Novel Fe3O4@ZnO@mSiO2 Nanocarrier for Targeted Drug Delivery

Article pubs.acs.org/JPCC

Novel Fe3O4@ZnO@mSiO2 Nanocarrier for Targeted Drug Delivery and Controllable Release with Microwave Irradiation Hongjin Qiu, Bin Cui,* Guangming Li, Jianhui Yang, Hongxia Peng, Yingsai Wang, Nini Li, Ruicheng Gao, Zhuguo Chang, and Yaoyu Wang Key Laboratory of Synthetic and Natural Functional Molecule Chemistry (Ministry of Education), Shaanxi Key Laboratory of Physico-Inorganic Chemistry, School of Chemistry & Materials Science, Northwest University, Xi’an 710069, PR China S Supporting Information *

ABSTRACT: In this paper, we constructed a novel core−shell structured nanocarrier used as a drug carrier to investigate the storage and controllable release properties of the cancer chemotherapeutic drug etoposide (VP16). The new composite nanocomposite composed of a mesoporous silica shell with magnetic Fe3O4 core and ZnO interlayer with a core−shell structure was prepared by a simple process. The mesoporous nanocarrier possesses high surface area (643.9 m2/g), provides large accessible pore volume (0.32 cm3/g) for the adsorption of drug molecules, and has a high magnetization saturation value (56.8 emu/g) for drug targeting under foreign magnetic fields, and the ZnO interlayer acts as a good microwave absorber with excellent microwave thermal response property for microwave-triggered drug release (the VP16 release of over 85% under microwave discontinuous irradiation outclasses the 14% within 10 h only stirring release). This multifunctional system shows a good performance for targeting delivery and controllable release of anticancer drugs based on all the properties they possess. either internal or external triggers.15 Internal trigger systems release the drug as a response to unique physicochemical properties of cancers such as high levels of certain enzymes or redox and pH stimuli.16−18 Alternatively, external trigger systems usually release their payload as a response to external stimuli from magnetic fields or hyperthermia.19,20 However, the construction of internal trigger release systems that respond to subtle changes in the surroundings represents a significant challenge. Therefore, externally triggered release systems’ remotely controlled release has received increasing attention.21−23 In all formulation and processing strategies for drug release modulation, microwave irradiation is one of the most promising external triggers for smart drug release because it is noninvasive, microwave heats inside and outside with the heat being better and having faster thermal efficiency, and penetrates deep into the interior of the body (heated depths up to 10−15 cm). Thus, it is suitable for noninvasive local heating and can be accurately controlled by altering a number of parameters including frequency, power density, duty cycles, and time of application.24,25 The microwave has been widely used in biomedical fields. Yoon et al. used the microwave ablation method to treat a small-sized tumor with minimized collateral damages.26 Jiao et al. reported the treatment of liver cancer with

1. INTRODUCTION Magnetite Fe3O4 nanoparticles have widespread applications in magnetic bioseparation,1 drug delivery,2,3 and magnetic resonance imaging,4 especially in targeted drugs. One of the most promising targeting methods is using magnetic particles loaded with drugs due to their excellent magnetic properties together with low toxicity and biocompatibility.5−7 In recent years, core−shell nanocarriers with Fe3O4 for targeted drugs and controlled release have attracted great interest and become one of the international hotspots in research. Nanocarriers with controlled delivery of drugs can overcome problems caused by conventional free drugs, including poor solubility, limited stability, rapid clearing, and, in particular, lack of selectivity.8,9 For efficient drug action, improving the drug loading efficiency is critical in drug carrier research. Many studies on modification or coating of magnetic nanoparticles with silica or polymers have been extensively performed for potential applications in biomedical fields. For example, He et al. synthesized a functionalized silica-coated Fe3O4 nanocrystal as a biological carrier system.10 Yallapu et al. prepared PEG-functionalized magnetic nanoparticles for drug delivery.11 Xu et al. synthesized a multifunctional magnetic nanocomposite with mesoporous silica shell to load ibuprofen.12 Mesoporous silica was widely used in coating/modification of magnetite nanoparticles due to their high surface area, large pore volume, tunable pore size, low cytotoxicity, biodegradability, and biocompatibility.13,14 On the other hand, nanocarriers for controlled delivery and release are usually constructed to leak the loading drug in response to © 2014 American Chemical Society

Received: March 21, 2014 Revised: June 11, 2014 Published: June 16, 2014 14929

dx.doi.org/10.1021/jp502820r | J. Phys. Chem. C 2014, 118, 14929−14937

The Journal of Physical Chemistry C

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Scheme 1. Schematic Illustration Showing the Formation Process of the Multifunctional Fe3O4@ZnO@mSiO2 Composite Microspheres and the Subsequent Drug Loading and Release Control with Microwave

a 2.45 GHz cooled-shaft microwave antenna.27 The previous studies found that zincite (ZnO) nanomaterials have excellent microwave thermal response properties, and they can absorb microwave radiation and convert it to thermal energy. The produced thermal energy can heat the nanocarrier and stimulate the drug release.28,29 Therefore, the core−shell structured microspheres have mesoporous silica shells as supporters to increase the anticancer drug loading, and a further combination of Fe3O4 and ZnO nanoparticles in a single nanocomposite endows these kinds of materials with drug target delivery and microwave-controlled release. In this work, we present a multistep procedure for synthesizing multifunctional nanocomposites composed of pellets of the ZnO-coated Fe3O4 core and further coated with mesoporous silica shell designated Fe3O4@ZnO@mSiO2. To demonstrate the multiple properties of these core−shell structured nanocomposites with magnetization, we study mesoporous and etoposide (VP16) loading and controlled release through microwave irradiation. To the best of our knowledge, this is the first report on the use of Fe3O4@ZnO@ mSiO2 as the carrier to deliver VP16 and controlled release through microwave irradiation. This multifunctional nanocomposite would be very promising for in vivo biomedical targeted drug delivery and controlled drug release systems using microwave. The synthesis route of magnetic Fe3O4@ZnO@mSiO2 nanocomposites with the mesoporous core−shell structure for microwave-controlled drug release is presented in Scheme 1.

Powder X-ray diffraction (XRD) patterns were obtained on an XRD measurement (Bruker, D8 Advance) at room temperature using Cu Kα radiation (kα = 1.54059 Å). The morphology and microscopic structure were characterized using a scanning electronic microscope (SEM; FEI, Quanta600) equipped with an energy-dispersive X-ray spectrum (EDS) and transmission electron microscope (TEM; FEI, Tecnai G2 F20 S-TWIN). Stability properties of the nanocarriers were studied in a Zetasizer Nano-ZS90 from Malvern Instruments. Fourier-transform infrared (FT-IR) spectra were preformed on a Tensor-27 infrared spectrophotometer (Bruker) with the KBr pellet technique. Nitrogen adsorption/ desorption analysis was measured at a liquid nitrogen temperature (77 K) using a micromeritics ASAP 2010 M instrument. The MDS-6 microwave sample preparation system is used for control of drug release with microwaves. UV−vis adsorption spectral values were measured on an UV-1800 spectrophotometer. Magnetization measurements were performed on a vibrating-sample magnetometer (VSM, Quantum Design, MPMS-XL-7). 2.2. Synthesis of Core−Shell Structured Fe3O4@ZnO Microspheres. The magnetic Fe3O4 nanoparticles with a mean particle size of 170 nm were obtained through a solvothermal reaction according to the reported method with some modification.30 The interlayers of ZnO were prepared through a precipitation process. Briefly, 0.10 g of obtained spherical Fe3O4 particles was dispersed in a mixed solvent containing 20 mL of water and 30 mL of ethanol with the aid of ultrasound, and then the solution was heated to 90 °C. After 10 min, 1.6 mol/L of triethanolamine and 0.02 mol/L of Zn(Ac)2· 2H2O were dropped simultaneously through latex tubes into the homogeneous suspension of Fe3O4 nanoparticles at a constant flow rate, controlled by the multichannel syringe pump. The system was then continuously stirred for 1 h at 90 °C. The obtained brown powders were collected by magnetic separation and washed with ethanol and water several times and then dried at 60 °C for 6 h to prepare Fe3O4@ZnO nanoparticles. 2.3. Synthesis of Fe3O4@ZnO@mSiO2 Microspheres. The core−shell Fe3O4@ZnO@mSiO2 microspheres were prepared according to the literature method with some modifications.31 Briefly, 0.10 g of Fe3O4@ZnO particles was redispersed in a mixed solution containing CTAB (0.30 g, 0.823 mmol), deionized water (80 mL), concentrated ammonia

2. EXPERIMENTAL SECTION 2.1. Reagents and Characterization. Ferric chloride hexahydrate (purity ≥99.0%, FeCl3·6H2O), sodium acetate (purity ≥99.0%, CH3COONa), trisodium citrate (purity ≥98.0%, C6H5Na3O7·2H2O), ethylene glycol (purity 96.0%, EG), and zinc acetate dihydrate (Zn(Ac)2·2H2O, 99%, Aldrich) were purchased from Xi’an Chemical Reagent Limited China. Tetraethyl orthosilicate (TEOS; A.R.), cetyltrimethylammonium bromide (CTAB; A.R.), ammonium hydroxide (28%), and absolute ethanol were purchased from Xi’an Chemical Reagent Company. All chemicals are used without any further purification. 14930



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aqueous solution (1.00 g, 28 wt %), and ethanol (60 mL). The mixed solution was homogenized for 0.5 h to form a uniform dispersion, and 0.40 g of TEOS (1.90 mmol) was added dropwise to the dispersion with continuous stirring. After 6 h, the product was collected with a magnet and repeatedly washed with ethanol and water to remove nonmagnetic byproducts. Finally, the purified microspheres were redispersed in 60 mL of isopropyl methylphenol and refluxed at 85 °C for 6 h to remove the template CTAB. The extraction was repeated three times; the microspheres were washed with deionized water; and Fe3O4@ZnO@mSiO2 microspheres were finally produced. The successful removal of CTAB was verified by Fourier transform infrared (FT-IR) spectra analysis. 2.4. In Vitro VP16 Loading and Release. For etoposide loading, 0.30 g of Fe3O4@ZnO@mSiO2 samples was mixed with 50 mL of VP16 solution with concentration of 0.30 mg/ mL and soaked in a sealed vial for 6 h with stirring to reach the equilibrium state. Then the VP16 adsorbed particles were separated by a permanent magnet, and the supernatant was collected for UV−vis spectrophotometer measurement to determine the adsorbed amount of VP16. Finally, the sample was dried at 60 °C for 12 h, which was denoted as Fe3O4@ ZnO@mSiO2−VP16. In a typical procedure for determining the release amount, 1.00 mL of the solution was withdrawn at predetermined time intervals and immediately replaced by an equal volume of sodium chloride solution to keep the volume constant. The withdrawn solution was properly diluted and monitored for etoposide content at 285 nm using a UV−vis spectrophotometer. As the time increased, the intensity of the absorption band at 285 nm slowly decreased, suggesting that the loaded amount of VP16 increased. Until the loading was close to balanced, the free etoposide weight in the solution was determined by UV−vis spectrophotometry using the Lambert− Beer law and the concentration of VP16 calculated according to an obtained standard curve of VP16 (C = 0.0903A + 0.0013, r = 0.9983). The amount of drug loaded was calculated by the free etoposide in the solution. Drug loading (w/w %) = Mads/Madd, where Mads is the mass of drug adsorbed, and Madd is the mass of drug added during the loading process. The in vitro release test of VP16 was performed in the release media of sodium chloride solution (0.9% w/v, similar to the normal saline of the human blood system) with mild stirring. To study the effect of microwave on the drug release, the influence of temperature and pH on the drug release was investigated in various media. Finally, the immersing temperature was kept at 37 °C and pH 7.0, and the VP16 carriers were kept in sodium chloride solution under microwave irradiation for 15 min in a 2.45 GHz microwave generator for drug release. Then the microwave generator was shut down, and the solution was stirred for 30 min at 37 °C and then transferred to the microwave irradiation environment for 15 min, until the release was close to balanced according to the loop. The release process was measured by an UV−vis spectrophotometer.

Figure 1. XRD powder pattern of pure Fe3O4 (a), Fe3O4@ZnO (b), and Fe3O4@ZnO@mSiO2 (c).

and 62.51° observed for the Fe3O4 nanocrystals, which can be assigned to (220), (311), (400), (422), (511), and (440) planes of the cubic spinel structured magnetite (JCPDS No. 19-0629), respectively. In the case of Fe3O4@ZnO nanocomposites, the peaks of cubic spinel structured magnetite were observed in the nanocomposites, revealing that the Fe3O4 nanocrystals do not change their phases. The added major diffraction peaks at 31.76°, 34.42°, 36.52°, 47.53°, and 56.60° (Figure 1b) can be readily indexed to the hexagonal ZnO structure according to the standard JCPDS (No. 36-1451). The hexagonal ZnO shell coating resulted in an increase in the permittivity of the material and greatly enhanced their microwave absorption performance.32 The amorphous SiO2 has no characteristic peak, only a rising background in the lower angle side (20°−25°).33 Combined with TEM and EDS spectrum analysis, after coating of SiO2 (Figure 1c), the new broad peak in the XRD pattern around 20° can be assigned to the amorphous SiO2 shell of Fe3O4@ZnO@mSiO2 (PDF#38-0651). Field-emission scanning electron microscopy (FE-SEM) images of pure Fe3O4, Fe3O4@ZnO, and Fe3O4@ZnO@ mSiO2 nanoparticles with different magnifications together with the corresponding particle size distribution histograms are shown in Figure 2, respectively. From the FE-SEM image of the pure Fe3O4 (Figure 2a and b), we can observe that the asprepared magnetite consists of monodisperse nanoparticles with a mean particle size of 170 nm and rough surfaces. These particles are nonaggregated with narrow size distribution (the inset in Figure 2a). Figure 2c shows that the Fe3O4@ZnO nanoparticles still keep the morphological properties of pure Fe3O4 except for a slightly larger particle size of about 40 nm, which may be caused by the coating of ZnO on the surface of the magnetic core. As for Fe3O4@ZnO@mSiO2 (Figure 2e and f), the nanoparticles exhibit much smoother surface than that of pure Fe3O4 (Figure 2b), further confirming the uniform coating of the silica shell, and Fe3O4@ZnO@mSiO2 shows good morphological features, such as the spherical morphology, nonaggregation, smooth surface, and narrow size distribution. The average particle diameter increases from 210 nm for Fe3O4@ZnO microspheres to 260 nm for Fe3O4@ZnO@ mSiO2 core−shell nanoparticles. Similarly, the particle sizes are uniform with good monodispersity and narrow size distribution (inset in Figure 2e). The morphological and structural features of the samples of Fe3O4 and Fe3O4@ZnO were further examined by TEM, as shown in Figure 3. TEM images obviously indicate that

3. RESULTS AND DISCUSSION 3.1. Phase, Formation, Morphology, and Structure of As-Prepared Fe3O4@ZnO@mSiO2 Nanocarriers. The composition and crystallinity of the fabricated nanomaterials were checked with XRD technology. As shown in Figure 1, all of the identified peaks in the XRD pattern (Figure 1a) can be attributed to magnetite Fe3O4, based on the standard data for magnetite (JCPDS No. 19-0629). There are six major diffraction peaks at 30.09°, 35.42°, 43.05°, 53.39°, 56.94°, 14931



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monodisperse nanoparticles with narrow size distribution are obtained for the samples of Fe3O4 and Fe3O4@ZnO, which are well consistent with the corresponding SEM images. Additionally, from the TEM images of the Fe3O4@ZnO particles (Figure 3b), compared with the bare Fe3O4 it can be seen that ZnO is coated on the surface of Fe3O4 as a thin layer or single nanoparticle. The Fe3O4@ZnO nanoparticles exhibit much rougher surface than that of pure Fe3O4, further confirming the uniform coating of the ZnO shell. Figure 3c is the dark-field image of two core−shell particles by setting the ZnO(110) ring, and thus the ZnO shell layers are imaged as brighter dots. The above observations demonstrate that Fe3O4@ZnO core−shell nanoparticles are successfully fabricated by the method used in this work. Moreover, the obvious lattice fringes in the HRTEM image (Figure 3d) further confirm the high crystallinity of the sample, which is in good agreement with the wide-angle XRD results. The lattice spacings in the core and shell regions are significantly different. The spacing labeled in the shell region is about 0.281 nm, corresponding to the (100) plane of ZnO, whereas it is about 0.253 nm in the core region, corresponding to the (311) plane of Fe3O4. TEM images of the Fe3O4@ZnO@mSiO2 nanoparticles are shown in Figure 4. The core−shell structure can be clearly

Figure 2. FE-SEM images of pure Fe3O4 with low (a) and high (b) magnification, Fe3O4@ZnO with low (c) and high (d) magnification, and Fe3O4@ZnO@mSiO2 with low (e) and high (f) magnification, and the insets at the top-right corners are their corresponding particle size distribution histograms.

Figure 4. TEM images of Fe3O4@ZnO@mSiO2 with low (a) and high (b) magnification and the EDS spectrum of Fe3O4@ZnO@mSiO2 (c).

distinguished due to the different electron penetrability between the cores and shells. The magnetic cores are black spheres with an average size of about 220 nm. The dark dots act as a layer on the surface of the black magnetic cores for the single nanoparticles of the ZnO shell, and the uniform mesoporous silica shell shows gray color with an average thickness of about 30 nm. Notably, the mesoporous channels are clearly found in the surface of Fe3O4@ZnO@mSiO2 spheres (Figure 4b). The EDS of Fe3O4@ZnO@mSiO2 (Figure 4c) confirms the presence of silicon (Si), zinc (Zn), oxygen (O), and iron (Fe) in the Fe3O4@ZnO@mSiO2 sample. To investigate the hydrodynamic sizes and stability of magnetic nanocarriers, the dried magnetic nanocarriers were redispersed in physiological saline to make aqueous dispersions, and hydrodynamic sizes of nanocarriers were determined by dynamic light scattering (DLS). The zeta potential of Fe3O4

Figure 3. Bright-field TEM images of pure Fe3O4 (a) and Fe3O4@ ZnO (b), dark-field TEM image (c), and HRTEM image of Fe3O4@ ZnO (d). The inset at the top-right corner in (c) is the selected area electron diffraction pattern (SAED) analysis of Fe3O4@ZnO. 14932



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results suggest that the pore structure nanoparticles have mesoporous nature and suitability as drug carriers. The FT-IR spectra of Fe3O4@ZnO@mSiO2, Fe3O4@ZnO@ mSiO2−VP16, and VP16 are given in Figure 6. In the FT-IR

and Fe3O4@ZnO@mSiO2 is shown in Figure 1 of the Supporting Information. The Fe3O4@ZnO@mSiO2 nanocarriers have been proposed to have excellent stability at pH 7 and to provide positive charged groups at the surface that can be used to attach other biomolecules. The dispersion of nanocarriers in aqueous solution mainly depends on the particle surface zeta potential, the particles have certain zeta potential which produces electrostatic repulsion between particles. It will have a better dispersion and dispersion stability when its absolute value is higher. At physiological pH, the zeta potential of the coated samples is over 30 mV, providing longterm stability of the dispersions.34 For Fe3O4@ZnO@mSiO2, owing to its several intrinsic properties, the mesoporous shell not only provides high surface area and large pore volume but also gives them excellent water solubility, long time stability against aggregation and oxidation, and biocompatibility. The hydrodynamic sizes of magnetic nanocarriers at pH 5, pH 6, and pH 7 and mean particle sizes measured by SEM are reported in Table 1 of the Supporting Information. It was observed from DLS analysis that the hydrodynamic size was only slightly altered in different pH values leading to suspensions with a wider pH range of stability. The hydrodynamic size of the nanocarriers is gradually decreased with decreasing pH value, and the hydrodynamic sizes obtained from the DLS method were larger than the actual size of the nanocarriers obtained with SEM results, which can be attributed to the presence of few aggregates due to a lack of charge at this pH and the hydrophobic capping effect of nanocarrier nuclei when dispersed in aqueous media. Nitrogen sorption measurements were conducted to further characterize the pore parameters of the products. The liquid nitrogen adsorption/desorption isotherms of Fe3O4@ZnO@ mSiO2 are shown in Figure 5. The loops of the sample exhibit

Figure 6. FT-IR spectra of (a) Fe3O4@ZnO@mSiO2, (b) Fe3O4@ ZnO@mSiO2−VP16, and (c) pure VP16.

spectrum of Fe3O4@ZnO@mSiO2 (Figure 6a), the strong bands of OH (3417 cm−1) and H2O (1636 cm−1) suggest that a large number of OH groups and H2O molecules exist on the surface, which play a key role for adsorbing VP16 molecules by a hydrogen bond. The absorption bands related with Si−O−Si (1072 cm−1), Si−OH (946 cm−1), Si−O (467 cm−1), and Fe− O (569 cm−1) are also present. As shown in Figure 6b and c, in the infrared spectrum of Fe3O4@ZnO@mSiO2−VP16 (Figure 6b) and VP16 (Figure 6c), the characteristic peaks around the absorption bands at 1483 cm−1 were due to the stretching vibrations of CC in the backbone of the aromatic phenyl ring. The IR absorption bands at 1756 cm−1 are the characteristic stretching frequencies of CO. Moreover, other VP16 absorption bands at 1249 and 1105 cm−1 observed in Fe3O4@ZnO@mSiO2−VP16 were due to C−H vibration. The absorption bands of the quaternary carbon atom at 1461 and 1518 cm−1, tertiary carbon atom at 1338 cm−1, and C−H2 bond at 2853 and 2924 cm−1 are also clear. It confirms the successful incorporation of VP16 into the pores of the mesoporous SiO2 shell of Fe3O4@ZnO@mSiO2 nanoparticles. 3.2. Magnetic and Microwave Thermal Response Properties. Magnetic measurement (Figure 7) shows that pure Fe 3 O 4 , Fe 3 O 4 @ZnO@mSiO 2 , and Fe 3 O 4 @ZnO@ mSiO2−VP16 have magnetization saturation values of 85.9, 64.7, and 56.8 emu/g, respectively. The reduction in Ms value could be attributed to the lower density of the magnetic component in the Fe3O4@ZnO@mSiO2 nanoparticle samples because the presence of ZnO and SiO 2 dilutes the concentration of Fe3O4 nanoparticles. It should be noted that the VP16-loaded sample still shows high magnetization, indicating its suitability for targeting and separation as a drug carrier. The magnified hysteresis loops (Figure 7e) confirm the nanocomposites were nearly superparamagnetic at room temperature with a remanent magnetization (Mr) of 3.2 emu/g and coercivity (Hc) of 26.8 Oe. Moreover, the multifunctional nanocomposites with homogeneous dispersion show fast response to the external magnetic field due to its high magnetization, and no residual magnetism is detected. Figure 7d shows the magnetic separation behavior of the Fe3O4@ ZnO@mSiO2 nanocomposites. A good magnetic separation

Figure 5. N2 adsorption/desorption isotherms of Fe3O4@ZnO@ mSiO2. The inset shows the pore size distribution curve obtained from the adsorption data.

typical IV-type isotherms with H1-hysteresis according to the IUPAC classification, which is typical for mesoporous materials that exhibit capillary condensation and have mesoporous pore sizes with narrow size distributions.35 The result reveals that the silica layer formed the mesoporous structure using CTAB as the template. The BET surface area and total pore volume of Fe3O4@ZnO@mSiO2 are calculated to be 643.9 m2/g and 0.32 cm3/g, respectively. The pore size distribution curves (inset in Figure 5) further confirm that the average pore size of Fe3O4@ ZnO@mSiO2 was 2.6 nm. The N2 adsorption/desorption 14933



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was 16 °C, and it could reach 50 °C in 100 s. However, the pure sodium chloride solution and Fe3O4 mixed liquor had a relatively poor heating effect (it cost 100 s to reach 44 and 41 °C, respectively). The results indicated that Fe3O4@ZnO@ mSiO2 nanocomposites exhibit a greater ability for microwave absorption and good microwave thermal conversion effect. As part of the same group, ZnO has a greater proportion of the better absorption of the microwave, and under the conditions of the same microwave power, ZnO can quickly transfer the electromagnetic energy into heat. Because ZnO has piezoelectric properties, the electromagnetic wave can be incident on the surface of the vibration energy and change into other forms of energy or heat.37,38 This shows that the as-prepared Fe3O4@ ZnO@mSiO2 nanocomposites were suitable for localized hyperthermia to controlled drug release and treatment of cancers. 3.3. Drug Loading and Release Properties. To study the drug storage and release properties of this system VP16 was selected as a model drug, which has good pharmacological activity and serves as a good anticancer (“antineoplastic” or “cytotoxic”) chemotherapy drug. To eliminate the influence of other factors, drug loading and release experiments were performed in sodium chloride solution (0.9% w/v, similar to the normal saline of the human blood system) and at the temperature of 37 °C. The temperature of 37 °C was selected because it is close to physiological temperature. The mesoporous shell provides a large accessible pore volume for the adsorption of drug molecules, and the average pore size of Fe3O4@ZnO@mSiO2 was 2.6 nm, which is larger than the molecular length of VP16 (≈1.34 nm).39 VP16 was absorbed onto the surface of the samples with silanol groups and a mesoporous silica layer, and VP16 molecules have been absorbed on the silica surface of the mesoporous layer and released via a diffusion-controlled mechanism and microwave control. The loading amount of VP16 in Fe3O4@ZnO@mSiO2 is about 35 mg of VP16/g of Fe3O4@ZnO@mSiO2. The large VP16 loading can be ascribed to the porous surface of the mesoporous silica layer. The drug loading process is shown in the inset of Figure 9. At the initial stage, the loading rate is high, up to 10% within 10 min in sodium chloride solution (0.9% w/v, similar to the normal saline of the human blood system) at 37 °C. As the time increases, the intensity of the absorption band at 285 nm

Figure 7. Magnetic hysteresis loops of pure Fe3O4 (a), Fe3O4@ZnO@ mSiO2 (b), and Fe3O4@ZnO@mSiO2−VP16 (c). Inset: photographs of magnetic Fe3O4@ZnO@mSiO2−VP16 nanocomposites dispersed in aqueous solution without and with external magnetic field (d) and expanded region at the applied field of −500 to 500 Oe (e).

performance of the Fe3O4@ZnO@mSiO2 nanocomposites was observed by using a magnet for only 10 s in an aqueous solution. The result reveals that the particles exhibit good magnetic responsible and redisperse properties, which suggests a potential application for targeting and separation.36 Because the shape and thickness of the material have a great impact on the microwave absorption properties, we confirm the microwave absorption of Fe3O4@ZnO@mSiO2 indirectly by testing the material of microwave thermal response. Microwave heating experiments were performed at room temperature, and the frequency of microwave applied was 2.45 GHz, which was just in the range for biomedical applications (2450 ± 50 MHz). The time−temperature curves of sodium chloride solution, Fe3O4, Fe3O4@ZnO, and Fe3O4@ZnO@mSiO2 under microwave irradiation are shown in Figure 8. The Fe3O4@ZnO@ mSiO2 exhibited a good heating effect. The initial temperature

Figure 8. Microwave thermal response of the time-dependent temperature curve for the Sodium chloride solution (a), Fe3O4 (b), Fe3O4@ZnO (c), and Fe3O4@ZnO@mSiO2 (d) dispersed in sodium chloride solution with microwave irradiation at 2.45 GHz.

Figure 9. Kinetic analysis of drug loading: (a) drug loading versus time and (b) UV−vis spectrophotometer. 14934



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Figure 10. Kinetic release curves of VP16 in different conditions: (a) at 37 °C in different pH and (b) at pH 7 at different temperature.

slowly decreased, suggesting that the loaded amount of VP16 increased. Finally, we found that approximately 70% of the total VP16 that was adsorbed and loaded onto the surface of Fe3O4@ZnO@mSiO2 composite particles indicates that the mesoporous nanomaterials have great drug loading capacity. Figure 10 shows the kinetic release curves of Fe3O4@ZnO@ mSiO2−VP16 in different conditions plotted based on the sustained release using the absorption of the peak at 285 nm. As shown in Figure 10a, VP16 is released from Fe3O4@ZnO@ mSiO2−VP16 in solutions at pH 5, pH 6, and pH 7 and maintains the temperature of 37 °C. At the early stage, it can be seen that a quick release and, subsequently, a gradual release of VP16 molecules were measured at pH 5 and pH 6, with released percentages of 36% and 54% after 600 min, respectively. The release of Fe3O4@ZnO@mSiO2−VP16 was persistent and gradual at pH 7. It was observed that only 14% VP16 was released at pH 7 at 600 min. The effect of temperatures on the cargo release of the nanocarrier was also investigated. The cumulative VP16 release at 37, 42, and 45 °C in solutions at pH 7 has been depicted in Figure 10b. A burst release during the first time can be seen, and then a slower release behavior was observed, with released percentages of 14%, 45%, and 61% after 600 min, respectively. According to the kinetic release curves of VP16 in different conditions, low pH and high temperature exhibit higher rates and more VP16 release. It indicates that the low pH and high temperature is favorable for fast molecular diffusion through the pore channels. The release of the Fe3O4@ZnO@mSiO2−VP16 controlled by microwave irradiation was determined with UV−vis spectroscopic analysis. To evaluate the repeatability and control of the release, the nanocarrier solutions were manipulated with microwave irradiation and stirring without microwave irradiation as a cycle. For each cycle, the sample was irradiated for 15 min, and then the microwave generator was turned off and stirred for 30 min at 37 °C. Figure 11 shows that the VP16 molecules could be released under microwave irradiation, and when the microwave was turned off, the release of the VP16 molecules was inhibited. At the initial stage, about 24% VP16 molecules were released upon the first irradiation for 15 min of the Fe3O4@ZnO@mSiO2−VP16 solution, higher than stirring without microwave irradiation, where only 2% VP16 molecules were released in 30 min. A quick release was observed of the loaded VP16 from the magnetic nanocomposites under microwave. It can be seen that the VP16 release rate is a lot faster under microwave than that under stirring for Fe3O4@ ZnO@mSiO2−VP16 systems, indicating the microwave-

Figure 11. Controlled release profile of Fe3O4@ZnO@mSiO2−VP16 under microwave irradiation and stirring release cycles.

promoting effect on the release of the drug. The results show that the nanocarrier is capable of controlling the drug release accurately by adjusting the irradiation time and microwave on/ off states. With increasing time, the release keeps nearly constant, and approximately 85% VP16 was released after seven cycles. While the Fe3O4@ZnO@mSiO2 sample exhibits an improved sustained property which can markedly control the release of VP16, this indicates that the controlled release could be achieved for microwave irradiation. The results show that the current nanocarrier is capable of controlling the drug release by adjusting the microwave irradiation.

4. CONCLUSION We have demonstrated a successful synthesis of multifunctional Fe3O4@ZnO@mSiO2 core−shell structured nanocomposites by combining the interfacial deposition, sol−gel process, and surfactant assistant approach. The as-prepared core−shell structured material possesses a high magnetization saturation value (56.8 emu/g), high surface area (643.9 m2/g), large accessible pore volume (0.32 cm3/g), and excellent microwave thermal response properties for microwave-triggered drug release (the VP16 release of over 85% under microwave discontinuous irradiation outclasses the 14% within 10 h only stirring release) that would be very promising for in vivo biomedical drug targeting and controlled drug release systems using microwave. 14935



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magnetic, mesoporous, and near-IR absorption properties. J. Phys. Chem. C 2010, 114, 16343−16350. (13) Christian, A.; Veronika, W.; Christoph, B.; Thomas, B. Multifunctional Mesoporous Silica Nanoparticles as a Universal Platform for Drug Delivery. Chem. Mater. 2014, 26, 435−451. (14) Zhu, Y. F.; Meng, W. J.; Gao, H.; Hanagata, N. Hollow Mesoporous Silica/Poly(L-lysine) Particles for Codelivery of Drug and Gene with Enzyme-Triggered Release Property. J. Phys. Chem. C 2011, 115, 13630−13636. (15) Wang, Y. C.; Brown, P.; Xia, Y. N. Nanomedicine: Swarming Towards the Target. Nat. Mater. 2011, 10, 482−483. (16) Cui, J. W.; Wang, Y. J.; Caruso, F. Templated Assembly of pHlabile Polymer-Drug Particles for Intracellular Drug Delivery. Adv. Funct. Mater. 2012, 22, 4718−4723. (17) Wang, Y. J.; Yan, Y.; Cui, J. W.; Hosta, R. L.; Heath, J. K.; Nice, E. C.; Caruso, F. Encapsulation of Water Insoluble Drugs in Polymer Capsules Prepared Using Mesoporous Silica Templates for Intracellular Drug Delivery. Adv. Mater. 2010, 22, 4293−4297. (18) Yuan, L.; Tang, Q. Q.; Yang, D.; Zhang, J. Z.; Zhang, F. Y.; Hu, J. H. Preparation of pH-Responsive Mesoporous Silica Nanoparticles and Their Application in Controlled Drug Delivery. J. Phys. Chem. C 2011, 115, 9926−9932. (19) Riedinger, A.; Guardia, P.; Curcio, A.; Garcia, M. A.; Cingolani, R.; Manna, L.; Pellegrino, T. Subnanometer Local Temperature Probing and Remotely Controlled Drug Release Based on AzoFunctionalized Iron Oxide Nanoparticles. Nano Lett. 2013, 13, 2399− 2406. (20) Yang, J. P.; Shen, D.; Zhou, L.; Li, W.; Li, X. M.; Yao, C.; Wang, R.; Ahmed, M. E.; Zhang, F.; Zhao, D. Y. Spatially Con Fined Fabrication of Core−Shell Gold Nanocages@Mesoporous Silica for Near-Infrared Controlled Photothermal Drug Release. Chem. Mater. 2013, 25, 3030−3037. (21) Wu, G. H.; Mikhailovsky, A.; Khant, H. A.; Caroline, F.; Chiu, W.; Joseph, A. Z. Remotely Triggered Liposome Release by NearInfrared Light Absorption Via Hollow Gold Nanoshells. J. Am. Chem. Soc. 2008, 130, 8175−8177. (22) Brian, P. T.; Dvir, T.; Kohane, D. S. Remotely Triggerable Drug Delivery Systems. Adv. Mater. 2010, 22, 4925−4943. (23) Zhang, S. l.; Chu, Z. Q.; Yin, C.; Zhang, C. Y.; Lin, G.; Li, Q. Controllable Drug Release and Simultaneously Carrier Decomposition of SiO2-Drug Composite Nanoparticles. J. Am. Chem. Soc. 2013, 135, 5709−5716. (24) Wong, T. W. Use of Microwave in Processing of Drug Delivery Systems. Curr. Drug Delivery 2008, 5, 77−84. (25) Wong, T. W.; Nurjaya, S. Drug Release Property of Chitosan− Pectinate Beads and Its Changes Under the Influence of Microwave. Eur. J. Pharm. Biopharm. 2008, 69, 176−188. (26) Yoon, G. H.; Cho, J. W.; Kim, N.; Kim, D. D.; Lee, E. S.; Cheon, C. Y.; Kwon, Y. W. High-frequency Microwave Ablation Method for Enhanced Cancer Treatment with Minimized Collateral Damage. Int. J. Cancer. 2011, 129, 1970−1978. (27) Jiao, D. C.; Zhou, Q.; Han, W. X.; Wang, Y. F.; Wu, G.; Fu, M. T. Microwave Ablation Treatment of Liver Cancer with a 2,450-MHz Cooled-shaft Antenna: Pilot Study on Safety and Efficacy. Asian Pac. J. Cancer Prev. 2012, 13, 737−742. (28) Wang, Z. J.; Wu, L. N.; Zhou, J. G.; Shen, B. Z.; Jiang, Z. H. Enhanced Microwave Absorption of Fe3O4 Nanocrystals After Heterogeneously Growing with ZnO Nanoshell. RSC Adv. 2013, 3, 3309−3315. (29) Yang, C.; Hong, K.; Jang, J.; Chung, D. S.; Tae, K. A.; Choi, W. S.; Park, C. E. Solution-Processed Flexible ZnO Transparent ThinFilm Transistors with a Polymer Gate Dielectric Fabricated By Microwave Heating. Nanotechnology 2009, 20, 465201−465206. (30) Yuan, Q.; Li, N.; Geng, W. C.; Chi, Y.; Li, X. T. Preparation of Magnetically Recoverable Fe3O4@SiO2@meso-TiO2 Nanocomposites with Enhanced Photocatalytic Ability. Mater. Res. Bull. 2012, 47, 2396−2402. (31) Deng, Y. H.; Qi, D. W.; Deng, C. H.; Zhang, X. M.; Zhao, D. Y. Superparamagnetic High-Magnetization Microspheres with an

ASSOCIATED CONTENT

S Supporting Information *

Additional data about the zeta potential of nanocarriers, DLS experimental characterization of particles, and molecular formula of etoposide. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +86 029 8830-2129. Fax: +86 029 8830-3798. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This project is financially supported by the National Natural Science Foundation of China (Grant No. 21071115) and the Innovative and Entrepreneurial Training Program for the National College Students (No. 201210697010).

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REFERENCES

(1) Park, H. Y.; Schadt, M. J.; Lim, S.; Kim, S. H.; Jang, M. Y.; Luo, J.; Zhong, C. J. Fabrication of Magnetic Core@Shell Fe Oxide@Au Nanoparticles for Interfacial Bioactivity and Bio-separation. Langmuir 2007, 23, 9050−9056. (2) Zhu, Y. F.; Fang, Y.; Kaskel, S. Folate-Conjugated Fe3O4@SiO2 Hollow Mesoporous Spheres for Targeted Anticancer Drug Delivery. J. Phys. Chem. C 2010, 114, 16382−16388. (3) Luo, Z.; Cai, K. Y.; Hu, Y.; Li, J. H.; Ding, X. W.; Zhang, B. L.; Xu, D. W. Redox-responsive Molecular Nanoreservoirs for Controlled Intracellular Anticancer Drug Delivery Based on Magnetic Nanoparticles. Adv. Mater. 2012, 24, 431−435. (4) Wang, L. Y.; Bao, J.; Wang, L.; Zhang, F.; Li, Y. D. One-pot Synthesis and Bioapplication of Amine-Functionalized Magnetite Nanoparticles and Hollow Nanospheres. Chem.Eur. J. 2006, 12, 6341−6347. (5) Tong, L. Z.; Shi, J. H.; Liu, D. M.; Li, Q. H.; Ren, X. Z.; Yang, H. Luminescent and Magnetic Properties of Fe3O4@SiO2@Y2O3:Eu3+ Composites with Core −Shell Structure. J. Phys. Chem. C 2012, 116, 7153−7157. (6) Liu, S.; Xing, R.; Lu, F.; Rana, R. K.; Zhu, J. J. One-Pot TemplateFree Fabrication of Hollow Magnetite Nanospheres and Their Application as Potential Drug Carriers. J. Phys. Chem. C 2009, 113, 21042−21047. (7) Zhang, J.; Misra, R. D. K. Magnetic Drug-Targeting Carrier Encapsulated With Thermosensitive Smart Polymer: Core−Shell Nanoparticle Carrier and Drug Release Response. Acta Biomater 2007, 3, 838−850. (8) Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an Emerging Platform for Cancer Therapy. Nat. Nanotechnol. 2007, 2, 751−760. (9) Zhu, M. Y.; Diao, G. W. A Magnetically Recyclable Pd Nanoparticles Immobilized on Magnetic Fe3O4@C Nanocomposites: Preparation, Characterization and Their Catalytic Activity Toward Suzuki and Heck Coupling Reactions. J. Phys. Chem. C 2011, 115, 24743−24749. (10) He, Y. P.; Wang, S. Q.; Li, C. R.; Miao, Y. M.; Wu, Z. Y.; Zou, B. S. Synthesis and Characterization of Functionalized Silica-Coated Fe3O4 Superparamagnetic Nanocrystals for Biological Applications. J. Phys. D: Appl. Phys. 2005, 38, 1342. (11) Yallapu, M. M.; Susan, P. F.; Jain, T. K.; Labhasetwar, V. PEGFunctionalized Magnetic Nanoparticles for Drug Delivery and Magnetic Resonance Imaging Applications. Pharm. Res. 2010, 27, 2283−2295. (12) Xu, Z. H.; Li, C. X.; Kang, X. J.; Yang, D. M.; Yang, P. P.; Hou, Z. Y.; Lin, J. Synthesis of a multifunctional nanocomposite with 14936



Article

Fe3O4@SiO2 Core and Perpendicularly Aligned Mesoporous SiO2 Shell for Removal of Microcystins. J. Am. Chem. Soc. 2008, 130, 28− 29. (32) Wang, Z. J.; Wu, L. N.; Zhou, J. G.; Shen, B. Z.; Jiang, Z. H. Enhanced Microwave Absorption of Fe3O4 Nanocrystals After Heterogeneously Growing with ZnO Nanoshell. RSC Adv. 2013, 3, 3309−3315. (33) Yang, P. P.; Quan, Z. W.; Hou, Z. Y.; Li, C. X.; Kang, X. J.; Cheng, Z. Y.; Lin, J. A magnetic, luminescent and mesoporous core− shell structured composite material as drug carrier. Biomaterials 2009, 30, 4786−4795. (34) Presa, P. L.; Luengo, Y.; Multigner, M.; Costo, R.; Morales, M. P.; Rivero, G.; Hernando, A. Study of Heating Efficiency as a Function of Concentration, Size, and Applied Field in γ-Fe2O3 Nanoparticles. J. Phys. Chem. C 2012, 116, 25602−25610. (35) Zhang, W. M.; Fang, K. G.; Lin, M. G.; Hou, B.; Zhong, L. S.; Zhu, W. W.; Sun, Y. H. Controlled Fabrication of Iron Oxide/ Mesoporous Silica Core−Shell Nanostructures. J. Phys. Chem. C 2013, 117, 21529−21538. (36) Shao, M. F.; Ning, F. Y.; Zhao, J. W.; Wei, M.; Evans, D. G.; Duan, X. Preparation of Fe3O4@SiO2@Layered Double Hydroxide Core−Shell Microspheres for Magnetic Separation of Proteins. J. Am. Chem. Soc. 2012, 134, 1071−1077. (37) Zhang, Y.; Huang, Y. H.; Li, H. F. Electromagnetic Wave Absorption Properties of Nanoscaled ZnO. Wave Propag. 2011, B, 379−386. (38) Zhuo, R. F.; Feng, H. T.; Chen, J. T.; Yan, D.; Feng, J. J.; Li, H. J.; Geng, B. S.; Cheng, S.; Xu, X. Y.; Yan, P. X. Multistep Synthesis, Growth Mechanism, Optical, and Microwave Absorption Properties of ZnO Dendritic Nanostructures. J. Phys. Chem. C 2008, 112, 11767− 11775. (39) Qin, L. L.; Wang, M.; Zhu, R. R.; You, S. H.; Zhou, P.; Wang, S. L. The in Vitro Sustained Release Profile and Antitumor Effect of Etoposide-Layered Double Hydroxide Nanohybrids. Int. J. Nanomed. 2013, 8, 2053−2064.

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Novel Fe3O4@ZnO@mSiO2 Nanocarrier for Targeted Drug Delivery

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