Luminescent and Magnetic Î±-Fe2O3@Y2O3:Eu3+ Bifunctional Hollow

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Luminescent and Magnetic alpha-FeO@YO:Eu Bifunctional Hollow Microspheres for Drug Delivery Liao Yuan Xia, Xiangling Li, Fangjia Zhu, Shaoheng Hu, and Le Huang J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.7b05228 • Publication Date (Web): 22 Aug 2017 Downloaded from http://pubs.acs.org on August 23, 2017

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The Journal of Physical Chemistry

Luminescent and Magnetic alpha-Fe2O3@Y2O3:Eu3+ Bifunctional Hollow Microspheres for Drug Delivery

Liaoyuan Xia, * Xiangling Li, Fangjia Zhu, Shaoheng Hu and Le Huang

College of Material Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, P. R. China

*Corresponding author, (E-mail) [email protected]; (phone & fax) +86-739-85658531

ACS Paragon Plus Environment

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ABSTRACT: Fluorescent and magnetic bifunctional nanomaterials have found several applications in life sciences, including biological labelling, magnetic resonance imaging, gene therapy, and nanodrug delivery. In this work, we develop a facile route that combines the assisted-template approach with a homogeneous co-precipitation method and a high-temperature calcination process, allowing the successful preparation of fluorescent-magnetic αFe2O3@Y2O3:Eu3+ bifunctional hollow microspheres (BHMs) with mesoporous shells and hollow-core structures. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), emission spectroscopy, magnetic testing, and N2 adsorption techniques were employed to characterize the fluorescent-magnetic α-Fe2O3@Y2O3:Eu3+ BHMs. The results showed that the resulting BHMs exhibited uniformly spherical morphologies with mesoporous shells and hollow-core structures, and were characterized by good dispersibility, photofluorescence, and magnetic responsiveness in solution. Ibuprofen loading and drug-release simulation experiments showed that the BHMs exhibited a high drug-loading capacity (126 mg/g) and a sustained drugrelease profile, which would allow them to be employed as nanodrug carriers for the therapeutic treatment of malignant tumors.


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1. INTRODUCTION In recent years, the design and synthesis of multifunctional nanomaterials with well-defined structures has attracted widespread attention in the fields of photoelectricity, environmentalism, biology, nanomedicine, and single-/multi-layer metal oxides and chalcogenides.1-6 In particular, bifunctional nanomaterials with fluorescent-magnetic properties and unique core-shell structures have received great interest as candidates for fluorescent labelling, magnetic resonance imaging, bio-separation, and drug delivery.7-10 So far, a variety of methods have been developed for the preparation of fluorescent-magnetic bifunctional nanomaterials, including hydrothermal/ solvothermal methods,11, 12 homogeneous co-precipitation approaches,13 and so-gel routes.14 The most commonly used strategy for preparing bifunctional nanomaterials with core-shell structures is based on the use of a magnetic nanoparticle core and a fluorescent coating layer. For instance, Ma and co-workers developed a facile homogenous precipitation method of fabricating bifunctional nanomaterials in which Fe3O4 nanoparticles were used as the magnetic core and Y2O3:Eu as the shell layer.13 As is well known, magnetic nanoparticles have been widely applied in targeted drug-delivery systems owing to their high saturation magnetization intensities and low toxicities.15,

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Moreover, the fluorescent coating shell layers are usually biocompatible

inorganic materials or polymers containing fluorescent components with stable physical and chemical properties.17, 18 The fluorescent components are usually quantum dots, organic dyes, or rare-earth (RE)-doped luminescent materials.19-21 RE-doped luminescent materials have been reported to show excellent chemical stability, low biotoxicity, narrow emission spectra, and long fluorescence lifetimes, which allow them to be directly used as coating shell layers in bifunctional nanomaterials.22, 23


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Fluorescent and magnetic bifunctional nanomaterials have been demonstrated to have immense potential for use in drug delivery systems, with significant therapeutic effects when used as targeted drugs for the treatment of malignant tumors.24-27 This is mainly attributed to the unique fluorescent and magnetic properties of the bifunctional nanomaterials, which enable cell imaging and positioning and result in accurate diagnosis. Moreover, the drug-loading properties of these nanomaterials can enable targeted drug delivery for therapeutic treatments, thereby alleviating the side effects associated with anticancer drugs. However, the fluorescent-magnetic bifunctional nanomaterials reported in the literature have solid “core-shell” structures that exhibit drawbacks such as low drug-loading capacities, irregular shapes, and poor sustained-release profiles, limiting their development for biological and medicinal applications.8, 12, 28 It is well accepted that hollow mesoporous microspheres (HMMs) possess high drugloading capacities and good sustained-release properties due to their unique hollow cores and mesoporous shell structures.9, 29-31 In addition, their spherical morphologies are conducive to the in vivo delivery of spheres;32 hence, these materials are widely employed as carriers for targeted drug delivery. Until now, the fabrication of well-defined HMMs has been carried out primarily using various template-assisted methods,32-36 such as hard-/soft-templating approaches, dualtemplate routes, or template-free techniques. HMMs prepared by hard-template assisted methods generally show more controllable shapes and particle sizes, along with better dispersities. Obviously, the aforementioned drawbacks of the bifunctional nanomaterials would be completely overcome if their fluorescent-magnetic properties could be combined with the high drug storage capacities of hollow-core structures using a simple hard-template assisted method. Herein, fluorescent-magnetic α-Fe2O3@Y2O3:Eu3+ bifunctional hollow microspheres (BHMs) were successfully prepared by using c-PS/Fe3O4/RE3+ (RE3+ = Y3+, Eu3+) hetero-


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aggregates as an assisted template, followed by homogeneous co-precipitation to form an RE(OH)CO3 coating shell layer on the template surface, after which high-temperature (700 °C) calcination was carried out remove the c-PS to obtain a hollow-core structure. The fabrication procedure involved five main steps, as shown in Scheme 1. In addition, ibuprofen was employed as a target drug in this study to allow the drug-loading capacities and sustained drug-release profiles of the BHMs to be evaluated. This is because ibuprofen is used as a basic drug for relieving cancer-induced pain, and it has evident anti-inflammatory and analgesic properties with minimal side effects. Furthermore, ibuprofen molecules contain carboxyl groups (see Figure S1) that allow the molecules to be connected to the hollow microspheres via hydrogen bonding, thus making it highly suitable for drug-loading studies.34

2. EXPERIMENTAL SECTION 2.1. Chemical Reagents. Fe3O4 nanoparticles (≤50 nm, Sigma-Aldrich), ibuprofen (IBU, 99%, Alfa Aesar), phosphate-buffered saline (PBS) tablets (99%, Alfa Aesar), Y2O3 (99.99%), Eu2O3 (99.99%), concentrated HCl (37%, AR), styrene (AR), acrylic acid (AR), K2S2O8 (AR), NaHCO3 (AR), urea (AR), and anhydrous ethanol (AR) were obtained from Sinopharm Chemical Reagent Co., Ltd., while deionized water was used as-prepared. All chemicals were of analytical reagent grade and were used without further purification, with the exceptions of the styrene and acrylic acid monomers, which were purified by distillation under reduced pressure. 2.2. Synthesis of the Carboxylated Polystyrene (c-PS) Emulsion.35 Deionized water (200 mL) and NaHCO3 (0.24 g) were added to a three-necked round bottom flask equipped with a mechanical stirrer, under nitrogen gas. Subsequently, purified styrene (10 mL) and purified


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acrylic acid (1.2 mL) were added to the mixture. After the mixture was stirred for 0.5 h, K2S2O8 (0.1 g) was added to initiate the polymerization reaction, which was allowed to proceed at 70 °C for 12 h. The mixture was then allowed to cool to room temperature, separated using a centrifuge, and rinsed several times with deionized water to yield a 4.0 wt. % c-PS emulsion. 2.3. Preparation of the c-PS/Fe3O4/RE3+ Hetero-Aggregate Template. A typical synthetic procedure was as follows: the c-PS emulsion (70 g with a solid content of 4 wt. %) was slowly added to a HCl solution (140 mL, pH = 2.3), and then ultrasonically dispersed for 0.5 h. After this, 1 mL of a 0.2 M RE3+ solution (RE = Y and Eu, with Y3+: Eu3+ in a 19:1 molar ratio) was added dropwise and stirred for 1 h to form Solution A. Meanwhile, Fe3O4 nanoparticles (0.4 g) were added to a HCl solution (160 mL, pH = 2.3), ultrasonically dispersed for 0.5 h, and then added dropwise into Solution A. The resulting solution was then stirred for 8 h. Finally, the hetero-aggregates were separated through magnetic adsorption and washed thoroughly using several changes of deionized water and ethanol until a neutral pH was reached, thus forming a 1.8 wt. % c-PS/Fe3O4/RE3+ hetero-aggregate solution. 2.4. Synthesis of the Fluorescent-Magnetic α-Fe2O3@Y2O3:Eu3+ BHMs. A typical synthetic procedure proceeded as follows: 3.70 g of c-PS/Fe3O4/RE3+ hetero-aggregate solution was added dropwise to a 1.8 M urea solution (400 mL), and then ultrasonically dispersed for 15 min. After this, 3.75 mL of a 0.2 M RE3+ solution was added dropwise, and the reaction was allowed to proceed for 4 h in a water bath at 90 °C with continuous stirring. To understand how the c-PS/Fe3O4/RE3+ hetero-aggregate template to Y2O3:Eu3+ mass ratio affected the morphology, dispersibility, and fluorescent-magnetic properties of the functionalized hollow spheres, the amount of the RE3+ solution that was added to the hetero-aggregate solution was varied, such that the resulting theoretical c-PS/Fe3O4/RE3+ to Y2O3:Eu3+ mass ratios were 0.4,


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0.8, 1.0, and 1.25; all other conditions remained unaltered. The as-reacted products were separated magnetically, washed with deionized water and anhydrous ethanol three times, and dried overnight at 40 °C. This product was then placed in a tube furnace and heated from room temperature to 380 °C at a rate of 1 °C/min, followed by heating to 700 °C at a rate of 2 °C/min, and then held at this temperature for 2 h. After cooling, the fluorescent-magnetic αFe2O3@Y2O3:Eu3+ BHMs were obtained and denoted as BHM-n, where n refers to the theoretical c-PS/Fe3O4/RE3+ to Y2O3:Eu3+ mass ratio. 2.5. Drug Loading and Drug Release.

PBS buffers (pH = 7.4) with ibuprofen

concentrations of 0.1, 0.2, 0.3, 0.4, and 0.5 mg/mL were prepared. A UV spectrophotometer (λ = 264.1 nm) was used to measure the absorptions of these solutions. A standard fitting curve of ibuprofen concentration versus absorbance was calculated as follows: y = 1.838x + 0.0326, where y denotes the absorbance and x represents the concentration of ibuprofen in the PBS solution. As is well known, the drug-loading capacity of the BHM is closely related to the drug concentration used during the drug-loading process, as well as the hollow structure and pore width of the shell layer.36 Therefore, the drug-loading capacity of α-Fe2O3@Y2O3:Eu3+ BHM-0.8 was determined in a 20 mg/mL solution of ibuprofen in hexane, as excessive drug-loading concentrations may block the channels in smaller pores. Typically, fluorescent-magnetic αFe2O3@Y2O3:Eu3+ BHM-0.8 (0.20 g) was dispersed in 40 mL of a 20 mg/mL solution of ibuprofen in hexane using ultrasound, and then the mixture was sealed and oscillated for 48 h at 25 °C, after which the spheres were centrifugally separated from the solution. Hexane was used to wash off any ibuprofen that may have been adsorbed on the surface of the spheres, and the


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drug-loaded α-Fe2O3@Y2O3:Eu3+ BHMs were vacuum dried for 12 h at 40 °C. These spheres were denoted as BHM-IBU-20. Typically, the BHM-IBU-20 samples (0.1 g) were placed in PBS buffer solutions (20 mL) and sealed, and then oscillated in a thermostatic water bath at 37 °C. At specific times from the start of the experiment, i.e., 1, 2, 4, 6, 8, 12, 14, 25, and 30 h, 2 mL of the solution in the upper layer was removed, and an equal volume of PBS buffer solution was added to the mixture. The drug-release process was carried out for a total of 30 h. The extracted sample solutions were diluted appropriately, and the absorbance was measured using a UV spectrophotometer in order to calculate the amount of drug released and allow a corresponding cumulative drug-release plot to be obtained. 2.6. Characterization. X-ray powder diffraction (XRD, Rigaku 2200) was used to examine the phases of the samples, with the following measurement conditions: 10° ≤ 2θ ≤ 80°, Cu target, λ= 0.154 nm. A fluorescence spectrometer (RF-5301) was used to analyze the photoluminescence emission and excitation spectra of the hollow fluorescentmagnetic spheres. Scanning electron microscopy (SEM, Carl Zeiss) was performed with an applied voltage of 10 kV. Transmission electron microscopy (TEM, JEM2010HR) was performed with an applied voltage of 200 kV. Magnetic measurements were carried out on an MPMS XL-7 magnetometer at 300 K. A UV spectrophotometer (TU-1901) was used to measure the ibuprofen content in the PBS solutions, with a 0.1 nm step size. A N2 adsorption measurement was carried out using a Micromeritics ASAP 2020 analyzer at 77 K.

3. RESULTS AND DISCUSSION


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Scheme 1. Illustration showing the fabrication of the fluorescent-magnetic α-Fe2O3@Y2O3:Eu3+ BHMs. Scheme 1 shows the proposed synthesis of the fluorescent-magnetic α-Fe2O3@Y2O3:Eu3+ BHMs with well-defined structures. First, c-PS spheres were obtained via emulsion polymerization. Then, moderate amounts of Fe3O4 nanoparticles and RE3+ ions were attached onto the surface of the c-PS spheres via electrostatic attraction under acidic conditions (pH = 2.3), thereby forming a c-PS/Fe3O4/RE3+ hetero-aggregate template. Next, a homogeneous co-precipitation reaction was performed: urea was decomposed at approximately 90 °C to form OH- and CO32-, which then reacted with RE3+ ions to form RE(OH)CO3.37 The reaction proceeded as follows: RE3+ + (NH2)2CO + 4H2O → RE(OH)CO3·H2O + 2NH4+ + H+. It should be noted that the RE3+ ions adsorbed on the surface of c-PS/Fe3O4/RE3+ acted as nucleating agents, facilitating the growth of RE(OH)CO3 on the surface of the c-PS/Fe3O4/RE3+ hetero-aggregate template during the homogeneous co-precipitation reaction, thus forming a uniform coating layer. In contrast, c-


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PS/Fe3O4 was used as the assisted hard-template to synthesize the fluorescence-magnetic nanomaterials under the same reaction conditions, in which the c-PS/Fe3O4 to Y2O3:Eu3+ mass ratio was 0.8; the resulting bifunctional nanomaterials were denoted as BN-0.8. As shown in Figure 1a, BN-0.8 is clearly an aggregate and does not show spherical morphology (indicated by red arrows). In other words, this proves that RE3+ attached onto the surface of c-PS/Fe3O4/RE3+ acted as a nucleation agent and played an important role during the homogeneous coprecipitation reaction, helping the formation of a uniform RE(OH)CO3 coating layer on the surface of the c-PS/Fe3O4/RE3+ hetero-aggregate template. Finally, the fluorescent-magnetic αFe2O3@Y2O3:Eu3+ BHMs with well-defined hollow-cores and porous shell structures were obtained via calcination at 700 °C.

Figure 1. SEM images (all scale bars = 500 nm) of BN-0.8 (a), BHM-0.4 (b), BHM-0.8 (c), and BHM-1.0 (d). SEM images of the α-Fe2O3@Y2O3:Eu3+ BHMs with c-PS/Fe3O4/RE3+ hetero-aggregate template to Y2O3:Eu3+ mass ratios of 0.4, 0.8, and 1.0 are shown in Figure 1. All these samples displayed uniform spherical shapes (Figure 1b, c, and d), with differences only in dispersibility,


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shell morphology, and diameter. When the c-PS/Fe3O4/RE3+ to Y2O3:Eu3+ ratio was 0.4, there was an excess of RE ions, as shown by those on the surface of the c-PS/Fe3O4/RE3+ template undergoing nucleation to form the RE(OH)CO3 shell layer and self-aggregating to generate nanoparticles, causing significant aggregation of BHM-0.4 (see Figure 1b). When the cPS/Fe3O4/RE3+ to Y2O3:Eu3+ RE mass ratio was increased to 1.0, excess RE ions were no longer observed. The RE3+ ions on the surface of the c-PS/Fe3O4/RE3+ template acted as nucleating agents, causing the growth of the RE(OH)CO3 shell layer to preferentially occur on the surface of the c-PS/Fe3O4/RE3+ assisted template during the homogeneous co-precipitation process. As a result, increasing the c-PS/Fe3O4/RE3+ to Y2O3:Eu3+ mass ratio from 0.4 to 1.0 improved the dispersibility of the BHMs and caused the shell layer to become smoother. Furthermore, when the mass ratio of c-PS/Fe3O4/RE3+ to Y2O3:Eu3+ was increased to 1.0, the shell layers of a small amount of the BHMs were damaged (Figure 1d) and the sizes of the spheres varied slightly. This occurred because the increase in the c-PS/Fe3O4/RE3+ heteroaggregate template to Y2O3:Eu3+ mass ratio made the RE(OH)CO3 layer coating on the surface of the c-PS/Fe3O4/RE3+ thinner, which ultimately caused the BHM shells to become thinner (see Figure S2 and Figure 2c). Consequently, the diameter of the BHMs also decreased slightly.


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Figure 2. (a) SEM-EDS mapping images of a single bifunctional hollow microsphere, (b) TEM image of BHM-0.8 (scale bar = 400 nm), and (c) high-magnification TEM image of BHM-0.8 (scale bar = 20 nm). Energy-dispersive X-ray spectrometer (EDS) was used on the BHM-0.8 samples in combination with SEM in order to identify the compositions of the shell layers of the BHMs. Figure 2a shows an SEM image of an arbitrarily selected single bifunctional hollow microsphere, along with the corresponding energy dispersive X-ray spectrometer maps for various elements and an overlapped map showing all the elements. The EDS maps of Y, Eu, O, and Fe are consistent with the SEM image, indicating that the shell layers of the BHMs were comprised of homogenously distributed compounds containing Y, Eu, O, and Fe atoms. In addition, TEM was employed to characterize the morphology and structure of the BHMs. As shown in Figure 2b and c, BHM-0.8 exhibited a uniform spherical morphology and possessed a hollow-core structure


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with a shell layer of uniform thickness (~27 nm), which is fully consistent with the previously described SEM observations. Furthermore, it can be seen that small amounts of particles were adsorbed onto the shell layer of the BHM. High-magnification TEM characterization indicated that these particles (Figure 2c, as indicated by arrows) were composed mainly of magnetic cores embedded within the shell layer, as well as RE particles formed via self-aggregation during the homogeneous co-precipitation process.

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Figure 3. XRD patterns of BHM-0.4 (a), BHM-0.8 (b), and BHM-1.0 (c). Figure 3 shows the XRD patterns of the BHMs with c-PS/Fe3O4/RE3+ hetero-aggregate to Y2O3:Eu3+ mass ratios of 0.4, 0.8, and 1.0. Through comparisons with a standard card (PDF#330664), it can be seen that the BHMs uniformly displayed diffraction peaks that are clearly consistent with Y1.9Eu0.1O3,31, 38 with peaks at 2θ = 20.59°, 29.12°, 33.78°, 48.5°, and 57.63°, which are attributed to the (211), (222), (400), (440), and (662) crystal diffraction peaks of Y2O3:Eu3+, respectively. It should be noted that the XRD diffraction peaks of the BHMs display characteristic peaks that match those of α-Fe2O3 (PDF#25-1011) instead of Fe3O4, which may be


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because calcination at 700 °C caused a phase change in the Fe3O4 nanoparticles.23 This indicates that the shell layer of the BHMs was a composite of Y1.9Eu0.1O3 and α-Fe2O3 magnetic nanoparticles embedded within the shell layer, which is consistent with the results shown by SEM elemental analysis (Figure 2a) and high-resolution TEM observations (Figure 2c).

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Figure 4. Emission spectra of BHM with different mass ratios of c-PS/Fe3O4/RE3+ to Y2O3:Eu3+. Figure 4 shows the photoluminescence emission spectra of the fluorescent-magnetic BHMs with various mass ratios. The emission peaks of the BHMs were derived from the 5D0→7FJ (J = 1–4) energy level transition of Eu3+. The strongest emission peak at 609 nm could be attributed to Eu3+ replacing a Y3+ ion located at the C2 symmetrical position of the cubic Y2O3 crystal lattice,39 resulting in the loss of a center of symmetry and generating an electric dipole transition. Furthermore, the photoluminescence intensity of the fluorescent-magnetic BHMs decreased as the c-PS/Fe3O4/RE3+ to Y2O3:Eu3+ mass ratio increased. This was because increases in the magnetic ferrite nanoparticles would quench the fluorescence of Y2O3:Eu3+ and thus affect the


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luminescence intensity of the BHMs.40 When the mass ratio of c-PS/Fe3O4/RE3+ heteroaggregate to Y2O3:Eu3+ increased to 1.0, shell layers of the resulting BHM-1.0 were further damaged, resulting in a noticeable decline in the photoluminescence intensity. In light of the previously described morphological, structural, and fluorescence characteristics of the BHMs, it can be seen that BHM-0.8 exhibited superior structural and functional features, making it more suitable for application in drug-delivery systems.

Figure 5. Magnetic hysteresis loops of BHM-0.4, BHM-0.8, and BHM-1.0; the inset show the magnetic separation photographs of BHM-0.8 under UV irradiation at 254 nm. Figure 5 shows the magnetic hysteresis curves of the BHMs with different mass ratios at 300 K. As the mass ratio of the c-PS/Fe3O4/RE3+ hetero-aggregate to Y2O3:Eu3+ was increased from 0.4 to 1.0, the saturation magnetization values of BHM-0.4, BHM-0.8, and BHM-1.0 accordingly increased to 0.062, 0.271, and 0.318 emu/g, respectively. Thus, the saturation magnetization of the BHM can be changed by varying the mass ratio of c-PS/Fe3O4/RE3+ heteroaggregate to Y2O3:Eu3+. Figure 5 (inset a) shows a photograph of BHM-0.8 in an ethanol


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solution in the absence of an externally applied magnetic field under UV excitation at 254 nm. Figure 5 (inset b) shows the same system in the presence of an externally applied magnetic field. Figure 5 (inset a) shows that the BHM-0.8 was uniformly dispersed in the PBS solution, with an obvious red emission under UV excitation. Figure 5 (inset b) demonstrates that under the influence of an externally applied magnetic field, BHM-0.8 rapidly separated and was adsorbed on the wall of the quartz cuvette adjacent to the magnet, exhibiting an obvious red emission (indicated by the arrow). These observations demonstrate that BHM-0.8 was characterized by good dispersibility, magnetic responsiveness, and photo-luminescence in polar solutions.

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the presence of micropores.41 The PSD curve was obtained using density functional theory (DFT), and showed an obvious characteristic peak at 2.8 nm and a weak characteristic peak at 8.6 nm, both of which indicate that BHM-0.8 had the characteristics of a mesoporous material. It should be noted that the PSD peak at about 1.8 nm is mainly ascribed to slot-shaped pores formed by the shell layer owing to high-temperature calcination at 700 °C. Moreover, there is a clear H4-type hysteresis loop at a relative pressure P/P0 of 0.9–1.0, which can be attributed to the hollow-core structure of BHM-0.8.42 The result is in accordance with both the SEM and TEM observations.

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Figure 7. TG curves of samples of ibuprofen, BHM-0.8, and BHM-0.8-IBU-20. To investigate the drug-delivery ability of the BHM, the loading of ibuprofen was evaluated by thermogravimetric (TG) analysis. As shown in Figure 7, BHM-0.8 displayed a weight loss due to physically adsorbed water at around 100 °C. There was no subsequent weight loss, indicating that the shell of this BHM had a high level of thermal stability. Therefore, the drug-


17


loading capacity of BHM-0.8 can be estimated by comparing the TG variation rate before and after drug loading. The TG variation rate for BHM-0.8 and drug-loaded BHM-0.8-IBU-20 samples after heating to 750 °C was 12.60% (Figure 7), which indicates that the drug-loading capacity of BHM-0.8-IBU-20 was 126 mg/g. This was achieved due to the unique hollow-core structure of the spheres. The BHM-0.8 prepared in this work displayed slightly lower loading capacities than those shown in an earlier report,36 probably because of their lower surface areas and pore volumes.

70

pH=7.4

Accmulated released (%)

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60

50

40

30

20

10

0 0

5

10

15

20

25

30

Time (h)

Figure 8. Ibuprofen release behavior of BHM-0.8-IBU-20 in PBS solution over a 30-h period at 37 °C. To demonstrate the drug-release behavior of BHM-0.8 in biological bodies, we selected a PBS solution (pH = 7.4) that is similar to human body fluids as a dispersal fluid and examined the drug-release behavior of ibuprofen-loaded BHM-0.8-IBU-20 samples in this PBS solution. As shown in Figure 8, the release of ibuprofen by BHM-0.8-IBU-20 in the PBS solution was


18

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relatively rapid over the first 4 h, with 34.0% of the drug being released within this timeframe. After this period, the drug-release process slowed, and the total amount of ibuprofen released after 30 h was 62.8%. This may be because the pore diameters on the mesoporous shells of these functionalized hollow microspheres were relatively small (~2.8 nm), which could slow the drugrelease process in the later stages. These drug-release results indicate that BHM-0.8 showed excellent sustained-release performance in the PBS solution, and that it could be used in drug delivery systems. In addition, the toxicity of magnetic nanoparticles is also a factor that must be considered for drug delivery systems.

4. CONCLUSIONS In summary, a facile template-assisted and homogeneous co-precipitation combination method was developed for the synthesis of fluorescent-magnetic α-Fe2O3@Y2O3:Eu3+ BHMs. In this method, c-PS/Fe3O4/RE3+ hetero-aggregates were employed as an assisted template, with RE3+ ions adsorbed on the surface acting as nucleating agents that facilitated the growth of Y(OH)CO3 during the homogeneous co-precipitation process, leading to the formation of a uniform coating layer on the template surface. Calcination was then carried out to remove the c-PS to obtain a hollow-core structure. Moreover, simply varying the c-PS/Fe3O4/RE3+ hetero-aggregates to Y2O3:Eu3+mass ratio allowed us to prepare fluorescent-magnetic BHMs with good dispersibilities, uniform spherical shapes, and fluorescent-magnetic properties. Emission spectra, magnetic tests, and drug loading and release experiments showed that BHM-0.8 exhibited photofluorescence and magnetic responsiveness, as well as having excellent drug-loading capacities and sustained-release profiles. Therefore, fluorescent-magnetic BHM-0.8 is expected to be employed in targeted nanoscale drug delivery systems for therapeutic treatment of


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cancerous tumors. Additionally, we believe similar approaches can be used for the development of certain fluorescent-magnetic nanocomposites with unique hollow core and mesoporous shell structures.

SUPPORTING INFORMATION Electronic Supplementary Information (ESI) available: Figure S1 and S2, including molecular structure of ibuprofen, TEM images of BHM-0.4. This material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGMENTS The authors are grateful for the support of the National Natural Science Foundation of China (Grant 31200438), Hunan Provincial Natural Science Foundation of China (Grant 2015JJ2199), and Doctoral Program Foundation of Institutions of Higher Education of China (Grant 20124321120002). We greatly thank Mr. Qunjie Li for experimental assistance.

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