Controllable Fabrication of Rare-earth-doped Gd2O2SO4@SiO2

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Controllable Fabrication of Rare-earth-doped Gd2O2SO4@SiO2 Double-Shell Hollow Spheres for Efficient Upconversion Luminescence and Magnetic Resonance Imaging Fashen Chen, Cejun Yang, Xiaohe Liu, Ning Zhang, Pengfei Rong, Shuquan Liang, and Renzhi Ma ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b01828 • Publication Date (Web): 22 Jun 2018 Downloaded from http://pubs.acs.org on June 25, 2018

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ACS Sustainable Chemistry & Engineering

Controllable Fabrication of Rare-earth-doped Gd2O2SO4@SiO2 Double-Shell Hollow Spheres for Efficient Upconversion Luminescence and Magnetic Resonance Imaging Fashen Chen,† Cejun Yang,‡ Xiaohe Liu,*† Ning Zhang,† Pengfei Rong,‡ Shuquan Liang,† Renzhi Ma*§

†

State Key Laboratory of Powder Metallurgy and School of Materials Science and

Engineering, Central South University, No.932 South Lushan Road, Changsha, Hunan 410083, China

‡

Department of Radiology, The Third Xiangya Hospital, Central South University, No. 172

Tongzipo Road, Changsha, Hunan 410013, P. R. China

§

International Center for Materials Nanoarchitectonics (MANA), National Institute for

Materials Science (NIMS), Namiki 1-1, Tsukuba, Ibaraki 305-0044, Japan.

Corresponding Author

* E-mail: [email protected] (X. L.), [email protected] (R. M.)

Keywords: rare-earth compound, hollow spheres, upconversion, magnetic resonance imaging

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Abstract Uniform hollow spheres of Yb and Er co-doped Gd2O2SO4 (noted as Gd2O2SO4:Yb,Er) have been developed as novel bifunctional contrast agents for efficient upconversion optical and magnetic resonance imaging (MRI) for the first time. Gd-containing organic precursory spheres were first obtained by a facile hydrothermal process. Owing to the innate hydrophilic nature of the precursory spheres, surface modification with a layer of stable and biocompatible silica could be readily achieved through the Stöber sol-gel method and subsequent calcination. The morphology and thickness of the silica shell can be tailored by adjusting the reaction time. Compared with Gd2O2SO4:Yb,Er hollow spheres without silica coating, well-dispersed Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres could generate intense upconversion fluorescence, and showed a significant contrast enhancement of T1-weighted MRI both in vitro and in vivo. These gadolinium oxysulfate-based hollow spheres are thus regarded as a new type of potential bimodal optical-MRI contrast agents. Introduction

Magnetic resonance imaging (MRI), making use of the nuclear magnetic resonance signals provided by the relaxation of water protons in various tissues, is a widely applied noninvasive clinical diagnostic tool with high spatial resolution and deep tissue penetration. But MRI is still poor in sensitivity.1-3 Meanwhile, upconversion optical imaging, which converts the low-energy near infrared excitation light into higher-energy visible emission, is another noninvasive diagnostic tool with high molecular-level sensitivity and resolution owing to the absence of autofluorescence, the decrease of light scattering, and deep penetration of near 2 ACS Paragon Plus Environment

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infrared excitation light in tissue. However, upconversion optical imaging fails to provide adequate anatomic details as achieved by MRI.4-7 The combination of multiple complementary imaging modalities such as optical-MRI has thus been initiated to increase the accuracy of imaging and diagnosis, as well as broaden the applicability.7-9 Various hybrid nanomaterials (based on metal complexes of Gd, Y, Mn, Fe, and Cu) have been evaluated as bimodal optical-MRI contrast agents.10-14 In particular, due to the merit of Gd3+ ions with seven unpaired electrons, gadolinium-based compounds are regarded as an effective longitudinal relaxation (T1) contrast agent in MRI.15 Recently, gadolinium-based nanomaterials including chelates,16,17 fluorides,18 phosphates,19 vanadates,20 oxides,21 sulfides,22 and oxysulfides,23 have been developed as bimodal optical-MRI contrast agents. They showed evident signal enhancement, allowing a more accurate diagnosis compared to the conventional single imaging modality. Nevertheless, for practical biomedical applications as contrast agents, it needs to further improve the dispersability, stability, and compatibility of these nanomaterials. Silica coating on such nanomaterials has been proven very effective to improve the dispersability, stability (both chemical and physical) and biocompatibility.24-28 For example, Zhang

et

al.

have

prepared

silica-coated

NaYF4:Yb,Er

nanocrystals

by

using

polyvinylpyrrolidone (PVP) as a chelating agent and stabilizer, which exhibited excellent photostability and dispersability in water.29 Moreover, silica-coated nanomaterials can also be functionalized by introducing specific functional groups or conjugating of desired molecules.30-33 For example, Bridot and co-workers have reported the synthesis of biocompatible Gd2O3 nanoparticles coating with a polysiloxane shell, in which inner side was



functionalized by organic dyes while the outer side by polyethylene glycol (PEG). Such coated and functionalized Gd2O3 nanoparticles were demonstrated as very attractive contrast agents for in vivo bimodal optical-MRI applications.33

In the current study, we report a novel gadolinium-based compound of Gd2O2SO4:Yb,Er as bimodal optical-MRI contrast agents. The crystal structure of Gd2O2SO4 was similar to the gadolinium oxysulfide (Gd2O2S), which are constructed as an alternated stacking of Gd2O22+ and anion groups layers SO42- and S-, respectively.34 Osseni et al. reported that suspension of Gd2O2S could be stable in water or physiological serum for several weeks and no release of toxic Gd3+ was detected. The composite was able to be finally removed by the body after months.23 We therefore deduce that the Gd2O2SO4 can be stable in water solution. In our case, the process of silica coating can further minimize the release of toxic not-ligated Gd3+ ion in solution. Gd2O2SO4:Yb,Er hollow spheres with a uniform diameter of approximately 300 nm could be prepared by calcination of corresponding rare earth-cysteine (RE-Cys) precursory spheres obtained by a facile hydrothermal process. Further surface silica coating was carried out to improve the stability and biocompatibility of these Gd2O2SO4:Yb,Er hollow spheres. Since the hydrothermal RE-Cys precursory spheres showed superior hydrophilic nature, surface modifications through the well-known Stöber sol-gel method was more favorable to achieve a uniform coating layer of silica than silica coating directly on calcinated Gd2O2SO4:Yb,Er hollow spheres.35,36 After a suitable calcination procedure, well-dispersed Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres with controlled silica shell thickness


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were synthesized, which demonstrated an excellent photostability as well as substantially enhanced T1-weighted MRI contrast.

Experimental Section

Materials Synthesis. All the reagents were of analytical grade and used without further purification. In a typical preparation , 1 mmol of hydrated rare-earth (RE) nitrate (molar ratio of Gd: Yb: Er was 90:9:1), 2.0 mmol of L-cysteine (L-Cys) and 0.3 g of PVP, and 30 ml deionized water were sealed in 50 ml Teflon-lined stainless steel autoclave and heated at 140 °C for 24 h. The resulting RE-Cys precursory spheres were rinsed by deionized water and ethanol several times. Gd2O2SO4:Yb,Er hollow spheres were prepared by subsequently calcinating the RE-Cys precursor at 700 °C for 2 h. For the preparation of Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres, as-prepared RE-Cys precursory spheres (18.5 mg) were dispersed in a mixed solution of water and ethanol (1:4, v/v, 40 ml), and 1.5 ml of ammonia (NH3·H2O) was added under continuous stirring for 0.5 h. Then 50 µl of tetraethyl orthosilicate (TEOS) was dropped into the above suspension. After further stirring for 0.5 h ~ 2h, the resulting SiO2-coated RE-Cys precursor was recovered by centrifugation at 5000 rpm for 10 min, and rinsed by deionized water and ethanol several times. The recovered product was calcinated at 700 °C for 2 h to prepare Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres.

Materials Characterization. The phase identification was conducted by a D/max2550 VB+ diffractometer with Cu-Kα (λ = 0.15418 Å). The morphologies of as-prepared products were characterized by the FEI Helios Nanolab 600i scanning electron microscopy (SEM) and



Tecnai G2 F20 S-Twin transmission electron microscopy (TEM). Energy dispersive x-ray spectroscopy (EDS) was recorded on the SEM. High-resolution TEM (HRTEM), selected area electron diffraction (SAED), scanning transmission electron microscopy (STEM), and elemental mapping were performed on the TEM. Thermogravimetric (TG) analysis was carried out on a Netzsch STA 449C instrument at a heating rate of 10 °C min-1 under an air flow. Nicolet Nexus 6700 spectrophotometer was used to collect Fourier transform infrared (FT-IR) spectra. The up-conversion emission spectrum was recorded on FP-6500 ﬂuorescence spectrophotometer at room temperature using 980 nm infrared laser excitation. Epifluorescence images were taken by using a Caliper Life Sciences IVIS LuminaII optical imaging system with a laser power density of 1.2 W cm-2. The zeta-potentials of as-prepared nanoparticles dispersed in water were determined by an ELSZ-2 instrument (Otsuka Electronics Co., Ltd.). MRI scanning was performed with a Philips Ingenia 3.0 T MR imaging instrument at the Third Xiangya Hospital of Central South University. Both in vitro and in vivo T1 structural images were acquired by using a coronal and transverse magnetization prepared rapid spin echo sequence (repetition time = 567 msec, echo time = 20 msec, a field of view of 100 mm × 51 mm, flip = 90°, voxel size = 0.4 × 0.45 × 1.5 mm). The as-prepared hollow spheres were dispersed in normal saline at various Gd concentrations of 0, 0.05, 0.1, 0.2, 0.5, 1 mM and placed in rows of 2 ml tubes for in vitro T1-weighted MRI. According to the in vitro experimental results, Gd concentration of 1 mM was chosen to investigate the efficacy of in vivo T1-weighted MRI through the subcutaneous injection of nude mouse, which were anesthetized by 1.5 ml 1% Pentobarbital sodium. The nude mouse used in T1-weighted MRI


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assays were obtained from the Experimental Animal Center of the Third Xiangya Hospital and all animal work experiments in this study were carried out in accordance with the guidelines of the Institutional Animal Care and Use Committee. The concentration of free Gd3+ was measured by an inductively coupled plasma-atomic emission spectrometer (ICP-AES, PS-6, Baird Inc.).

Results and discussion

A

schematic

synthetic

procedure

of

Gd2O2SO4:Yb,Er

hollow

spheres

and

Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres is shown in Figure 1. First, well-dispersed hydrophilic precursory spheres were obtained by employing L-Cys as biomolecule template and PVP as a surfactant. RE(ш) ions may tend to coordinate with the amino and carboxyl group of L-Cys and form RE-Cys complexes under hydrothermal condition. On the one hand, Gd2O2SO4:Yb,Er hollow spheres were readily synthesized by calcination of the precursory spheres at elevated temperatures. On the other hand, the hydrophilic precursory spheres, served as a “seed”, were coated with a layer of silica by employing TEOS as Si source and ammonia as catalyst. The morphology and thickness of the silica shell may be adjusted by changing the reaction time. Finally, all the inner organic parts were burnt out at a calcination temperature, resulting in porous Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres. It was notable that a direct silica coating on calcinated Gd2O2SO4:Yb,Er hollow spheres was not feasible, which seemed to lack comparable hydrophilic property with the RE-Cys precursory spheres.



Figure 2a and 2b showed typical SEM and TEM images of the spherical precursory product after hydrothermal treatment. The spheres had smooth surfaces with a uniform particle size of approximately 500 nm. As shown in Figure S1, powder X-ray diffraction (XRD) pattern taken from the hydrothermal product did not yield any obvious diffraction peaks, indicating an amorphous characteristic of the precursory spheres. The mass loss during calcination was depicted in Figure S1b. It can be seen that a mass loss of approximately 6.6% was recorded as the temperature was raised to 250 °C, which was ascribed to the water evaporation. Subsequently, a substantial mass loss of 32.6% was noted as the temperature was increased to 450 °C, which was attributed to the oxidation and decomposition of the organic content. Further oxidation and crystallization into Gd2O2SO4:Yb,Er occurred from 450 °C to 700 °C with a mass loss of approximately 8.4%. No obvious mass loss was recorded at the temperature higher than 700 °C. Based on the above observations, a calcination temperature of 700 °C was chosen to crystallize the organic precursor. All of the reflections in the XRD pattern (Figure S1a) can be indexed to the monoclinic structure of RE2O2SO4 (space group: C2/c),34,37 and no other impurity phases was observed. EDS result in Figure S2 illustrated the successful doping of Yb and Er elements into the Gd2O2SO4 host lattice (Cr signals were originated from the metal coating on insulating samples for SEM observations).The molar ratio of Gd: Yb: Er was estimated as 89.5:8.7:1.8, which was close to the stoichiometric ratio of starting rare-earth materials used in the synthesis. As shown in Figure 2c and 2d, Gd2O2SO4:Yb,Er hollow spheres with particles size of approximately 300 nm and shell thickness of approximately 25 nm were obtained after calcination at 700 °C. The formation mechanism of the hollow


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structure appeared to be the same as reported in our previous work.38 Figure 2f displayed a HRTEM image, in which the distances between lattice fringes were measured as 0.29 and 0.64 nm, corresponding to the interplanar spacing of the (310) and (200) crystallographic planes of Gd2O2SO4, respectively. Figure 2e shows typical SAED pattern, revealing a polycrystalline _

feature of the calcinated spheres. The rings could be indexed to be (310), (020), and (204) of Gd2O2SO4, respectively, which were in good accordance with the XRD result.

Typical SEM and TEM images of SiO2-coated RE-Cys precursory spheres were displayed in Figure 3a and 3c. The mean diameter of the frog egg-like SiO2-coated precursory spheres was estimated to be approximately 640 nm. A statistical analysis of the diameter distribution was summarized in Figure S3a. The silica shell thickness was approximately 95 nm. After calcination at 700 °C for 2 h, Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres were obtained. SEM and TEM observations shown in Figure 3b, 3d and 3e clearly identified the spherical shape and hollow core feature. The mean diameter and silica shell thickness were slightly decreased to approximately 630 nm (Figure S3b) and 85 nm, respectively. Different from the formation mechanism of the Gd2O2SO4 hollow spheres, the silica coating might play a role as a rigid shell in the surface, whereas the inner organic precursor was pulled outward during the calcination and finally confined in the silica shell. As a result, the mean diameter of Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres was larger than that of Gd2O2SO4:Yb,Er ones. The detailed view in Figure 3d indicated apparent contrast differences among grayish center, dark middle, and grayish periphery, which revealed a double-shelled structure. It is noteworthy that the morphology and thickness of the silica shell could be adjusted by changing 9 ACS Paragon Plus Environment


the reaction time. When the reaction time was decreased to 0.5 h, as shown in Figure S4, the thickness of silica shell was decreased. It composed of many irregular silica particles, resulting in a rough surface of the double-shell hollow spheres. XRD measurements on the double-shell hollow spheres confirmed that they were of Gd2O2SO4 phase (Figure S5), similar to those of the Gd2O2SO4:Yb,Er hollow spheres. In addition, a broad peak at around 23° was attributed to amorphous silica.39 The SAED pattern obtained on the silica shell also revealed the amorphous feature, as displayed in the inset of Figure 3e, which agreed well with the XRD result. The elemental mapping profiles of Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres were presented in Figure 4, which revealed a homogenous distribution of Si, O, S, and rare earth elements (Gd, Yb, Er). The profile strongly indicated not only the successful doping of Yb and Er elements in the Gd2O2SO4 host structure, but also the formation of a double-shell hollow spherical structure with outer amorphous SiO2 and inner Gd2O2SO4:Yb,Er layers. FT-IR spectra was further employed to verify the structural and functional group evolution in the formation of Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres, as shown in Figure S6. The broad absorption band located at 3400-3600 cm-1 was associated with water and hydroxyl groups. The hydrophilic nature of the RE-Cys precursor was favorable for surface modifications with silica. The intensity of the broad absorption band increased after coating with a silica layer, which might be caused by the introduction of Si-OH.40 After silica coating, two characteristic bands located at 1099 cm-1 and 473 cm-1 appeared, implying the existence of Si-O.39-41 These characteristic bands remained in the Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres after calcination at 700 °C, which attested the high thermal stability of the silica


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shell. The expected sulfates absorption located at 1198 cm−1, 1121 cm−1 and 1063 cm−1 were very close to the broaden Si-O absorptions (1099 cm-1), which was difficult to distinguish. The peaks located at 660 cm−1, 620 cm−1 and 600 cm−1 in the final product were observed, which was assigned to sulfates absorption. Instead of the RE-Cys precursory spheres, Gd2O2SO4:Yb,Er hollow spheres were also employed as a “seed” for the silica coating process. As can be seen in Figure S7, the silica did not coat the Gd2O2SO4:Yb,Er hollow spheres well and caused them to aggregate together. It thus confirmed that a hydrophilic nature of the RE-Cys precursor was a key factor in the successful fabrication of well-dispersed Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres.

The introduction of Yb and Er elements endowed the Gd2O2SO4 host material with a promising upconversion application. Yb3+ ions, as a sensitizer, have an intense absorption at 980 nm, whereas Er3+ ions possess abundant energy levels available for the energy transfer from Yb3+ to Er3+ ions, acting as emitter centers. The upconversion luminescence measurement of Gd2O2SO4:Yb,Er hollow spheres under an infrared laser with a wavelength of 980 nm was depicted in Figure 5. All of the peaks in the emission spectrum could be attributed to the characteristic emissions of Er3+ ions. Figure S8 displays the integrated green (500-600 nm) and red (600-750 nm) upconversion emissions intensities versus the excitation power in logarithmic scale, while the slopes were considered as the number of photons involved in upconversion process.42,43 The slopes of 1.48 (red emission) and 1.92 (green emission) could be assigned to a two-photon process in this system. The proposed energy transfer mechanism was schematically shown in the inset of Figure 5. Upon excitation by an infrared laser of 980 11 ACS Paragon Plus Environment


nm, Yb3+ ions were excited into the 2F5/2 state from the ground state (2F7/2). The excitation energy could easily be transferred to the Er3+ ions (4I15/2→4I11/2).44-46 On the one hand, the 4I11/2 state could be further excited into the 4F7/2 state by absorbing one more phonon from Yb3+ ions. Fast non-radiative relaxation might occur from 4F7/2 to 2H11/2 or 4S3/2 state. On the other hand, the 4I11/2 state might relax to 4I13/2 state in a non-radiative manner, and then be further excited into the 4F9/2 state by absorbing one more phonon energy. Finally, the high excitation states (4F7/2, 2H11/2, 4S3/2 and 4F9/2) of Er3+ ions could relax radiatively to the ground-state (4I15/2), generating green and red emissions.47 Because of the quenching of the Er3+ emitting states causing by high energy S-O oscillators (~1100 cm-1), red emission was mainly obtained in Gd2O2SO4 host, which shows a relatively low efficiency of the upconversion luminescence. Nevertheless, the red emission within the “transparency window” of biological tissues (650-1200 nm) is more favorable for the in vivo deep fluorescence imaging. In addition, these upconversion luminescent materials with reasonable efficiency can be used for not only fluorescence labeling, but also functional design of contrast agent taking advantages of the hollow structure, such as drug deliver host carriers. Epifluorescence images of the samples dispersed in normal saline of the same volume at the same rare earth concentration were compared in Figure 6. Contrasted with bare Gd2O2SO4:Yb,Er, double-shell nanospheres coated with silica were able to emit relatively less intense upconversion fluorescence upon excitation at 980 nm as shown in Figure S9. With increasing thickness of SiO2 shell, the photoluminescence intensity decreases. However, after coating, more uniform fluorescence across the test tube as well as an increase of zeta-potential from +8.6 mV to +22.4 mV


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indicated better dispersability of Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres in water. After surface modification with a silica layer, the SiO2-coated RE-Cys precursory spheres were less likely to aggregate together during the calcination. As a result, Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres exhibited favorable dispersibility in both TEM and fluorescence images.

To evaluate the efficacy of the Gd2O2SO4:Yb,Er hollow spheres as T1 MRI contrast agents, in vitro and in vivo T1-weighted MRI assays were performed on a Philips Ingenia 3.0 T MR imaging instrument. As displayed in Figure 7, the contrasts were enhanced accordingly with increased

Gd

concentrations.

The

brighter

T1-weighted

MRI

contrast

for

Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres demonstrated a much more apparent contrast enhancement effect than that of Gd2O2SO4:Yb,Er ones. In addition, the similar signal enhancement trends observed from top to bottom of the test tube also revealed excellent dispersability of the silica-coated samples (Figure S10). The greater contrast enhancement for Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres seemed to be derived from silica coating. It has been reported that Gd complexes confined by water permeable nanoparticles, such as silicon particles,48 apoferritin,49 hydrogels,50 and zeolites,51 were applicable as highly efficient T1 MRI contrast agents. A better dispersability causing by silica coating may offer more accessibility for water molecules to each magnetic center, which could enhance the efficiency of water proton relaxation.52,53 Furthermore, a thicker silica layer might also lead to a higher relaxivity. A longer passageway of water molecules in a thicker silica layer slowed down the motion of water molecules and correspondingly improved the proton longitudinal relaxivity.54 13 ACS Paragon Plus Environment


In vivo T1-weighted MRI result of nude mice after subcutaneous injection of 0.1 ml Gd2O2SO4:Yb,Er@SiO2/normal saline (1 mM) was shown in Figure 8. The right side without injection marked by a circle was served as a reference node. Significant contrast enhancement differences in the T1-weighted image were observed between left (injected) and right (non-injected) sides in both horizontal and coronal slice. For possible clinical application, an MRI contrast agent should minimize the release of toxic not-ligated Gd3+ ion. The as-prepared hollow spheres were dispersed in water with a Gd3+ concentration of 30 mM and stirred for 2 days. After centrifuged at 8000 rpm for 10 min, the separated supernatants were used to detect free Gd3+ concentration by ICP-AES. Compared to a Gd3+ leached concentration of 1.90 µM from bare Gd2O2SO4:Yb,Er, double-shell hollow spheres with silica coating showed a decreased concentration of 0.89 µM, corresponding to ~63 ppm and ~30 ppm, respectively. This low level of leached concentration was comparable to the Eu-doped GdVO4 nanoparticles,20 which demonstrated the stability of Gd2O2SO4:Yb,Er@SiO2 hollow spheres. There is still an issue about the long-time stability of Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres because the particles’ size is beyond that of the bio-entities. Dextran-coated superparamagnetic iron oxide with a particles size about 150 nm had been approved by the Food and Drug Administration (FDA) for MRI contrast imaging on human beings recently. In this direction, we were able to synthesize Gd2O2SO4:Yb,Er nanoparticles with a size around 100 nm by substituting ethylene glycol for water as solvent, as shown in Figure S11. These results clearly indicated a very promising future of utilizing Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres as a new type of efficient T1 MRI contrast agents.


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Conclusions

In summary, uniform Gd2O2SO4:Yb,Er hollow spheres have been successfully prepared as a novel bifunctional contrast agent for both upconversion optical and magnetic resonance imaging. Benefited from the innate hydrophilic nature of the RE-Cys precursory spheres, their surface can be readily coated with a layer of stable and biocompatible silica by employing TEOS as a source of silicon and ammonia as catalyst. After calcination at 700 °C for 2 h, well-dispersed Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres were successfully synthesized. The epifluorescence images and T1-weighted MRI results demonstrated that the Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres were more favorable in both attaining better dispersibility and enhanced T1-weighted MRI contrast than bare Gd2O2SO4:Yb,Er. This study reveals that these rare-earth-doped Gd2O2SO4 hollow spheres, after co-doping with luminescence centers as well as silica surface coating, are very promising as bimodal optical-MRI contrast agents for potential medical applications.

Figures



Figure 1. Schematic illustration for the synthesis of Gd2O2SO4:Yb,Er hollow spheres and Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres.

Figure 2. SEM and TEM images of spherical RE-Cys precursor (a,b) and Gd2O2SO4:Yb,Er hollow spheres (c,d). HRTEM image (e) and SAED pattern (f) of Gd2O2SO4:Yb,Er hollow spheres.


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Figure 3. SEM and TEM images of SiO2-coated RE-Cys precursory spheres (a,c) and Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres (b,d,e). The inset in (e) is a corresponding SAED pattern taken from the red circle area.



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Figure 4. TEM image, STEM high angle annular dark field (HAADF) and elemental mapping profiles of Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres.

Figure 5. Emission spectrum of Gd2O2SO4:Yb,Er hollow spheres under an infrared laser excitation with a wavelength of 980 nm. (Inset) Corresponding scheme of energy levels and energy transitions.

Figure

6.

Epifluorescence

images

of

Gd2O2SO4:Yb,Er

hollow

spheres

(a),

Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres with different silica coating time of 0.5 h (b) and 2 h (c).


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Figure 7. T1-weighted MR images at various Gd concentrations of Gd2O2SO4:Yb,Er hollow spheres (Gd:Yb,Er, top row), and Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres with different silica coating time (0.5 h, middle row; 2 h, bottom row).



Figure 8. In vivo T1-weighted MR image of nude mice after subcutaneous injection (left circle area) of Gd2O2SO4:Yb,Er@SiO2 double-shell hollow spheres (top, horizontal view; bottom, coronal view).


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ASSOCIATED CONTENT

Supporting Information

Typical XRD, TG, EDS, statistical analysis, SEM, TEM, FT-IR, T1-weighted MR images of as-prepared samples. This material is available free of charge via the Internet at http://pubs.acs.org.

Corresponding Author

*[email protected], [email protected]

Author Contributions †F.S.C. and ‡C.J.Y. contributed equally to this work.

Notes

The authors declare no conflict of interest.

Acknowledgment The authors acknowledge the financial support by National Natural Science Foundation of China (51372279, 81471715, 30900359), Hunan Provincial Natural Science Foundation of China (13JJ1005). X. L. acknowledges support from Shenghua Scholar Program of Central South University. R. M. acknowledges support from JSPS KAKENNHI (15H03534, 15K13296, 18H03869).



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For Table of Contents Use Only

Well-dispersed Gd2O2SO4:Yb,Er hollow spheres have been developed as novel bifunctional contrast agents for efficient upconversion optical and magnetic resonance imaging.


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Controllable Fabrication of Rare-earth-doped Gd2O2SO4@SiO2

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