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Biomaterials 30 (2009) 4786–4795

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Biomaterials

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A magnetic, luminescent and mesoporous core–shell structured compositematerial as drug carrier

Piaoping Yang a,b, Zewei Quan a, Zhiyao Hou b, Chunxia Li a, Xiaojiao Kang a, Ziyong Cheng a, Jun Lin a,*

a State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR Chinab College of Materials Science and Chemical Engineering, Harbin Engineering University, Harbin 150001, PR China

a r t i c l e i n f o

Article history:Received 3 May 2009Accepted 18 May 2009Available online 10 June 2009

Keywords:Drug deliveryMagnetismLuminescenceCore–shellMesoporous

* Corresponding author. Fax: þ86 431 85698041.E-mail address: jlin@ciac.jl.cn (J. Lin).

0142-9612/$ – see front matter � 2009 Elsevier Ltd.doi:10.1016/j.biomaterials.2009.05.038

a b s t r a c t

In this paper, hydrothermal synthesized Fe3O4 microspheres have been encapsulated with nonporoussilica and a further layer of ordered mesoporous silica through a simple sol–gel process. The surface ofthe outer silica shell was further functionalized by the deposition of YVO4:Eu3þ phosphors, realizinga sandwich structured material with mesoporous, magnetic and luminescent properties. The multi-functional system was used as drug carrier to investigate the storage and release properties usingibuprofen (IBU) as model drug by the surface modification. X-ray diffraction (XRD), scanning electronmicroscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectra (XPS), Fouriertransform infrared spectroscopy (FT-IR), N2 adsorption/desorption, photoluminescence (PL) spectra, andsuperconducting quantum interference device (SQUID) were used to characterized the samples. Theresults reveal that the material shows typical ordered mesoporous characteristics, and have mono-disperse spherical morphology with smooth surface and narrow size distribution. Additionally, themultifunctional system shows the characteristic emission of Eu3þ (5D0–7F1–4) even after the loading ofdrug molecules. Magnetism measurement reveals the superparamagnetic feature of the samples. Drugrelease test indicates that the multifunctional system shows drug sustained properties. Moreover, theemission intensities of Eu3þ in the drug carrier system increase with the released amount of drug, thusmaking the drug release be easily tracked and monitored by the change of the luminescence intensity.

� 2009 Elsevier Ltd. All rights reserved.

1. Introduction

Ordered mesoporous silica materials have been the subject ofintensive research during the past decades [1–5], due to theirunique properties including stable mesoporous structure, tunablepore size, high specific surface area, and well modifiable surface,which endow them with great potential applications in the fields ofcatalysis [6,7], sensing [8], and optically active materials [9].Recently, there has also been considerable attention in modifyingthe host matrices to either increase the magnetism or introducenew functional groups [10–12]. The combination of mesoporoussilica with magnetic or/and luminescent functional groups to formcore–shell structured composite is undoubtedly of special interestin diagnostic analysis [13], enzyme immobilization [14], bio-separation [15], and controlled drug release [16–18] based on theirunique magnetic responsivity, visible luminescence, low cytotox-icity, good biocompatibility, and mesoporous properties.

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Up to now, there have been a few reports on the preparation ofmultifunctional microspheres consisting of a magnetite core witha mesoporous shell [19–30]. The uniform-sized magnetic core wasusually prepared via a hydrothermal process [22], or high-temperature decomposition method [23]. The formation of thecore–shell structured composites is conventionally followed by anencapsulation process, where the magnetite core is encapsulatedby the silica shell using a sol–gel technique. And the luminescentmaterials in general, organic dyes [21,24,31] or CdSe/ZnS [22,23]quantum dots (QDs), are either subsequently attached, or form partof the shell, resulting in the formation of the core–shell structuredmaterials with luminescent and magnetic properties. However, thephotobleaching and quenching of dye molecules and the toxicity ofQDs (from heavy metal ions such as Cd2þ or Pb2þ) have seriouslylimited their applications in biomedical areas, especially for use inhuman body [26]. Furthermore, high performance in function-specific biological applications requires that the composites possesssome unique features, such as spherical morphology, smoothsurfaces, narrow size distributions, large surface areas (for drug,maximal protein or enzyme binding), high saturation magnetiza-tion to provide maximum signal, and good dispersion in liquid

P. Yang et al. / Biomaterials 30 (2009) 4786–4795 4787

media [10,32–35]. Therefore, the design of core–shell structuredmicrospheres with these special properties should be highlypotential in various fields.

As suitable alternatives for dyes and QDs, lanthanide-dopedinorganic nanocrystals seem to be a promising fluorescent materialfor biodetection due to their good optical properties, high chemicaland photochemical stability and low toxicity [36,37]. However, sofar little attention has been paid to the combination of lanthanide-doped luminescent materials with magnetite materials due to thequenching effect of lanthanide luminescence by the Fe3O4

magnetite when they mix together [38,39]. Thus, the design of aninert layer that can effectively separate lanthanide based lumi-nescent component from the magnetite seems very important inprotecting the luminescence from quenching by magnetite. Herein,we propose a strategy for the fabrication of a novel monodisperse,core–shell structured drug storage/release system with a sphericalsilica-coated magnetite as core and ordered mesoporous silica asshell, which is further functionalized by the deposition of phosphorlayer through a sol–gel process. This multifunctional compositematerial that possesses excellent magnetic, mesoporous, andluminescent properties was further applied to the uptake andcontrolled release of ibuprofen (IBU) model drugs. It is shown thatthis composite is an ideal system for targeting drug delivery via itssuperparamagnetic feature, and the luminescence property can beused to track the position and release efficiency of the drugs. Herewe select relatively larger Fe3O4 submicrospheres (300 nm) insteadof smaller ones (<50 nm) in order to obtain larger magnetizationfor drug targeting, and UV-excitable Eu3þ (YVO4:Eu3þ, a well

TEOS

TEOS + CTAB

PL functionalizawith YVO4:Eu3+

Fe3O4

Fe3O4@nSiO2

Fe3O4@nSiO2@

Extractionof CTAB

Fe3O4@nSiO2@mSiO2 Fe

CTAB

Scheme 1. The formation process of the multifunctional Fe3

known efficient phosphor) instead of upconverting (near infrared-excitable) lanthanide ion (Er3þ) to achieve suitable luminescenceintensity to correlate it with the extent of drug release.

2. Materials and methods

2.1. Synthesis of Fe3O4@nSiO2@mSiO2 microspheres

2.1.1. Synthesis of spherical Fe3O4 particlesAll the chemical agents used in this experiment were of analytical grade and

were used without further purification. The spherical magnetic particles wereprepared according to the literature with some modification [14]. Typically, 4.04 g ofFe(NO3)3$6H2O and 8.20 g of sodium acetate were dissolved in 100 mL of ethyleneglycol (EG) with stirring. After stirred for 30 min, the obtained solution was trans-ferred to a Teflon-lined stainless-steel autoclave and heated at 200 �C for 8 h. Thenthe autoclave was naturally cooled to room temperature. The obtained blackmagnetite particles were washed with ethanol for several times, and dried invacuum at 60 �C for 12 h.

2.1.2. Synthesis of Fe3O4@nSiO2@mSiO2 spheresThe core–shell structured Fe3O4@nSiO2 microspheres were prepared via

a modified Stober sol–gel process [40]. In a typical procedure, 0.10 g of obtainedspherical Fe3O4 particles was treated using 0.1 M HCl solution by ultrasonication for20 min. Subsequently, the treated particles were separated by centrifugation,washed with deionized water, and then well dispersed in the mixture solution of80 mL of ethanol, 20 mL of deionized water, and 1.0 mL of concentrated ammoniaaqueous solution (28 wt.%). After this, 0.03 g of tetraethoxysilane (TEOS) was addeddropwise to the solution. After stirred at room temperature for 6 h, the obtainedparticles were separated and washed with ethanol and water, and re-dispersed ina mixed solution containing 0.30 g of cetyltrimethylammonium bromide (CTAB),80 mL of deioned water, 1.0 g of concentrated ammonia aqueous solution (28 wt.%),and 60 mL of ethanol. After the solution was stirred for 0.5 h, 0.40 g of TEOS wasadded dropwise to the solution with vigorous stirring. After reaction for 6 h, the

tion

CTAB/mSiO2

3O4@nSiO2@mSiO2@YVO4:Eu3+

O4@nSiO2@mSiO2@YVO4:Eu3þ composite microspheres.

1 2 3 4 5 6

3.5 4.0 4.5 5.0

(b)

200

Inte

nsity

(a. u

.)

2θ (degree)

110

(a)

(b)

In

te

ns

ity

(a

. u

.)

2θ (degree)

(a)

100

X 5

Fig. 1. Low-angle XRD patterns of Fe3O4@nSiO2@mSiO2 (a), and Fe3O4@nSiO2-@mSiO2@YVO4:Eu3þ (b).

10 20 30 40 50 60 70 80

JCPDS 19-0629

111 44

0

2θ (degree)

551

422

400

311

YVO4

* (c)

(b)

In

ten

sity (a. u

.)

(a)

*

220

SiO2

*

Fig. 2. Wide-angle XRD patterns of pure Fe3O4 (a), Fe3O4@nSiO2@mSiO2 (b), andFe3O4@nSiO2@mSiO2@YVO4:Eu3þ (c), and the standard data for magnetite (JCPDS No.19-0629).

P. Yang et al. / Biomaterials 30 (2009) 4786–47954788

product was collected with a magnet and washed several times with ethanol andwater. The above coating process was repeated twice. The structure-directing agent(CTAB) was subsequently removed by ultrasonication in acidic (HCl) ethanol (about0.12 w/w) for three times. The obtained precipitate was separated, washed withdeionized water, and dried in vacuum at 60 �C for 12 h. The produced microsphereswere designated as Fe3O4@nSiO2@mSiO2.

2.2. Luminescence functionalization of Fe3O4@nSiO2@mSiO2 by YVO4:Eu3þ

Functionalization of YVO4:Eu3þ on the template free Fe3O4@nSiO2@mSiO2 wasachieved according to the reported process with the doping concentration of Eu3þ of5 mol% to Y3þ in YVO4:Eu3þ [41–43]. Typically, 0.429 g (1.9 mmol) of Y2O3, 0.0352 g(0.1 mmol) of Eu2O3, and 0.232 g (2 mmol) of NH4VO3 were dissolved in dilute HNO3

and then added to a water–ethanol solution (v/v¼ 1/7). Then 0.84 g of citric acid(4 mmol) was added as a chelating agent. Then polyethylene glycol (PEG) was addedas a cross-linking agent with a concentration of 0.04 g/mL. After stirred for 1 h,a homogenous sol was formed. Then desired amount of treated Fe3O4@nSiO2@mSiO2

powders was added into the sol with stirring. After further stirred for another 3 h,the resulting material was separated by centrifugation, dried at 100 �C for 1 h, thenheated from room temperature to 500 �C with a heating rate of 1 �C/min andmaintained at this temperature for 2 h. The obtained material was denoted asFe3O4@nSiO2@mSiO2@YVO4:Eu3þ.

2.3. Silica shell modified with amino groups

The obtained sample was dried under vacuum at 100 �C for 6 h to removeadsorbed water. To modify the silica surface with amino groups, 0.3 mL of 3-(amino-propyl) triethoxysilane (APTS) was added to 20 mL of toluene solution ofFe3O4@nSiO2@mSiO2@YVO4:Eu3þ and stirred for 24 h. After the reaction, theprepared sample was centrifuged and further washed with ethanol and toluene. Theas-prepared material was denoted as Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ–NH2.

2.4. Preparation of drug storage/release system

The drug storage system was prepared according to the previous reports withsome modifications [44–48]. Briefly, 0.3 g of Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ wasadded to 50 mL of hexane–IBU solution with IBU concentration of 60 mg/mL, andsoaked in a sealed vial for 24 h with stirring. Then the IBU adsorbed particles wereseparated by centrifugation for 10 min at 4500 rpm, washed several times withhexane to remove adsorbed IBU on the exterior surface. Finally, the sample wasdried at 60 �C for 12 h, which was denoted as IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ.

The in vitro release test of IBU was performed by immersing 0.3 g of the samplein the release media of simulated body fluid (SBF) with mild stirring, and theimmersing temperature was kept at 37 �C. The ionic composition of the as-preparedSBF solution was similar to human body plasma (142.0/5.0/2.5/1.5/147.8/4.2/1.0/0.5¼Naþ/Kþ/Ca2þ/Mg2þ/Cl�/HCO3

�/HPO42�/SO4

2�) (pH¼ 7.4) [23,45]. Filtrate(1.0 mL) has been sucked and properly diluted to determine the loading amount ofthe drug by UV–vis spectrophotometer. In a typical procedure for determining therelease amount, 1 mL of the solution was withdrawn at predetermined time inter-vals and immediately replaced by an equal volume of SBF to keep the volumeconstant. The withdrawn solution was properly diluted and monitored for ibuprofencontent at 222 nm using UV–vis spectrophotometer.

The formation process of the Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ microspherestogether with the corresponding pellet photographs under the irradiation of 254 nmUV lamp is shown in Scheme 1.

2.5. Characterization

Powder XRD patterns were obtained on a Rigaku-Dmax 2500 diffractometerusing Cu Ka radiation (l¼ 0.15405 nm). The morphologies and structures of the as-prepared samples were inspected on a field emission scanning electron microscope(FESEM, S4800, Hitachi) equipped with an energy-dispersive X-ray spectrum (EDS,JEOL JXA-840). TEM and high-resolution TEM (HRTEM) were performed on a FEITecnai G2 S-Twin transmission electron microscope with a field emission gunoperating at 200 kV. The X-ray photoelectron spectra (XPS) were measured on anECSALAB 250. Fourier Transform IR spectra were recorded on a Perkin–Elmer 580BIR spectrophotometer using KBr pellet technique. Nitrogen adsorption/desorptionanalysis was measured at a liquid nitrogen temperature (77 K) using a MicromeriticsASAP 2010M instrument. The specific surface areas were calculated by theBrunauer–Emmett–Teller (BET) method. The total pore volume was obtained fromthe t-plot method. The photoluminescence (PL) excitation and emission spectrawere performed on a Hitachi F-4500 spectrofluorimeter equipped with a 150 Wxenon lamp as the excitation source. The UV–vis adsorption spectral values weremeasured on a TU-1901 spectrophotometer. Magnetization measurements wereperformed on an MPM5-XL-5 superconducting quantum interference device(SQUID) magnetometer at 300 K. All the measurements were performed at roomtemperature.

3. Results and discussion

3.1. Phase, formation, morphology and structure of as-preparedFe3O4@nSiO2@mSiO2 and Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ

Fig. 1 shows the low-angle XRD patterns of Fe3O4@nSiO2@mSiO2

and Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ. A strong (100) peak withtwo low (110) and (200) peaks in the low-angle XRD pattern(Fig. 1b) reveals the ordered mesopore symmetry for theFe3O4@nSiO2@mSiO2@YVO4:Eu3þ samples, suggesting the mainte-nance of the mesoporous structure with respect to Fe3O4@-nSiO2@mSiO2 sample (Fig. 1a). The decrease of the intensity of (100)peak for the YVO4:Eu3þ loaded sample may be due to the coating ofthe luminescent layer, which results in the decrease of order of theuniform mesopore structure.

The wide-angle XRD patterns of pure Fe3O4, Fe3O4@nSiO2@-mSiO2, Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ, and the standard data formagnetite (JCPDS No. 19-0629) are displayed in Fig. 2. ForFe3O4@nSiO2@mSiO2 (Fig. 2b), the broad band at 2q¼ 22� can beassigned to the amorphous SiO2 shell (JCPDS No. 29-0085). The

P. Yang et al. / Biomaterials 30 (2009) 4786–4795 4789

other diffraction peaks can be readily indexed to a face-centeredcubic structure (Fd3m space group) of magnetite according to JCPDScard No. 19-0629. In the case of Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ

(Fig. 2c), besides the characteristic diffractions of amorphous SiO2

and cubic Fe3O4, the obvious diffraction peaks at 2q¼ 25.0� and49.5� can be indexed to the tetragonal phase of YVO4 (JCPDS No. 17-0341), suggesting the successful crystallization of YVO4:Eu3þ on thesurface of mesoporous silica shell. Additionally, no additional peaksfor other phases can be detected, indicating that no reactionoccurred between core and shell during the annealing process.

Fig. 3. SEM images of pure Fe3O4 with low (a) and high (b) magnification, Fe3O4@nSiO2@mS(e) and high (f) magnification, and the EDS spectrum of Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (

FESEM images of pure Fe3O4, Fe3O4@nSiO2@mSiO2, andFe3O4@nSiO2@mSiO2@YVO4:Eu3þ microspheres with differentmagnifications together with the EDS of Fe3O4@nSiO2@m-SiO2@YVO4:Eu3þ are shown in Fig. 3, respectively. From the SEMimage for the pure Fe3O4 (Fig. 3a), we can observe that the as-prepared magnetite consists of monodisperse microspheres witha mean particle size of 300 nm and rough surface. These particlesare non-aggregated with narrow size distribution. Fig. 3b showsthat the Fe3O4@nSiO2@mSiO2 particles still keep the morphologicalproperties of pure Fe3O4 except for a slightly larger particle size

iO2 with low (c) and high (d) magnification, Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ with lowg).

Fig. 4. TEM images of pure Fe3O4 (a), Fe3O4@nSiO2@mSiO2 (b), Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (c and d), HRTEM (f), and SAED (g) images of Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ.

P. Yang et al. / Biomaterials 30 (2009) 4786–47954790

about 30 nm, which may be caused by the coating of nonporoussilica through a sol–gel approach and further deposition of mes-oporous silica on the surface of the magnetic core. Interestingly,the Fe3O4@nSiO2@mSiO2 microspheres exhibit much smoothersurface than that of pure Fe3O4 (Fig. 3b), further confirming theuniform coating of silica shell. As for Fe3O4@nSiO2@mSiO2-@YVO4:Eu3þ, the morphological features are much similar toFe3O4@nSiO2@mSiO2, such as the spherical morphology, non-aggregation, smooth surface, and narrow size distribution.Furthermore, no irregular particles related with the introducedphosphors are detected. The results suggest that the deposition haslittle influence on the spherical morphology and the phosphorlayer uniformly disperses on the silica surface. The EDS (Fig. 3g)confirms the presence of silicon (Si), oxygen (O), yttrium (Y),vanadium (V), and iron (Fe) in the Fe3O4@nSiO2@mSiO2-@YVO4:Eu3þ sample (the C signal is from the C membrane formeasurement).

The morphological and structural features of the samples werefurther examined by TEM, as shown in Fig. 4. TEM images obviouslyindicate that monodisperse microspheres with narrow size

distribution are obtained for all the samples, which are wellconsistent with the corresponding SEM images. Additionally, fromthe TEM images of the Fe3O4@nSiO2@mSiO2 and Fe3O4@nSiO2@m-SiO2@YVO4:Eu3þ particles (Fig. 4b and c), the core–shell structurecan be clearly distinguished due to the different electron penetra-bility between the cores and shells. The magnetic cores are blackspheres with an average size of about 300 nm, and the silica shellshows gray color with an average thickness of 30 nm (inset ofFig. 4b and c). Notably, quasi hexagonal mesopore channels areclearly found to be perpendicular to the spheres’ surface (Fig. 4d).The calculated distance (4 nm) of the mean pore size just corre-sponds to the d100 value (3.9 nm) in the low-angle XRD patterns(Fig. 1). Moreover, the obvious lattice fringes in the HRTEM image(Fig. 4f) further confirm the high crystallinity of the sample, whichis in good agreement with the wide-angle XRD results (Fig. 2). Thedistances of 0.35 nm between the adjacent lattice fringes are inagreement with the d200 spacing (0.355 nm) of the tetragonal YVO4

phase (JCPDS No. 17-0341). The selected-area electron diffraction(SAED, Fig. 4g) reveals the polycrystalline feature of the as-prepared product.

P. Yang et al. / Biomaterials 30 (2009) 4786–4795 4791

XPS have been tested as a useful tool for qualitatively deter-mining the surface component and composition of a sample. Thesurvey and the respective element XPS of Fe3O4@nSiO2@mSiO2-@YVO4:Eu3þ are given in Fig. 5. The binding energy of V (3p,516.5 eV), Y (3d5/2, 157.1 eV), O (1s, 529 eV), and Si (2p, 103.3 eV) isobvious. By combination of the XRD result, it can be concluded thatthese signals can be assigned to Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ

microspheres. It should be noted that the binding energy of iron(Fe) can’t be detected in the XPS. This may be due to the limitationof XPS analysis which can’t penetrate the silica shell with thethickness of 30 nm.

The FT-IR spectra of Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ, IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ, and IBU are given in Fig. 6. Inthe FT-IR spectrum of Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (Fig. 6a),

1200 1000 800 600 400 200 0

115 110 105 100 95

C1s

Y3d

In

ten

sity (a

. u

.)

Binding energy (eV)

O1s

Si2p

In

ten

sity (a. u

.)

Binding energy (eV)

Si2p

170 165 160 155 150

In

ten

sity (a. u

.)

Binding energy (eV)

Y3d

Fig. 5. XPS of Fe3O4@nSiO

the strong bands of OH (3429 cm�1) and H2O (1635 cm�1)suggest that a large number of OH groups and H2O moleculesexist on the surface, which play a key role for adsorbing IBUmolecules by hydrogen bond. The absorption bands related withSi–O–Si (1092 cm�1 and 809 cm�1), Si–OH (950 cm�1), Si–O(469 cm�1), and Fe-O (579 cm�1 and 639 cm�1) are also present.For IBU loaded IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (Fig. 6b),the band assigned to –COOH (1720 cm�1) is apparent except fora slight intensity decrease compared with pure IBU (Fig. 6c).Moreover, the absorption bands of the quaternary carbon atom at1461 and 1518 cm�1, tertiary carbon atom at 1338 cm�1, and C–Hx

bond at 2890 cm�1 are also clear [49], confirming the successfulincorporation of IBU onto the surface of the outer mesoporoussilica.

545 540 535 530 525

530 525 520 515 510Binding energy (eV)

In

ten

sity (a

. u

.)

V3p

Binding energy (eV)

In

ten

sity (a. u

.)

O1s

2@mSiO2@YVO4:Eu3þ.

4000 3500 3000 2500 2000 1500 1000 500 0

CH2

2890

3429

639

579

(a)46980

9Si

-OH

950

1092

(c)

(b)

Tra

ns

mitta

nc

e (%

)

Wavenumber (cm-1

)

OH

3429

1635

H2O

Si-O-Si

1720

Fig. 6. FT-IR spectra of Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (a), IBU–Fe3O4@nSiO2-@mSiO2@YVO4:Eu3þ (b), and pure IBU (c).

200 250 300 350 400 550 600 650 700 750

(b)

In

te

ns

ity

(a

. u

.)

Wavelength (nm)

698

5 D0-

7 F4

649

5 D0-

7 F3

615

5 D0-

7 F2

590

5 D0-

7 F1

276

λex = 276 nmλem = 615 nm

(a)

Fig. 8. Excitation (left) and emission (right) spectra of Fe3O4@nSiO2@mSiO2-@YVO4:Eu3þ (a), IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (b).

P. Yang et al. / Biomaterials 30 (2009) 4786–47954792

The N2 adsorption/desorption isotherms of Fe3O4@nSiO2@m-SiO2 and Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ are shown in Fig. 7. Asshown, all the samples exhibit typical VI-typed isotherms with H1-hysteresis loops, which are usually related with hexagonal cylin-drical channels. The result reveals that deposition of phosphor layeron the surface of outer silica hasn’t changed the basic pore structureof the Fe3O4@nSiO2@mSiO2 sample. The BET surface area and totalpore volume of Fe3O4@nSiO2@mSiO2 are calculated to be 378 m2/gand 0.41 cm3/g, respectively. For the YVO4:Eu3þ deposited sample,the respective BET surface area and pore volume are 328 m2/g and0.31 cm3/g, which is much similar to those of the un-doped sample.In the case of APTS modified sample, the corresponding BET surfacearea and pore volume are reduced to 217 m2/g and 0.27 cm3/g,respectively. The N2 adsorption/desorption results suggest that thefunctionalization of phosphor layer and further amino groups havenot altered the mesopore nature and suitability as drug carriers.

3.2. Photoluminescent and magnetic properties ofFe3O4@nSiO2@mSiO2 and Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ

The representative photographs of Fe3O4@nSiO2@mSiO2-@YVO4:Eu3þ and Fe3O4@nSiO2@mSiO2 under UV lamp irradiation

0.0 0.2 0.4 0.6 0.8 1.0

0

50

100

150

200

(a)(b)

Vo

lu

me A

dso

rb

ed

(cm

3/g

)

Relative Pressure (P/P0)

Fig. 7. N2 adsorption/desorption isotherms of Fe3O4@nSiO2@mSiO2 (a) andFe3O4@nSiO2@mSiO2@YVO4:Eu3þ (b).

(254 nm) are shown in Scheme 1. As shown, red luminescence canbe found from Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ, whereas noemission can be observed from Fe3O4@nSiO2@mSiO2.1 The resultconfirms the successful crystallization of YVO4:Eu3þ on the surfaceof outer silica.

The PL properties of the samples were further characterized byexcitation and emission spectra, as shown in Fig. 8. In the excitationspectra (Fig. 8, left), the strong excitation band at 276 nm moni-tored with 615 nm emission of Eu3þ (5D0 / 7F2) can be due to theVO4

3� group [43,50]. No obvious f / f transition lines of Eu3þ can befound because of their low intensity with respect to that of VO4

3�

group, indicating that the excitation of Eu3þmainly results from theenergy transform from VO4

3� to Eu3þ. In the emission spectra (Fig. 8,right) obtained by the excitation at 276 nm, the characteristictransition lines of Eu3þ (5D0 / 7FJ, J¼ 1–4) can be observed [51]. Noemission lines from VO4

3� groups are detected, indicating an effi-cient energy transfer from VO4

3� to Eu3þ. The labeled characteristicpeak in the red region originating from 5D0 / 7F2 (615 nm) tran-sition is clearly dominant, which may be due to the low localsymmetry (D2d) for the sites of Eu3þ in the YVO4 host lattices [43].Particularly, the characteristic emission and excitation peaks arestill obvious except for the decrease of intensity for IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (Fig. 8b). This reveals that thesystem can be easily tracked or monitored during the releaseprocess.

The magnetic properties of the microspheres were character-ized using a superconducting quantum interference device (SQUID)magnetometer measured at 300 K. Magnetic measurement showsthat pure Fe3O4, Fe3O4@nSiO2@mSiO2, Fe3O4@nSiO2@mSiO2-@YVO4:Eu3þ, and IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ havemagnetization saturation values of 108.3, 45.9, 36.3 and 21.3 emu/g,respectively. It should be noted that the IBU loaded sample stillshows high magnetization, indicating its suitability for targetingand separation as a drug carrier. The magnified hysteresis loops(Fig. 9A) confirm the superparamagnetic feature for all the samples.Moreover, the multifunctional spheres with homogenous disper-sion show fast response to the external magnetic field due to itshigh magnetization and no residual magnetism is detected

1 For interpretation of the references to colour in this text, the reader is referredto the web version of the article.

0 10 20 30 40 50 60 70 800

20

40

60

80

100

(a)(b)(c)

Re

le

as

e o

f IB

U(%

)

Time (hour)

Fig. 10. Cumulative IBU releases from the IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (a),IBU–Fe3O4@nSiO2@mSiO2 (b) and IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ–NH2 (c)systems versus release time.

0 20 40 60 80 1000

1000

2000

3000

4000

5000

6000

7000

Release of IBU (%)

PL

In

ten

sity (a. u

.)

Fig. 11. PL emission intensity of Eu3þ in IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ asa function of cumulative released IBU.

-6000 -4000 -2000 0 2000 4000 6000-150

-100

-50

0

(a)(b)(c)(d)

50

100

150

Ma

gn

etiza

tio

n (e

mu

/g

)

Applied Field (Oe)

A

B

30 second

Fig. 9. (A) The magnetic hysteresis loops of pure Fe3O4 (a), Fe3O4@nSiO2@mSiO2 (b),Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ (c), IBU–Fe3O4@nSiO2@mSiO2@YVO4: Eu3þ (d); (B)The separation process of the IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ microspheres.

P. Yang et al. / Biomaterials 30 (2009) 4786–4795 4793

(Fig. 9B). The result reveals that the particles exhibit good magneticresponsible and re-disperse properties, which suggests a potentialapplication for targeting and separation.

3.3. Drug loading and release properties

To study the drug storage and release properties of this systemas a candidate of drug carriers, IBU was selected as a model drug,which has been extensively investigated for sustained andcontrolled drug delivery due to its short biological half-life (2 h),good pharmacological activity and the suitable molecule size(1.0� 0.6 nm). An additional sample was prepared by furtherfunctionalization with APTS for obtaining the sample with –NH2

groups. Ibuprofen was absorbed onto the surface of the sampleswith silanol groups or amino groups for the APTS modified sample,respectively. IBU molecules have been absorbed on the silicasurface and released via a diffusion-controlled mechanism [52].The loading amounts of IBU in IBU–Fe3O4@nSiO2@mSiO2, IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ, and IBU–Fe3O4@nSiO2@mSiO2-@YVO4:Eu3þ–NH2 are 181 mg IBU/g, 125 mg IBU/g and 109 mg IBU/g, respectively. The decrease of IBU loading can be ascribed to thereduction of surface area by the surface modification. The cumu-lative drug release profiles of this multifunctional system versusrelease time in SBF are depicted in Fig. 10. It can be seen that bothIBU–Fe3O4@nSiO2@mSiO2 and IBU–Fe3O4@nSiO2@mSiO2-@YVO4:Eu3þ systems show a release of over 50% within 4 h, andmore than 95% of the adsorbed IBU has been released within 72 h,indicating a sustained property for the luminescence modifiedsample. The relatively quick drug release may be due to the weak

interaction between the Si–OH groups and carboxyl groups ofibuprofen. While the APTS modified sample exhibits an improvedsustained property which can markedly delay the release of IBU(Fig. 10c). For example, only 75% of adsorbed ibuprofen is releasedfrom the carrier even after 72 h incubation, suggesting that thefavorable ionic interaction between the amino groups and thecarboxyl group of ibuprofen prevents the easy release of ibuprofen.This reveals that the release rate of IBU from the systems can betuned by the surface modification of the silica surface.

Moreover, here it is of great interest and importance to note therelationship between the PL emission intensity of IBU–Fe3O4@nSiO2@mSiO2@YVO4:Eu3þ system and the cumulativereleased amount of IBU, as shown in Fig. 11. We can see that the PLintensity increases with the cumulative released drug until IBU iscompletely released. This may be related with the quenching effectof Eu3þ emission caused by the organic groups with high vibrationfrequencies (between 1000 and 3500 cm�1) in IBU molecules [53].The quenching effect is weakened with the drug release amount,resulting in the enhancement of PL intensity. This correlationbetween the PL intensity and drug release extent can be potentiallyused as a probe for monitoring the drug release and efficiency.

P. Yang et al. / Biomaterials 30 (2009) 4786–47954794

4. Conclusions

In summary, monodisperse magnetite (Fe3O4) microsphereshave been successfully encapsulated by mesoporous silica usingCTAB as template, and the luminescent layer has been coated on thesurface of outer mesoporous silica. The as-prepared core–shellstructured material possesses ordered hexagonal mesopores,bright luminescence, and high magnetization saturation value. Thismultifunctional system shows good sustained properties by thesurface modification, which can be potentially used as targeteddrug delivery system, in which the drug release amount can bemonitored by the change of the emission intensity. Enlightened bythis study, further research can be extended to the effects of themagnetite size on the drug storage/release property, and thecombination of upconversion nanophosphors with the magneticnanoparticles (<50 nm) that would be very promising for in vivobiomedical labels and controlled drug release system using 980 nmnear infrared as the excitation source (optical windows of humantissues).

Acknowledgements

This project is financially supported by National Basic ResearchProgram of China (2007CB935502), and the National NaturalScience Foundation of China (NSFC 50702057, 50872131, 00610227,20871035).

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