cfbd6ee5c (B.

Divband).f53f5ed78ad63186bceb19e8b8f67c1cfbd6ee5c/10.1016/j.msec.2016.04.090

0928-4931/?2016Elsevier B.V.All rights

reserved.

Contents lists available at ScienceDirect

Materials Science and Engineering C

j ou r n a l h o m e p a g e :w ww.e l s e v i e r.c om /l o c a t e /ms e c

As mentioned before,different forms of graphene will affect on cells dif-ferently and preparing safe composites of it has got a lot of interest so adding zeolite not only improves its biocompatibility but also doesn't de-crease surface area of nanocomposite so much because of high surface area of zeolite.In order to combine zeolite and graphene He et al.synthe-sized Cu-Zeolite A/graphene nanocomposite [37],they used Cu 2+as coor-dinating cation.In previous work,our group used Cu-Zeolite A/graphene nanocomposite as an absorbent in the removal of arsenic from contami-nated water [38].

Herein we synthesized Zn-Clin/GO nanocomposite as an in vitro drug carrier system for the anticancer drug,DOX.

Then its drug loading capacity was evaluated and its cytotoxicity has been studied using methyl thiazolyl tetrazolium (MTT)assay.2.Experimental

2.1.Material

Graphite,37%HCl,98%H 2SO4,30%H 2O 2,KMnO 4,NaNO 3,NaCl,Zn(acetate)2·2H 2O,NaBH 4(all obtain from Merck),natural Iranian zeo-lite known as Clinoptilolite (Clin)(Si/Al =9.53)were used.2.2.Preparation of Zn-Clin

Clin (0.5g)was ?rst suspended in aqueous NaCl solution (5mL,3M)and stirred for 24h.Then the resulted powder was separated and washed with water by using a centrifuge for several times at 2000rpm and dried at 60°C.Then the resulted powder was added to

an aqueous zinc (II)acetate solution (25mL,1M)and stirred for 24h,so its cations exchanged with Zn 2+.This powder was separated and washed with water by using a centrifuge for several times at 2000rpm and dried at 60°C.

2.3.Synthesis of Zn-Clin/GO nanocomposite

GO was synthesized using widely reported modi ?ed Hummers method starting from graphite [40].Then GO (0.05g)and Zn-Clin (0.05g)were dispersed in 30mL distilled water,using ultrasonic treat-ment for 1h and then NaBH 4(0.001g)was added into the suspension.This suspension was transferred to a microwave Te ?on reactor (Scheme 1)and treated for 20min at 300W.After cooling to room temperature,obtained residue was separated,washed with distilled water,dried at 60°C and gray composite of Zn-Clin/GO was obtained.This composite is named Zn-Clin/GO (M).

In the other method,GO and Zn-Clin (mass ratio of 1:1)were dis-persed in water by using ultrasonic irradiation,then NaBH 4was added and treated under re ?ux at 80°C for 8h.Then obtained powder was ?l-tered,washed with distilled water,dried at 60°C and is called Zn-Clin/GO (R).

2.4.Measurements

X-ray diffraction patterns (XRD)were collected using a Siemens D500diffractometer with Cu K αradiation (λ=1.5418A and 2θ=4–80°)at room temperature.FT-IR spectra were obtained with a Bruker Tensor 27Fourier Transform Infrared spectrometer with the KBr pellet technique.Scanning electron microscope (Philips XL30)equipped with energy dispersive X-ray (EDX)facility was used to capture SEM images and to perform elemental analysis.The SEM sample was gold coated prior to examination and SEM was operated at 5kV while EDX analysis was performed at 15kV.Thermal gravimetric (TG)was con-ducted under N 2atmosphere in the temperature range of 30–800°C at a heating rate of 5°C min ?1.

2.5.Preparation of drug loaded carriers

100mg of carriers (Clin,Zn-Clin,GO and Zn-Clin/GO (R))were im-pregnated in 20mL of doxorubicin (50ppm)in water under constant stirring at room temperature for 24h.Samples were taken out at given time intervals and the solution was centrifuged at 1500rpm for 5min and then ?ltered to remove the carrier particles completely.The supernatant was collected and analyzed with a Shimadzu UV-240spec-trophotometer at 485nm (λmax of DOX).After a certain adsorption time,there were no further changes in the concentration of DOX in the liquid phase,and it was assumed that the loading capacity of the particles had been reached.Residues were collected and dried and in-vitro toxicity of obtained powders were examined using MTT

assay.

Scheme 1.Microwave Te ?on

reactor.

Fig.1.Images of Zn-Clin/GO (M)and Zn-Clin/GO (R)powders.As seen in the picture Zn-Clin/GO (M)was not a uniform powder and could be easily separated to Zn-Clin and RGO.

252M.Khatamian et al./Materials Science and Engineering C 66(2016)251–258

2.6.Investigation of nanocomposite cytotoxicity (MTT assay)

A549alveolar adenocarcinoma cells (9×103cells/well)were incu-

bated in 96-well plates each containing 200μL of supplemented cell cul-

ture media for 24h at 37°C and 5%CO 2.The cells were divided in 4

groups in quadruplicates:blank,Zn-Clin/GO nanocomposite (different

concentrations:0.1,0.5and 1mg/mL)were treated.After an incubation

periods of 24and 48h,the spent media were removed and the plate

wells were washed with Phosphate-buffered solution.Brie ?y,50μL of

2mg/mL MTT and 150μL culture medium of was added to each well.

The cells were incubated at 37°C and 5%CO 2for 4h and then the

media was discarded and dimethyl sulfoxide and Sorenson buffer was added to each well as solubilizer buffer.Finally,absorbance was read using an ELISA plate reader (BioTeck,Bad Friedrichshall,Germany)at 570nm wavelength.3.Results and discussion 3.1.Characterization of Zn-Clin/GO nanocomposite Using a coordinating cation is necessary because it is impossible to prepare a uniform and stable composite without using a coordinating cation.As mentioned in our previous report [41],our group prepared a similar nanocomposite using Cu 2+as coordinating cation.In

this Fig.2.XRD patterns of the:(A)Clin,(B)RGO and (C)Zn-Clin/GO (R).

253M.Khatamian et al./Materials Science and Engineering C 66(2016)251–258

254M.Khatamian et al./Materials Science and Engineering C66(2016)251–258

paper we used Zn 2+cations because in this case the prepared nanocom-

posite was more homogenized,uniform and stable and Zn 2+cation is

safe,already presented in human body,cofactor in some enzymes and

has a crucial role in regulating how neurons communicate with one

another.

Here two different methods were used to synthesis of nanocompos-

ites.Fig.1shows images of Zn-Clin,Zn-Clin/GO (R)and Zn-Clin/GO

(M)powders.Zn-Clin is a white powder whereas GO is dark brown and Zn-Clin/GO (M)nanocomposite was not uniform and the white particles of zeolite were separated from black RGO and two different phases was clearly observed.But the Zn-Clin (R)nanocomposite was completely uniform and stable.In order to characterize the obtained composites,their XRD patterns (Fig.2)were analyzed.By using microwave reactor,the white particles of zeolite were separated from black RGO and two different phases was clearly observed so two phases were separated and their XRD

patterns

Fig.4.SEM images of Zn-Clin and Zn-Clin/GO (R)and EDX diagram of Zn-Clin/GO

(R).

Fig.5.TGA curve of Zn-Clin/GO

nanocomposite.Fig.6.Loading capacity of DOX by Clin,Zn-Clin,GO and Zn-Clin/GO.

Fig.3.FT-IR spectra of:(a)GO,(b)Zn-Clin/GO (R),(c)DOX loaded Zn-Clin/GO.255

M.Khatamian et al./Materials Science and Engineering C 66(2016)251–258

relieved that the light one is Clin (Fig.2A)and the dark phase is graphene oxide which is reduced (Fig.2B).In XRD pattern Zn-Clin/GO (R)(Fig.2C),all of Clinoptilolite peaks were clearly observed and it was highly crystalized and the peak at 2θ=11.33is related to GO.So in the following steps,Zn-Clin/GO (R)nanocomposite was chosen to be used.

For synthesis of composite,a minimum reduction in functional groups of GO is needed.It is reported that NaBH 4reduces epoxy and al-coholic groups on the surface on GO but carboxylic groups remains.These carboxylic groups can react with –OH groups on the surface of ze-olite so that a stable composite can be synthesized.Now the question is why still it is named GO,not reduced GO.Reduced GO is a form of graphene in which most of functional groups of GO is removed.XRD pattern of this nanocomposite showed the peak of GO.It means that most of functional groups of GO is still remains in the experimental condition.

Fig.3a shows FT-IR spectra of GO.The peaks at 3444cm ?1,1739cm ?1,1045cm ?1and 1222cm ?1,respectively attribute to O \\H stretching vibration,C _O stretching vibration,to vibration of C \\O (epoxy)and vibration of C \\O (alkoxy).The peaks 1630cm ?1and 1419cm ?1attribute to C _C stretching vibration [41].Fig.3b shows FT-IR spectra of Zn-Clin/GO (R).The peaks 464cm ?1,606cm ?1and 1066cm ?1are respectively related to vibrations of TO 4and T-O in Zn-Clin.The peak 1600cm ?1can be related to vibration of C \\O the O \\H stretching vibration peak at 3422cm ?1[42].Fig.3c shows FT-IR spectra of DOX loaded Zn-Clin/GO nanocomposite.All pre-vious peaks were observed.Moreover the peaks at 2899cm ?1and 2822cm ?1signify primary –NH 2group which exists in DOX structure.Also the C \\N stretch is at 1338cm ?1and the peak at 1549cm ?1can be related to N \\H bend.

Fig.4showed SEM images of Zn-Clin and Zn-Clin/GO nanocompos-ite.It is obvious that cubical Zn-Clin particles were randomly placed on graphene plates and graphene acted like a substrate for Zn-Clin par-ticles.Thin ?lms of graphene with thickness of 20–30nm is clearly

observed.It should be mentioned that the graphene plane which is shown in the image is almost curved.

The EDX diagram con ?rmed that about 40%of composite were C which presented GO and it approved that the Zn-Clin/GO nanocompos-ite were prepared successfully.It has 1.27%Zn due to cation exchange of Clin,about 17.2%Si and Al because they are main metals in structure of Clin and 41.5%Oxygen.Elemental analysis was performed to measure percentage of Zn in the compounds.It showed that Zn-Clin contains around 3%Zn and Zn-Clin/GO nanocomposite (ratio of Zn-Clin:GO is 1:1)has almost 1.35%Zn,as it was predicted.

The thermal stability of Zn-Clin/GO nanocomposite was measured using TGA in a N 2atmosphere.About GO,it has been reported that,be-cause of evaporation of adsorbed water and due to the removal of the oxygen-containing functional groups respectively,GO has a 21%mass loss below 200°C,a rapid 20%mass loss from 200to 250°C and about 50%of graphene remains below 600°C.According to references,graph-ite does not show any mass loss between room temperature and 600°C [43].As shown in Fig.5,TGA curve of Zn-Clin/GO nanocomposite has three steps,about 12.74%mass loss below 160°C which is because of evaporation of adsorbed water,about 8.95%from 160to 220°C due to removal of oxygen-containing functional groups and 13%mass between 220and 600°C.On the other hand,Clin has a 24%mass loss because of evaporation of adsorbed water.Overall it has 35%mass loss up to 600°C.Considering Clin content as x and GO content as y (in Zn-Clin/Go nano-composite),we will have two relations as below:x ty ?1

0:24x t0:5y ?0:35:

Solving these two relations,it can be calculated that about 57%of nanocomposite is Clin and 42%of nanocomposite is graphene oxide.So instead of mass ratio of 50:50Zn-Clin to GO,57:42is right.3.2.Investigating drug loading capacity and drug release behaviors of nanomaterials

In Fig.6loading capacity of DOX by different nanomaterials was compared.As mentioned before zeolites are porous materials contains OH groups and can absorb or be a host to DOX molecules.Loading ef ?-ciency of Clin and Zn-Clin for DOX is 70%in 120and 90min,respective-ly.In the case of Zn-Clin,Zn cations can coordinate to Heteroatoms (O in ketone,ester,carboxylic acid and alkali groups and N in amine groups)in structure of drug and facilitates drug loading.

On the other hand,GO owning a high speci ?c surface area,π–πstacking and electrostatic interactions of graphene can be a good candi-date to achieve high drug loading [7].And the test relieved that 78%of drug can be loaded within 30min.So it is expectable that Zn-Clin/GO nanocomposite would have a high drug loading capacity.As shown in Fig.7,before 30min 90%of DOX was loaded.So this nanocomposite had the highest loading ef ?ciency among compared nanostructures and can be a better choice as a drug carrier.

Drug release pro ?les of nanomaterials at neutral and acidic pH (pH =5.4,acetate buffers)are shown in Figs.7and 8,respectively.It can be seen that,even after washing,about 90%of the initial doxorubi-cin was still adsorbed in the Zn-Clin/GO nanocomposite,and it

was

Fig.7.Release pro ?le of GO,Zn-Clin and Zn-Clin/GO at pH =

7.

Fig.8.Release pro ?le of GO,Zn-Clin and Zn-Clin/GO at pH =5.4.

Table 1

Release results of DOX from carriers in 24h and 48h.Samples pH =7

pH =5.4

GO (11%:4.3ppm)24h (26.5%:10.3ppm)24h (14%:5.4ppm)48h (34.51%:13.5ppm)48h Zn-Clin (28.5%:10ppm)24h (68.5%:24ppm)24h (38.5%:13.5ppm)48h (83%:29ppm)48h Zn-Clin/GO

(21%:9.5ppm)24h (46%:20.7ppm)24h (24.5%:11ppm)48h

(60.5%:27ppm)48h

256M.Khatamian et al./Materials Science and Engineering C 66(2016)251–258

progressively released by desorption and diffusion to the buffer solution (pH =7),respectively,11%(4.29ppm),25.5%(8.9ppm)and 21%(9.45ppm)of the doxorubicin loaded on the GO,Zn-Clin and Zn-Clin/GO nanocomposite was released in 24h.But in the lower pH,similar to the cancer cell (pH =5.4),more desorption of the drug (Zn-Clin/GO)was occurred (46%of loaded DOX)in 24h.Results are summarized in Table 1.

3.3.Cytotoxicity of nanomaterials

The cytotoxicity of the Zn-Clin/GO nanocomposite were investigated in the A549cell line.Fig.9shows the relative cell viability ([C r /C 0]100%)vs.different concentration of DOX and nanocomposites,deter-mined by the MTT assay.Here,C 0is the viable cell numbers of the con-trol sample,and C r is the viable cell numbers treated with the nanomaterials.The error bars are the calculated standard deviation.Ac-cording to the Sun et al.[11]slight reductions of cell viability only for ex-tremely high GO concentrations (N 0.1mg/mL)was observed,so here the relative viabilities (%)of cells treated with 0.1,0.16&0.36mg/mL of Zn-Clin,GO,Zn-Clin/GO nanocomposite,DOX and DOX loaded Zn-Clin/GO nanocomposite are illustrated in Figs.7and 8after 24and 48h incubation,respectively.The results indicated that GO and Zn-Clin are not toxic even in high concentrations as well as Zn-Clin/GO

nanocomposite.GO and Zn-Clin/GO are completely cytocompatible below 0.1mg/mL and 0.16mg/mL,respectively.According to the DOX diagram (Fig.9),by increasing DOX concentration from 50to 150ppm,cell viability was decreased up to 25%(150ppm).

However in the case of DOX loaded Zn-Clin/GO which contains 45ppm DOX (90%loading),compare with free DOX (50ppm)only 22%of cells survived which this viability is adapted with 150ppm DOX.So by using drug loading system low concentration of drug (DOX)will be used.It gives this idea that the nanocomposite can release DOX in cell medium and import more DOX into cells (Fig.10).4.Conclusion

In this paper we have introduced Zn-Clin/GO nanocomposite as a new drug carrier with high loading capacity.It was synthesized using two different methods,microwave assisted hydrothermal method and re ?ux method.The nanocomposite synthesized using re ?ux method was homogeneous and stable so it was used as carrier.Moreover Zn-Clin/GO nanocomposite exhibited no toxic effect to cells especially at concentrations below 160mg/mL.Loading capacity of Zn-Clin,GO and Zn-Clin/GO nanocomposites for DOX are respectively,70%in 120min,80%in 30min and 90%in 30min.MTT assay for DOX loaded Zn-Clin/GO nanocomposite relieved that DOX loaded nanocomposite

exhibited

Fig.9..In vitro cell toxicity experiments.Relative viabilities of A549alveolar adenocarcinoma cells after being incubated with various concentrations of:(A)GO,(B)Zn-Clin,(C)Zn-Clin/GO,(D)free DOX and (E)DOX loaded Zn-Clin/GO nanocomposite for 24

h.

Fig.10.In vitro cell toxicity experiments.Relative viabilities of A549alveolar adenocarcinoma cells after being incubated with various concentrations of:(A)GO,(B)Zn-Clin,(C)Zn-Clin/GO,(D)free DOX and (E)DOX loaded Zn-Clin/GO nanocomposite for 48h.

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more cytotoxicity than free DOX so it can release DOX in cell medium and import more DOX into cells.So the nanocomposite can be a good choice as a drug delivery system.This paper presents a simple approach to prepare a new carrier with great potential in cancer therapy.

Acknowledgement

This work was?nancially supported by Iranian Nanotechnology Ini-tiative Council(Grant No.78538)and the Iran National Science Founda-tion:INSF(Grant No.92012004).

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