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��������8=,i\U$��������� #"#"#"#"#"#"#$	'��)PF#�������F#�����$����|���� #�� #�������� ao$��pd�#%$0U$��)�(�)����)�|�	��������F#F#����U$�������������������������������������������������������������������������)�����������:	In situ preparation of magnetic Fe3O4nanoparticles in presence of PLGA and PVAas magnetite nanocarrier for targeted drug delivery
MitraGhanbaria,b, TayebehShamspura, FaribaFathirada,b andSaeedEsmaeiliMahanic,d
a Department of Chemistry, Faculty of Sciences, ShahidBahonar University of Kerman, Kerman, Iran
b Young Research Society, ShahidBahonar University of Kerman, Kerman, Iran
cDepartment of Physiology and Pharmacology, Neuroscience Research Center, ShahidBeheshti University of Medical Sciences, Tehran, Iran
d Department of Biology, Faculty of Science, ShahidBahonar University of Kerman, Kerman, Iran

Abstract
Introduction:Drug targeting represents an interesting motivation to prevent side effects and increase doxorubicin cytotoxicity. Magnetic nanoparticles offer exciting new opportunities for developing effective drug delivery systems because it is feasible to produce characterize and specifically tailor their functional properties for drug delivery applications. To improve their stability and biocompatibility the Fe3O4 nanoparticles are often modified with surfactants or polymers.
Materials and Methods:In the present work, a nanocomposite was synthesized via in situ preparation of Fe3O4 nanoparticles inside poly lactic glycolic acid and poly vinyl alcohol.The anticancer drug of doxorubicin was loaded on the synthesized nanocompositein order to targeted drug delivery technique. The nanostructureswere characterized by FT-IR, SEM, VSM and XRD techniques. The in vitro drug release from synthesized nanocomposite as nanocarrier was investigated in 2 different pHs (equal blood and tumor environment) at 37 
C and extent of drug release was calculated by UV-Vis spectrophotometer.
Results: In vitro drug release experiments showed that the doxorubicin release at pH= 6.0 was promisingly more and faster than drug release at pH= 7.4. The fitted equation of release curves was corresponded to Peppas model.
Conclusion: All these results together suggest that the DOX-loaded nanocarrier may serve as a promising magnetic targeting therapy for the treatment of tumor cells.
Keywords: Magnetite nanoparticles, Nanocarrier, Doxorubicin, Drug delivery

Introduction:
The anthracycline antibiotic doxorubicin (10-(4-amino-5-hydroxy-6-methyl-tetrahydropyran-2-yl)oxy-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10tetrahydrotetracene 5,12-dione) is a widely usedanticancer drug in clinical practice for the treatment of a variety ofcancers like leukemia, ovarian, prostate, brain cancers, especiallylate stage breast cancer [1-3]. Even though doxorubicin is one of the most used anticancer drug, its application is still limited because of its side effects, including myelosuppression, gastrointestinal toxicity and cardiotoxicity.To prevent side effects and increase DOX cytotoxicity, drug targeting represents an interesting motivation [3,4].A number of approaches including chemical conjugation andphysical entrapment have been employed to target doxorubicinusing different carriers [5-8]. Nanotechnology is a useful strategy that has been used in drug delivery systems to improve the anticancer drugs release. It involves the use of nanoparticles, ferrites, biodegradable polymersand nanofibers[9].Magnetic nanoparticles offer exciting new opportunities fordeveloping effective drug delivery systems because it is feasibleto produce characterize and specifically tailor their functionalproperties for drug delivery applications [10-12].Among the numerous approaches used for thispurpose, targeting based on magnetic nanoparticles, mainly magnetite (Fe3O4)based nanoparticles (MNPs), iswidely considered as a promising targeted delivery system [13]. This is dueto its distinct advantages, such as a well biosafety, ease of preparation, the possibility ofcontrolling the characteristics of the nanocarriers, affordability of the materials needed for this procedure, and moreimportantly, possibility of targeting the drugs of interest to thedesired location within the host body by using an external magnetic field [14,15].Pure Fe3O4 nanoparticles tend to aggregationbecause of the strong magnetic dipole-dipole attractions between particles.To improve their stability and biocompatibility the Fe3O4 nanoparticles areoften modified with surfactants or polymers [16].Additionally,polymer-encapsulated Fe3O4nanoparticles can be designed inorder to provide further diverse and desirable functionality toenable conjugation to the drug of interest [17].
In the present investigation, a polymericnanocarrier was fabricated by encapsulating magnetite nanoparticles into the polylactic glycolic acid (PLGA) and poly vinyl alcohol (PVA) for loading anticancer drug of doxorubicin. The physical properties of the nanostructures, including their size, morphology, magnetic properties and in vitro drugrelease behavior, were thoroughly investigated.

Experimental
Apparatus and chemicals
A Sonorex RK255 ultrasonic water bath (Germany, HYPERLINK "http://www.sonorex.com"http://www.sonorex.com) was used.Product X-ray diffraction (XRD) data was recorded by a Rigaku D-max C III, X-ray diffractometer using Ni-filtered Cu K� radiation (Tokyo, Japan, http://www.rigaku.com). Fourier transform infrared (FT-IR) spectra were recorded on a Shimadzu system FT-IR 8400 spectrophotometer using KBr pellets (http://www.shimadzu.com). A Varian scanning spectrophotometer (CARY 50 Conc) was employed (Agilent, American, www.agilent.com/chem). The samples were characterized with scanning electron microscope (SEM, Hitachi S-9220, https://www.fabsurplus.com) with gold coating. 
Iron (III) chloride hexahydrate (FeCl3.6H2O) and iron (II) sulfate dihydrate (FeSO4.2H2O) were purchased from Sigma-Aldrich.Polyvinyl alcohol, tetrahydrofuran, N,N,dimethylformamide and ammonium hydroxide (NH4OH) were purchased from Merck. Poly lactic glycolic acid was purchased from ACROS. Anticancer drug of doxorubicin was prepared from Pharmacia Italia S.P.A.

Synthesis of magnetite nanocarrier
The in situFe3O4 nanoparticles synthesis in polymeric matrixwas carried out for nanocarrier preparationby coprecipitation method.First, PVA was dissolved in 10 mL distilled water and then added to 10 mL of 3:7 THF:DMF solution containing PLGA.In the following,100 mL solution containing FeSO4.2H2O and FeCl3.6H2O was added to above solution.Then, 10 mL of 20% NH3 solution was slowly added to the solution under ultrasonic waves (100 W/50 �C) for 15 min. The whole process was carried out under N2 atmosphere. After a period of time, a black suspension was obtained. The precipitated powders were separated from the suspension, washed three times with distilled water and several times with ethanol by applying an external magnetic field. Finally, the magnetite nanocarrier was dried in an oven at 70�C for 12 h and confirmed with FT-IR, XRD, SEMandVSM. 

Results and discussion
Characterization of the magnetite nanocarrier
Fig. 1is shown the FT-IR spectrum of polymeric nanocarrier containing Fe3O4 nanoparticles. The characteristic band of Fe-O at 590 cm-1 was indicative of Fe3O4. The existence of broad peak in 3310 cm-1is related to stretching vibration of OHin PVA and PLGA. The peaks at 1096,1723, 1404and 2866cm-1 were the characteristic of stretching vibration of C-O in PVA, C=O in PLGA,stretching and bending vibration of C-H in PVA and PLGA. Theseresults showtheinteraction between nanoparticles and polymers in magnetite nanocarrier.

Fig. 1

The crystalline structure of the synthesized Fe3O4 nanoparticles was characterized by XRD. As shown in Fig. 2, the position and relative intensity of the reflection peaks at (220), (311), (400), (422), (511), (440) and (533) can be well indexed to demonstrate the cubic structure of Fe3O4 (ICSD CARD # 01-072-2303).The peaks of Fe3O4 in XRD pattern of nanocomposite confirm existence of magnetite in the polymeric matrix. Moreover, the average size of the Fe3O4 nanoparticles were calculated 12.0 nm by Debye- Scherrerformula [18].

Fig. 2

The morphological characters of the synthesized nanocarrier were obtained by SEM image. As shown in Fig. 3, Fe3O4 NPs are dispersed with grain formin the polymeric matrix. The average size of the Fe3O4 nanoparticles in polymeric matrix was estimated 15.0 nm.

Fig. 3

Fig. 4 shows the magnetic hysteresis curves ofthe Fe3O4 nanoparticles. Because no hysteresis loop was observed in the magnetization curve, we concludedthat the nanoparticles exhibited typicalsuperparamagnetic behavior. The saturation magnetization (Ms)was approximately 23.0 emu g-1, which is sufficient for biomedicalapplications.

Fig. 4

Conditions for Doxorubicin loading on magnetitenanocarrier
0.8 mg mL-1 of the water-soluble anticancer drug DOX wasadded to PBS buffer solution containing 0.8 mg mL-1of nanocarrier and was stirred (1300 rpm) in the darkat 37�C for 24 h to facilitate DOX uptake. To removeresidued DOX, the solution containing nanocarrier was centrifuged and supernatant was separated. The obtained DOX loaded nanocarrier was dried in room temperature. Then, the optical absorbent of residual DOX inthe supernatant was measured at 480 nm by using UV-Vis spectrophotometer. After the measurement, the DOX loaded nanocarrierwas redispersed for further DOX adsorption. Beyonda certain time, no further changes were observed in the concentration of DOX in the supernatant because of saturation of loadingcapacity. 

Determination of drug loading content and drug loading capacity
The efficiency of drug loading (DLE( and percent of drug loading (DLP) were calculated from the following formulae [19]:
DLP (%)=(drug weight in nanocarrier/nanocarrierweight) �100 (1)
DLE (%)=(drugweight in nanocarrier/feed drug weight)�100             (2)
According to results, DLP and DLE were obtained 50% and 94% respectively.
Investigation of interaction between DOX and magnetitenanocarrier
In order to elucidate the interaction between DOX and magnetite PLGA-PVA nanocarrier, the FTIR spectra of nanocarrierbefore and afterDOX loading were shown in Fig. 5(a and c). For comparison,the FTIR spectrum of DOX was also presented (Fig. 5b). The Fe-O peak has shifted from 590 cm"1 (in Fig. 5a) to 580 cm"1(in Fig. 5c). Also, the characteristic bands of OH and NH2 related to stretching vibration of carboxylate and hydroxyl groups in PLGA and PVA were shifted to 3239cm"1 and bending vibration of NH2was shifted to 1570 cm"1compared to Fig 6a.The above evidences are sign of interaction between DOX and magnetite PLGA-PVAnanocarrier and substantially encapsulation of DOX in nanocarrier.

Fig. 5

Conditions for the release of DOX from the DOX-loaded nanocarrier
The release of doxorubicin from the DOX-loaded nanocarrierwas investigated in two different pH values of 7.4 and 6.0(equal blood and tumor environment) at the physiological temperature of 37�%C,to investigate the pH-based tissue targeting of this system,considering the acidic nature of the tumor tissue compared tothe healthy tissues.The 6 mg of DOX-loaded nanocarrierwas transferred to a dialysis bag and placed in 20 mLof PBS. In each of the selected time intervals, 2 mL from the solution was removed, and subjected to UV-Vis assay at 480 nm todetermine the doxorubicin content, and the amount of drugreleased was calculated.

In vitro release of DOX in pH=6 and 7.4
The release of the DOX-loaded nanocarrier investigated in PBS (pH 6) at 37 �%C. As shown in Fig. 6a, an initialascent of DOXrelease was observed in the first 6 h, andwas followed by a slow release over 3 days. Theinitialascent of DOXrelease from the nanocarrierwas attributed to the DOXmolecules absorbed onto the surface of the nanocarrier. Moreover, the total amount of DOX release from the nanocarrier was 30.2% over a 72 h.
Fig. 6b shows the release profiles of DOX from nanocarrierin PBS (pH 7.4)at 37 �%C. The total release amount of DOX from DOX-loaded nanocarrier was 19.9% after 72 h.

Fig. 6

According to the results,the pHis an effective parameter on the drug release, as well as the releasing time. The drugrelease at pH 7.4 was slow and stable with releasing ratio of19.9% within 72 h. At lower pH (6.0), the DOX release ratewas faster, with drug release of30.2% within 72 h. The most DOX willremain in the nanocarrier for a considerable time at normalphysiological conditions (pH 7.4), indicating the potential for prolonged DOX retention time in the blood circulation and therebyreducing the side effects to the normal tissues. On the otherhand, once the DOX loaded nanocarrier are taken up by tumorcells via endocytotic process, a faster release may occur at lowerlocal pH, i.e., surrounding the tumor site or inside the endosomeand lysosome of tumor cells, leading to the significant improvementin cancer treatment efficacy [20].

Drug release kinetics
For mathematical evaluations of the drug release process,the drug release kinetics was investigated by various standardrelease models and equations such as zero-, first-, Higuchi and Peppaswere characterized to the experimental data [21]. The simulated equations and correlation coefficients were compared in Table 1.The results shownthat the DOX release fromnanocarriers was better described using Peppasmodel where correlation coefficient was greaterthan 0.93.

Conclusions:
In this study, the antitumor drug doxorubicinwas successfully loaded into the magnetite PLGA-PVA nanocarrier. According to results, enhanced drug loading, high drug loading capacity and magnetic targeting wereachieved. The DOX-loaded nanocarrier showed a steady and sustained release profile in vitro up to72 h. In mathematical evaluations of the drug release process, DOX release fromnanocarrier was better described using Peppasmodel. All these resultstogether suggest that the DOX-loaded nanocarriermay serveas a promising magnetic targeting therapy for the treatmentof tumor cells.

Conflict of interestThe authors declare that they have no conflict ofinterest.


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Figure captions:
Fig. 1 FT-IR spectrum ofPLGA/PVA nanocarrier containing Fe3O4 nanoparticles
Fig. 2XRD pattern of magnetite nanocarrier
Fig. 3 SEM image of magnetite nanocarrier
Fig.4Magnetic hysteresis curves of magnetite nanocarrier
Fig. 5FT-IR spectra (a) magnetite nanocarrier, (b) doxorubicin, (c) DOX-loaded nanocarrier
Fig.6Release profiles of DOX from nanocarrierin PBS at 37 �%C (a) pH=6.0, (b) pH=7.4

Corresponding author. E-mail address: shamspur@gmail.com (T. Shamspur).











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