Fabrication of Hollow and Porous Structured GdVO4: Dy3+

Jan 3, 2013 - First of all, GdVO4 can act as T1-positvie contrast agents because Gd3+ ions ..... this DDS exhibits comparable drug effect for inducing...
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Fabrication of Hollow and Porous Structured GdVO4:Dy3+ Nanospheres as Anticancer Drug Carrier and MRI Contrast Agent Xiaojiao Kang,†,‡ Dongmei Yang,†,‡ Ping’an Ma,† Yunlu Dai,†,‡ Mengmeng Shang,†,‡ Dongling Geng,†,‡ Ziyong Cheng,*,† and Jun Lin*,† †

State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People’s Republic of China ‡ University of the Chinese Academy of Sciences, Beijing 100049, People’s Republic of China S Supporting Information *

ABSTRACT: Hollow and porous structured GdVO 4:Dy3+ spheres were fabricated via a facile self-sacrificing templated method. The large cavity allows them to be used as potential hosts for therapeutic drugs, and the porous feature of the shell allows guest molecules to easily pass through the void space and surrounding environment. The samples show strong yellow-green emission of Dy3+ (485 nm, 4F9/2 → 6H15/2; 575 nm, 4F9/2 → 6 H13/2) under UV excitation. The emission intensity of GdVO4:Dy3+ was weakened after encapsulation of anticancer drug (doxorubicin hydrochloride, DOX) and gradually restored with the cumulative released time of DOX. These hollow spheres were nontoxic to HeLa cells, while DOX-loaded samples led to apparent cytotoxicity as a result of the sustained release of DOX. ICP measurement indicates that free toxic Gd ions can hardly dissolate from the matrix. The endocytosis process of DOX-loaded hollow spheres is observed using confocal laser scanning microscopy (CLSM). Furthermore, GdVO4:Dy3+ hollow spheres can be used for T1-weighted magnetic resonance (MR) imaging. These results implicate that the luminescent GdVO4:Dy3+ spheres with hollow and porous structure are promising platforms for drug storage/release and MR imaging.

1. INTRODUCTION Synthesis of hollow structure materials with controllable size and shape has stimulated great research interest due to their superior properties, such as low density, large specific area, and surface permeability.1−6 These functional materials have proven to be promising in widespread applications, including drug delivery, catalysis, sensors, lithium-ion batteries, fillers, and waste removal.7−11 A variety of strategies have been adopted for the preparation of hollow spheres. Template process is the most efficient and common method for such materials.12 Based on hard templates such as colloid polystyrene (PS) beads, silica particles, and carbon spheres, the fabrication and the removal of the templates is a multistep and time-consuming process.13−18 As for soft templates (bacteria, gas bubbles, emulsion droplets, surfactants, other supramolecular, polymer vesicles, and more), it is relatively difficult to control the morphology and monodispersity of products.19−24 Meanwhile, template-free methods such as the Ostwald ripening process are also meaningful for formation of certain special particles with hollow structure morphology.25,26 Compared with above approaches, the self-sacrificing templated method can avoid the template removal and simultaneously obtain the controllable and uniform morphology.27−32 Recently, the application of hollow inorganic nanomaterials in drug delivery has attracted much attention because they not only have void space for high drug loading efficiency but also © 2013 American Chemical Society

represent another class of drug carrier with sustained release behavior compared with conventional mesoporous materials and polymeric particles.33−35 With the rapid progress in nanomedicine, inorganic nanoparticles possessing attractive optical, magnetic, and thermal properties have the potential to be in combination with tagging, tracing, and drug remotely controlled release. For instance, the development of multifunctional nanomaterials that incorporate targeting function and multimode image (MR and fluorescence) capabilities can realize simultaneous diagnosis and therapy.36−38 However, integrating various functions (such as magnetic/fluorescent/ porous properties) within one entity by a single facile synthesis route is still a challenge for material scientists.39,40 In view of the above situations, gadolinium orthovanadate (GdVO4)-based nanomaterials are promising single-phase candidate that can present both magnetic and fluorescent properties. First of all, GdVO4 can act as T1-positvie contrast agents because Gd3+ ions possess seven unpaired electrons which could efficiently alter the relaxation time of surrounding water protons.41−44 Furthermore, GdVO4 has been shown to be an efficient host for lanthanide ion-activated phosphors that can emit various colors. Although lanthanide ion-doped GdVO4 Received: November 14, 2012 Revised: December 29, 2012 Published: January 3, 2013 1286

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GdVO4:Dy3+ sample. The supernatant solutions were collected, and the content of DOX was determined by UV−vis spectral measurement at the wavelength of 480 nm. Loading efficiency (LE%) can be calculated using the formula

with a wealth of shapes and sizes such as nanofibers, nanowires, nanorods, and microspheres has been fabricated via various synthetic routes, hollow and porous structured GdVO4 nanospheres have rarely been prepared, let alone their potential biomedical applications such as drug delivery and MRI.45−51 Herein, we prepared luminescent hollow structured GdVO 4 :Dy 3+ nanospheres using amorphous Gd(OH)CO3:Dy3+ as template.52 The GdVO4:Dy3+ hollow spheres can be used to encapsulate various drugs and biomolecules; i.e., DOX loaded into hollow spheres was used as a model platform to assess their efficacy as a drug delivery tool. Additionally, GdVO4:Dy3+ hollow spheres can be applied as T1 contrast agents for biomedical application.

LE % =

Mdrug in sample Mdrug in sample + Msample

× 100%

Encapsulation efficiency (EE%) can be calculated using the formula EE % =

M total drug − Mdrug in supernatant M total drug

× 100%

To study the drug release kinetics, the DOX-loaded GdVO4:Dy3+ sample (6 mg of GdVO4:Dy3+, 0.74 mg of DOX) was immersed in 1 mL of phosphate buffer saline (PBS, pH 7.4 and 5.0) at 37 °C and shaken at 100 rpm. At selected time intervals, 1 mL of buffer solution was taken and replaced with 1 mL of fresh buffer solution. The amounts of released DOX in the supernatant solutions were measured by a UV−vis spectrophotometer. All data were averaged over three measurements. 2.6. In Vitro Cytotoxicity of DOX-Loaded GdVO4:Dy3+ Spheres and Biocompatibility of GdVO4:Dy3+ Hollow Spheres. In vitro cytotoxicity of GdVO4:Dy3+ spheres were assayed against HeLa cells. HeLa cells were seeded in a 96-well plate at a density of 8000 cells per well and cultured in 5% CO2 at 37 °C for 24 h. Then free DOX, DOX-loaded GdVO4:Dy3+, and GdVO4:Dy3+ were added to the medium, and the cells were incubated in 5% CO2 at 37 °C for 48 h. The concentrations of DOX were 1.5625, 3.125, 6.25, 12.5, 25, and 50 μg/mL. The concentrations of the nanospheres were 12.7, 25.4, 50.8, 101.6, 203.2, and 406.4 μg/mL, respectively. At the end of the incubation, 20 μL of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) solution was added into each cell and incubated for another 4 h. After that, the medium containing MTT was removed, and 150 μL of dimethyl sulfoxide (DMSO) was added to each well to dissolve the MTT formazan crystals. Finally, the plates were shaken for 10 min, and the absorbance of formazan product was measured at 570 nm by a microplate reader (Therom Multiskan MK3). Meanwhile, the biocompatibility of the sample was was also determined using MTT assay on L929 fibroblast cells, which was the same as the procedure for cytotoxicity assay for GdVO4:Dy3+ spheres. Averages and standard deviations were based on four samples and all tests performed in triplicate. To investigate the degradation characteristics of the sample, 5 mg of GdVO4:Dy3+ hollow sphere was soaked in 50 mL of simulated body fluid (SBF) maintained at 37 °C with slow stirring. The ionic composition of the as-prepared SBF solution was similar to that of human body plasma with a molar composition of 142.0/5.0/2.5/1.5/ 147.8/4.2/1.0/0.5 for Na+/K+/Ca2+/Mg2+/Cl−/HCO3−/HPO42−/ SO42− (pH = 7.4).53,54 After 1 week, the dispersions were centrifuged and dried at 60 °C for 12 h for further characterization. GdVO4:Dy3+ spheres were added into PBS (pH 7.4 and 5.0) with a concentration of Gd 157.25 mg/L, and ICP was applied to detect whether any toxic free Gd ions were leached from GdVO4:Dy3+ sample immersed in PBS at 37 °C for 48 h. 2.7. Internalization of DOX-Loaded GdVO4:Dy3+ in Vitro. HeLa cells were seeded in six-well culture plates (a clean coverslip was put in each well) and grown overnight as a monolayer and were incubated with DOX-loaded GdVO4:Dy3+ spheres at 37 °C for 10 min, 1 h, and 6 h. Thereafter, the cells were rinsed with PBS three times, fixed with 2.5% formaldehyde (1 mL/well) at 37 °C for 10 min, and then rinsed with PBS three times again. For nucleus labeling, the nuclei was stained with Hoechst 33342 solution (from Molecular Probes, 20 μg/mL in PBS, 1 mL/well) for 10 min and then rinsed with PBS three times. The coverslips were placed on a glass microscope slide, and the samples were visualized using CLSM (FV10-ASW). 2.8. Characterization. The X-ray diffraction (XRD) measurements were performed on a D8 Focus diffractometer (Bruker) with Cu Kα radiation (λ = 0.154 05 nm). The morphologies of the samples were obtained using a field emission scanning electron microscope

2. EXPERIMENTAL SECTION 2.1. Materials. The rare earth oxides Gd2O3 (99.99%) and Dy2O3 (99.99%) were purchased from Science and Technology Parent Company of Changchun Institute of Applied Chemistry. Rare earth chloride stock solutions of 0.5 M were obtained by dissolving the corresponding metal oxide in hydrochloric acid under heating with agitation. The other chemicals were obtained from Beijing Chemical Co. All chemicals are of analytical grade reagents and used directly without further purification. 2.2. Preparation of Monodisperse Gd(OH)CO3 and Gd(OH)CO3:Dy3+ Spheres. The monodisperse Gd(OH)CO3 spheres were prepared via a urea-based homogeneous precipitation process according to the literature with some modifications.52 In a typical process, 2 mL of GdCl3 (0.5 M) and 1.5 g of urea [CO(NH2)2] were dissolved in deionized water. The total volume of the solution was about 100 mL. The above solution was first homogenized under magnetic stirring at room temperature for 0.5 h. The resultant solution was then reacted at 90 °C for 3 h in the oil bath. The obtained suspension was separated by centrifugation and collected after washing with deionized water and ethanol several times. Gd(OH)CO3:Dy3+ (the doping concentration of Dy3+ is 5 mol % of Gd3+ in GdVO4 host) spheres were prepared by the same synthesis procedure for the Gd(OH)CO3 sample, except that a stoichiometric amount of DyCl3 aqueous solution was added to GdCl3 for the precursors in the initial stage as described above. 2.3. Preparation of Monodisperse GdVO4 and GdVO4:Dy3+ Hollow Spheres. In a typical experiment, the as-prepared Gd(OH)CO3 sample was dispersed into deionized water by ultrasonication for 0.5 h to obtain solution A. 0.0351 g of NH4VO3 and 30 μL of 2 M HCl were added into desionized water to form solution B. After stirring for 10 min, solution B was introduced into solution A. After additional agitation for 0.5 h, the mixing solution was transferred into a Teflon bottle (18 mL) held in a stainless steel autoclave, sealed, and maintained at 180 °C for 10 h. After allowing the autoclave to cool to room temperature naturally, the precipitates were separated by centrifugation, washed with deionized water and ethanol in sequence, and then dried in air at 80 °C for 12 h. The luminescent GdVO4:Dy3+ hollow spheres were prepared by the same procedure as GdVO4, except for using Gd(OH)CO3:Dy3+ as the starting materials. 2.4. MRI Measurements. The MRI measurements were performed in a 0.5 T MRI magnet (Shanghai Niumai Corporation Ration NM120-Analyst). GdVO4:Dy3+ samples were dispersed in water at various Gd concentrations. T1 was acquired using inversion recovery sequence. T1 measurements were performed using a nonlinear fit to changes in the mean signal intensity within each well as a function of repetition time (TR) using the provided quantification software. Finally, the r1 relaxivity values were determined through the curve fitting of 1/T1 relaxation time (s−1) vs the Gd concentration (mM). 2.5. In Vitro Loading and Release of DOX. To measure the loading amount of DOX, GdVO4:Dy3+ hollow spheres (6 mg) were added into DOX aqueous solution (4 mL, 1 mg/mL). The mixture was shaken for 24 h at room temperature to reach the equilibrium state. Then the solution was centrifuged to collect the DOX-loaded 1287

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Scheme 1. Scheme for the Preparation Process of GdVO4:Dy3+ and Subsequent Loading of DOX

(FE-SEM, XL30, Philips). Transmission electron microscopy (TEM) was performed using FEI Tecnai G2 S-Twin with a field emission gun operating at 200 kV. The Fourier transform infrared spectra were measured on a Vertex PerkinElmer 580BIR spectrophotometer (Bruker) with the KBr pellet technique. Nitrogen adsorption/ desorption analysis was performed with a Micromeritics ASAP 2020 M apparatus. The specific surface area was determined by the Brunauer−Emmett−Teller (BET) method. The UV−vis absorption spectral values were measured on a U-3100 spectrophotometer (Hitachi). Inductively coupled-plasma (ICP) measurement (ICPPLASMA 1000) was used to evaluate the amount of Gd ions dissociated from matrix. Zeta potential measurements were carried out on Malvern Zetasizer Nano ZS (Malvern Instruments Ltd., UK). The photoluminescence (PL) spectra were taken on an F-7000 spectrophotometer (Hitachi) equipped with a 150 W xenon lamp as the excitation source. CLSM images were observed by confocal laser scanning microscope (Olympus, FV 1000).

prepared Gd(OH)CO3 spheres and GdVO4 hollow spheres. In Figure 1a for precursor, no diffraction peak except for two broad bands at 30° and 48° is observed, which indicates that the as prepared precursor sample is amorphous.7 In Figure 1b, all the diffraction peaks of the product after hydrothermal process can be readily indexed to the tetragonal GdVO4 phase (JCPDS No. 17-0260). And the diffraction peaks of the samples are sharp and narrow, which means the GdVO4 hollow spheres with high crystallinity can be obtained at relatively low hydrothermal temperature (180 °C). The SEM and TEM images of the representative Gd(OH)CO3 sample, as presented in Figure 2a−c, show the spherical

3. RESULTS AND DISCUSSION 3.1. Structure, Morphology, and Properties of Gd(OH)CO 3 :Dy 3+ Precursors and GdVO 4 :Dy 3+ . The GdVO4:Dy3+ hollow spheres were obtained using a selfsacrificing templated method. Monodisperse Gd(OH)CO3:Dy3+ spheres were first made according to urea-based homogeneous precipitation (Scheme 1). The precursors interacting with NH4VO3 generates GdVO4:Dy3+ hollow spheres under hydrothermal conditions. The inner void space offers an opportunity for GdVO4:Dy3+ particles to be used as drug carrier. DOX, a water-soluble anticancer agent, was used as the model drug to evaluate the drug loading and release behavior of samples in the further discussion. The crystallinity and the phase purity of the samples were examined by XRD. Figure 1 shows the XRD patterns of the as-

Figure 2. (a, b) SEM images, (c) TEM image, and (d) EDS spectrum of Gd(OH)CO3 precursor.

morphology of particles with a uniform diameter of 220 nm. The spheres possess smooth surface. The uniformity and monodispersity of templates are propitious to obtain the samples with fine morphology. The energy dispersive X-ray spectroscopy (EDS) spectrum (Figure 2d) confirms the presence of gadolinium (Gd), oxygen (O), and carbon (C) in the precursor. The monodisperse Gd(OH)CO3 solid spheres acted as a template for the GdVO4 hollow spheres. As the template was in weak acidic condition, a part of precursors were dissolved and free Gd3+ cations could react with VO43− anions to form GdVO4 particles. During this ion exchange process, the Gd3+ cation is supposed to move faster than the VO43− anion, so the inner dissolved Gd3+ cation could easily diffused outside. This conversion leads to an outward growth of the hollow shell. Figure 3a,b shows the SEM images of the GdVO4 hollow spheres after the hydrothermal treatment of 10 h. The surface becomes rough and the diameter of sphere is about 290 nm,

Figure 1. XRD patterns of the Gd(OH)CO3 (a) and GdVO4 (b) samples and the standard data of GdVO4 (JCPDS No. 17-0620) as reference. 1288

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The porous nature of the product was confirmed by N2 sorption measurement. Figure S2 shows a typical adsorption/ desorption isotherm and the corresponding pore size distribution of GdVO4:Dy3+ hollow spheres with diameter of 290 nm. The type IV isotherm with typical H1 hysteresis loop in the range of 0.6−1.0 P/P0 is obtained. Additionally, a plot of the pore size distribution exhibits two peaks (at 3.6 and 10.6 nm) in the mesoporous range. The pores on the hollow sphere can be attributed to the interspaces of the constituent particles. Quantitative calculation shows that the BET surface area and pore volume are 48.36 m2/g and 0.21 cm3/g, respectively. The textural properties of sample provide the potential capability to load guest molecules into the cavity for the application of drug delivery. The FTIR spectra for Gd(OH)CO3, GdVO4:Dy3+, DOXloaded GdVO4:Dy3+, and pure DOX are depicted in Figure S3. In the case of Gd(OH)CO3 (Figure S3a), the obvious absorption bands from O−C−O (νas, 1510 and 1405 cm−1; νs, 1084 cm−1) and CO32− (δ, 841 and 686 cm−1) (where νs represents symmetric stretching, νas asymmetric stretching, and δ bending) are present, indicating the existence of the carbonate group in the precursor.7 After the precursor reacting with NH4VO3, the above-mentioned IR bands all disappear and the peaks at 802 and 448 cm−1 attributed to the vibration of V− O bond and Gd−O band can be clearly observed.55 For the DOX-loaded GdVO4:Dy3+ (Figure S3c), the absorption bands assigned to the stretching vibration of CO at 1617 and 1579 cm−1 from the anthraquinone ring of DOX are found.56 The results suggest that Gd(OH)CO3 precursor can be thoroughly converted into GdVO4 and DOX can be successfully encapsulated into GdVO4:Dy3+ hollow spheres. 3.2. Photoluminescence (PL) Properties and MR Imaging of GdVO4:Dy3+ Hollow Spheres. Figure 5 shows

Figure 3. (a, b) SEM images and (c) EDS spectrum of GdVO4 hollow spheres.

larger than that of template. Numerous nanoparticles were packed together, which constructed the shell of the hollow spheres. In Figure 3b, some broken spheres can be clearly observed, verifying their hollow structure. The atom ratio of Gd and V was determined 1.07:1 by EDS, which is close to the stoichiometric atomic ratio of the GdVO4 product. TEM investigations give a deeper insight into the fine structures and the hollow nature of samples, as shown in Figure 4. The strong

Figure 4. (a−c) TEM and (d) HRTEM images of GdVO4 hollow spheres.

Figure 5. Excitation (a) and emission (b) spectra for GdVO4:Dy3+. Inset is the corresponding photographs of the sample aqueous solution under daylight and 254 nm UV lamp irradiation.

contrast between the relatively darker edges and the brighter center of each sphere provides a further evidence for their hollow features. The thickness of shell is about 50 nm. The HRTEM image (Figure 4d) further confirms the identification of tetragonal GdVO4 phase. The interplanar distance between the adjacent lattice fringes can be calculated to 0.359 nm, which can be well indexed as d-spacing value of the (200) plane. From image of disaggregated spheres (Figure S1), it can be seen that ricelike building blocks have a length of 26 nm and width of 15 nm.

the excitation and emission spectra of GdVO4:Dy3+ hollow spheres. The excitation spectrum of GdVO4:Dy3+ exhibits a strong and broad band ranging 200 to 350 nm assigned to VO43− absorption. The emission spectrum of sample is composed of two characteristic emission peaks of Dy3+ upon excitation at 278 nm. The emission at 485 and 575 nm are associated with the typical transitions from the 4F9/2 level to 6 H15/2 and 6H13/2, respectively.57 In addition, the GdVO4:Dy3+ hollow spheres can be well dispersed in water to form a stable 1289

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cytotoxic effect on the L929 cells at 3.125−100 μg/mL after incubation for 24 h. As the concentration of GdVO4:Dy3+ hollow spheres was as high as 100 μg/mL, the cell viability was above 90%. These results demonstrate that the as-prepared samples have good biocompatibility and suitable to be used as the drug carriers. To analyze the degradation characteristics of the sample, GdVO4:Dy3+ hollow spheres were soaked in 50 mL of SBF for 1 week. XRD, SEM, and EDS measurements (Figure S6) indicated that the product after immersion treatment is still GdVO4 phase. The as-prepared GdVO4:Dy3+ hollow spheres do not react with medium. In addition, ICP was applied to detect whether any toxic free Gd ions were leached from GdVO4:Dy3+ sample immersed in PBS at 37 °C for 48 h. The concentrations of Gd ions in PBS solution (pH 7.4 and 5.0) are 24.95 and 100.4 ng/L, respectively. Such low values indicate that Gd ions can hardly dissociate from the matix. Further studies are also needed to assess the biodistribution and pharmacokinetics. We further studied the drug delivery property of the GdVO4:Dy3+ hollow spheres. After hydrothermal treatment, there are a large number of hydroxyl groups on the surface of GdVO4:Dy3+ hollow spheres, which is proved by FTIR result. In a neutral surrounding the hollow spheres presents a negative-charges surface (Figure S7), which has the interaction with the positive-charges DOX molecules due to the protonated primary amine group on DOX. Hence, the electrostatic interaction between DOX molecules and the GdVO4:Dy3+ hollow sphere is the main driving force for drug loading. Owing to large inner space of hollow spheres, a large number of drug molecules can be encapsulated into sample. The loading efficiency of adsorption DOX into GdVO4:Dy3+ hollow spheres was 11% determined by UV−vis spectra depending on the characteristic adsorption peak at 480 nm. The encapsulation efficiency calculated via the formula was 18.5%. The cumulative drug release profiles for the DOXloaded GdVO4:Dy3+ systems measured at pH = 7.4 and pH = 5.0 PBS buffer are shown in Figure 7a. At pH = 7.4, 45% of the drug was released within 36 h, whereas at pH = 5.0, it took only 20 h to attain a comparable level of drug release. The different drug release behaviors can be elucidated by the surface ζpotential measurements of the particles. As can be seen in Figure S7, pure GdVO4:Dy3+ hollow spheres gave all negatively charge surfaces at pH = 7.4 and pH = 5.0 PBS buffer, showing a change trend toward more positive with discreasing pH values. In more acidic condition (pH = 5.0), the electrostatic interaction between drug carrier and DOX was weaker. The drug molecules were liable to be liberated through porous shell via diffusion-controlled mechanism. These data imply that the physically bound DOX molecules could be released faster in mild acidic environments of tumor areas than at the physiologically neutral pH of blood in the vascular compartment. In addition, we found that there is a relationship between PL intensity and cumulative release amount of DOX. The emission intensity of GdVO4:Dy3+ sample was weakened after loading DOX and underwent a gradually restore process with the cumulative released time of DOX. This phenomenon is ascribed to two reasons as follows. On one hand, it is due to the spectral overlap between PL emission of sample and absorbance of DOX. As shown in Figure 7b, the absorbance of DOX is between 400 and 580 nm. On the other hand, we know that the emission of rare earth ions can be quenched to some extent in the environments that have a high phonon frequency.40 The organic groups in DOX will quench the

translucent colloidal solution due to the existence of abundant hydroxyl groups on the surface of sample (inset of Figure 5). Under the irradiation of a 254 nm UV lamp, the sample shows bright yellow-green luminescence, which can be seen from inset of Figure 5. Besides investigation of photoluminescence properties, we also determine whether these gadoliniumcontaining phosphors could be used as contrast agents in MRI, their contrast effect in solution was tested. The GdVO4:Dy3+ sample was found to decrease the longitudinal relaxation time (T1). Bright signal enhancement was observed in the T1 images (Figure 6a). The longitudinal relaxivity (r1)

Figure 6. T1-weighted MR image (a) and T1 relaxivity plot (b) of aqueous suspension of GdVO4:Dy3+ hollow spheres.

not only is closely related with applied magnetic field strength of MR equipment but also depends on the composition, morphology, and particle diameter.42,58,59 The relaxivity increases as the applied magnetic field increased.60 In addition, the Gd-based contrast agents with larger specific surface area generally have higher relaxivity (r1). This is due to they can provide more effective Gd3+ ions and give greater accessibility and interaction between the water molecules and the contrast agents. The specific surface area of our prepared GdVO4:Dy3+ hollow spheres is 48.36 m2/g, so the value of r1 is not very high at 0.5 T. From plots of 1/T1 versus Gd concentration (Figure 6b), r1 (0.3716 mM−1 s−1) is obtained. The data suggested that it has the potential to be used as a contrast agent for MR imaging. 3.3. In Vitro Cytotoxicity and Drug Storage/Release Properties of GdVO4:Dy3+ Hollow Spheres. The MTT assay is a common approach to evaluate the cytotoxicity of the drug carriers. This method is based on the ability of a mitochondrial enzyme to convert the yellow dye substrate to a blue formazan. The UV−vis absorbance spectrum of the GdVO4:Dy3+ hollow sphere shows that there is no absorption for pure hollow spheres at the wavelength (570 nm) used in measuring cytotoxicity (Figure S4). It could be seen from Figure S5 that GdVO4:Dy3+ hollow spheres showed no obvious 1290

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Figure 8. In vitro HeLa cell viabilities after incubation 24 h with bare GdVO4:Dy3+ hollow spheres, DOX-loaded GdVO4:Dy3+ sample, and free DOX at different concentrations.

trations. It also can be seen that the cytotoxicity of DOX-loaded GdVO4:Dy3+ hollow spheres is similar as that of the free DOX at higher concentration of DOX. As we know, DOX is a commonly used drug for the treatment of cancer. However, this drug has severe systemic toxicity to healthy tissues and organs, such as kidney, liver, bone marrow, and heart. The hollow spheres can protect the encapsulated DOX from rapid systemic metabolism and elimination and simultaneously reduce the side effect. The as-prepared sample is promising for applying as anticancer drug carrier because this DDS exhibits comparable drug effect for inducing cancer cells death and abates the side effect of DOX to a certain extent. The fluorescent nature of DOX (red fluorescence) molecules facilitates the observation of intracellular delivery and release of drugs from the carriers. The CLSM photographs of HeLa cells incubated with DOX-loaded GdVO4:Dy3+ for 10 min, 1 h, and 6 h at 37 °C are shown in Figure 9. In the first 10 min (Figure 9a−c), only a few of composites were taken up by HeLa cells. After incubation of 1 h (Figure 9d−f), the intensities of red signal increase; that is, DOX-loaded carriers have crossed the membrane, and DOX molecules were released and localized in the cytoplasm. With the increase of the incubation time (Figure 9g−i), more and more DOX molecules were released in the cytoplasm. The results mean the efficient intracellular delivery of DOX by the GdVO4:Dy3+ hollow spheres.

Figure 7. (a) Cumulative DOX release from GdVO4:Dy3+ hollow spheres at (a) pH = 7.4 and pH = 5.0 PBS buffer. (b) UV−vis absorption spectrum of pure DOX dissolved in PBS buffer (pH = 7.4). (c) PL emission intensity of DOX-loaded GdVO4:Dy3+ sample as a function of release time at pH 5.0 PBS buffer.

emission of Dy3+ to a great level. With the release of DOX, the quenching effect was weakened, which leads to the increase of PL intensity (Figure 7c). Hence, we can utilize this characteristic to track or monitor drug release. 3.4. In Vitro Cytotoxic Effect and Cell Uptake. To verify whether the released DOX was pharmacologically active, the cytotoxicity of DOX-loaded GdVO4:Dy3+ on HeLa cells was evaluated via MTT assay. Figure 8 shows the in vitro cellular cytotoxicity of DOX, DOX-loaded GdVO4:Dy3+ hollow spheres, and pure GdVO4:Dy3+ hollow spheres at different concentrations. The concentration of GdVO4:Dy3+ hollow spheres was set at the same level as the GdVO 4:Dy 3+ concentrations used in the DOX-loaded GdVO4:Dy3+ system. It is found that the bare GdVO4:Dy3+ hollow spheres have no obvious cytotoxic effect on cancer cells after 48 h treatment. The cytotoxicity of DOX and DOX-loaded GdVO4:Dy3+ hollow spheres increased with the increase of their concen-

4. CONCLUSIONS In this study we prepared luminescent GdVO4:Dy3+ hollow spheres via a facile self-templated approach. GdVO4:Dy3+ hollow spheres show strong yellow-green emission of Dy3+ (485 nm, 4F9/2 → 6H15/2; 575 nm, 4F9/2 → 6H13/2) under UV light excitation. Because of their large cavity, the hollow spheres were applied as carrier for DOX loading. The release amount of DOX can be monitored by change of PL intensity. The DOXloaded GdVO4:Dy3+ samples reveal similar efficiency for killing cancer cells compared with pure DOX. We have further measured the relaxivity and taken phantom images of GdVO 4 :Dy 3+ in the MR imaging mode (T 1 ). These luminescent hollow spheres have great potential in drug delivery and MR imaging. 1291

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Figure 9. Confocal laser scanning microscopy (CLSM) images of HeLa cells incubated with DOX-loaded GdVO4:Dy3+ sample ([DOX] = 20 μg/ mL) for 10 min (a−c), 1 h (d−f), and 6 h (g−i) at 37 °C. Each series can be classified to the nuclei of cells (being dyed in blue by Hoechst 33324 for visualization), DOX-loaded GdVO4:Dy3+ sample, and a merge of the two channels of both above, respectively. All scale bars are 40 μm.

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ASSOCIATED CONTENT

S Supporting Information *

(1) Chen, Y.; Chen, H. R.; Guo, L. M.; Zeng, D. P.; Tian, Y. B.; Chen, F.; Feng, J. W.; Shi, J. L. Core/Shell Structured Hollow Mesoporous Nanocapsules: A Potential Platform for Simultaneous Cell Imaging and Anticancer Drug Delivery. ACS Nano 2010, 4, 6001−6013. (2) Lou, X. W.; Archer, L. A.; Yang, Z. C. Hollow Micro-/ Nanostructures: Synthesis and Applications. Adv. Mater. 2008, 20, 3987−4019. (3) Li, L.; Ma, R. Z.; Iyi, N.; Ebina, Y.; Takada, K.; Sasaki, T. Hollow Nanoshell of Layered Double Hydroxide. Chem. Commun. 2006, 29, 3215−3217. (4) Cheng, K.; Sun, S. H. Recent Advances in Syntheses and Therapeutic Applications of Multifunctional Porous Hollow Nanoparticles. Nano Today 2010, 5, 183−196. (5) Li, G. L.; Yang, X. Y.; Wang, B.; Wang, J. Y.; Yang, X. L. Monodisperse Temperature-Responsive Hollow Polymer Microspheres: Synthesis, Characterization and Biological Application. Polymer 2008, 49, 3436−3443. (6) Wang, Z. X.; Wu, L. M.; Chen, M.; Zhou, S. X. Facile Synthesis of Superparamagnetic Fluorescent Fe3O4/ZnS Hollow Nanospheres. J. Am. Chem. Soc. 2009, 131, 11276−11277. (7) Xu, Z. H.; Cao, Y.; Li, C. X.; Ma, P. A.; Zhai, X. F.; Huang, S. S.; Kang, X. J.; Shang, M. M.; Yang, D. M.; Dai, Y. L.; Lin, J. Urchin-like GdPO4 and GdPO4:Eu3+ Hollow Spheres-Hydrothermal Synthesis, Luminescence and Drug-Delivery Properties. J. Mater. Chem. 2011, 21, 3686−3694. (8) Yu, X. F.; Wang, D. S.; Peng, Q.; Li, Y. D. High Performance Electrocatalyst: Pt-Cu Hollow Nanocrystals. Chem. Commun. 2011, 47, 8094−8096. (9) Kim, H.-J.; Choi, K.-II.; Pan, A. Q.; Kim, II.-D.; Kim, H.-R.; Kim, K.-M.; Na, C. W.; Cao, G. Z.; Lee, J.-H. Template-Free Solvothermal

TEM image of scattered nanoparticles making up GdVO4 hollow spheres (Figure S1); N2 adsorption/desorption isotherms and corresponding pore size distribution (inset) for GdVO4:Dy3+ hollow spheres (Figure S2); IR spectra of Gd(OH)CO3 (a), GdVO4:Dy3+ (b), DOX-loaded GdVO4:Dy3+ (c), and pure DOX (d) (Figure S3); UV−vis absorption spectrum of pure GdVO4:Dy3+ hollow spheres dispersed in water (Figure S4); cell viabilities of GdVO4:Dy3+ hollow spheres to L929 fibroblast cells measured by MTT assay (Figure S5); XRD pattern, SEM image, and EDS spectrum of the GdVO4:Dy3+ hollow spheres after immersing in SBF for 1 week (Figure S6); zeta-potential of GdVO4:Dy3+ hollow spheres as a function of the PBS solution pH value (Figure S7). This material is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (J.L.); [email protected] (Z.C.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This project is financially supported by National Basic Research Program of China (2010CB327704), National High Technology Program of China (2011AA03A407), and the National Natural Science Foundation of China (NSFC 51172228, 51272248, 21101149, 51172227, 21221061). 1292

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