Er3+-Codoped Bi2O3 Nanospheres: Probe for Upconversion

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Yb3+/Er3+-codoped Bi2O3 nanospheres: probe for upconversion luminescence imaging and binary contrast agent for computed tomography imaging Pengpeng Lei, Peng Zhang, Qinghai Yuan, Zhuo Wang, Lile Dong, Shuyan Song, Xia Xu, Xiuling Liu, Jing Feng, and Hongjie Zhang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.5b09990 • Publication Date (Web): 11 Nov 2015 Downloaded from http://pubs.acs.org on November 12, 2015

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ACS Applied Materials & Interfaces

Yb3+/Er3+-codoped Bi2O3 nanospheres: probe for upconversion luminescence imaging and binary contrast agent for computed tomography imaging Pengpeng Lei a,b, Peng Zhang c, Qinghai Yuan c, Zhuo Wang a,b, Lile Dong a,b, Shuyan Song a, Xia Xu a, Xiuling Liu a, Jing Feng a,*, Hongjie Zhang a,*

a

State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied

Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China b

c

University of Chinese Academy of Sciences, Beijing 100049, China

Department of Radiology, The Second Hospital of Jilin University, Changchun 130041, China

ABSTRACT: In this work, water-soluble Yb3+/Er3+ codoped Bi2O3 upconversion (UC) nanospheres with uniform morphology have been successfully synthesized via a solid-statechemistry thermal decomposition process. With 980 nm near-infrared irradiation, the Bi2O3:Yb3+/Er3+ nanospheres have bright UC luminescence (UCL). Moreover, multicolor UC emissions (from green to red) can be tuned by simply changing the Yb3+ ions doping concentration. After grafting citric acid molecules on the surface of Bi2O3:20% Yb3+/2% Er3+ nanospheres, the MTT assay on HeLa cells and CCK-8 assay on osteoblasts show the UC

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nanospheres exhibit excellent stability and biocompatibility. The possibility of using these nanoprobes with red UCL for optical imaging in vivo has been demonstrated. Furthermore, Bi3+ and Yb3+ containing nanospheres as binary contrast agent also exhibited significant enhancement of contrast efficacy than iodine-based contrast agent via X-ray computed tomography (CT) imaging at different voltage setting (80–140 KVp), indicating they have potential as CT imaging contrast agent. Thus, Yb3+/Er3+ codoped Bi2O3 nanospheres could be used as dual modality probe for optical and CT imagings. KEYWORDS: Lanthanide, Bi2O3, upconversion luminescence, dual-modal imaging, binary contrast agent 1. INTRODUCTION A variety of imaging modalities have emerged in recent years, such as optical imaging, X-ray computed tomography (CT), magnetic resonance (MR) imaging, thermal imaging, ultrasound (US) imaging, and positron emission tomography (PET).1-6 These imaging techniques are popular in clinical use because of its noninvasive to tissue and painlessness to patients. Due to the intrinsic and instrument restrictions of every imaging modality, single modality imaging is not sufficient to obtain enough information for the accurate diagnosis. For example, optical imaging usually provides high sensitivity and spatial resolution for bioimaging, which even can provide cellular-level information with almost single molecule sensitivity, but lacks the full capability to obtain anatomical and physiological details.7-9 CT imaging provides images with excellent anatomical details based on hard-tissue contrast and depth for in vivo imaging, but suffers from limited sensitivity and resolution for an imaging technique at the cellular level.10,11 By combining optical and CT imaging probes, it can obtain more accurate imaging and diagnosis


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data by taking the advantages of both the techniques. However, it is complicated to introduce two or more kinds of nanoparticles into a hybrid system with both strong fluorescence and CT signal. Thus, it is important to develop a single-phase multifunctional nanoparticle without adding any other particles or moieties. Lanthanide ions (Ln3+) doped upconversion nanoparticles (UCNPs) have attracted burgeoning research interest in bioimaging,12-17 due to their superior physicochemical features, such as sharp-band emissions, low autofluorescence background from biological samples, large antiStokes shifts (up to 500 nm), long lifetimes, low toxicity, tunable emission, high penetration depth, as well as high resistance to blinking and photobleaching.17-26 Compared with blue and green light, red light can reduce light scattering, absorbance and autofluorescence of tissue due to the lack of efficient endogenous absorbers.27 Researchers focus on tuning red UC emission by single-wavelength excitation, which makes both the emission and excitation wavelengths fall within the “tissue optical window” (i.e., 650-1200 nm), and more suitable for the deep-tissue imaging.28 However, a weak red emission whose signal is hard to collected. Hitherto, great efforts have been directed towards developing intense red UC emission for biological applications, especially for bioimaging. For example, a pure red UC emission (650–670 nm) has been achieved by rational controlling the Mn2+-doping level in NaYF4:Yb3+/Er3+ UCNPs.29 Likewise, Han et al. amplified the red-emission of α-NaYF4:Yb,Er@CaF2 UCNPs through adjusting Yb3+ ions concentration.30 In addition, cross relaxation effect among the activators at high content also can induced intense pure red UC emission.31 It is worth to note that a suitable host material is a key factor to gain red UCL.32 Bismuth is a high atomic number element (Z = 83), which possesses high K-edge value (Kedge value = 90.5 keV) and good X-ray attenuation properties (Bi = 5.74 cm2 g−1 > I = 1.94 cm2


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g−1 at 100 keV). In previous report, bismuth element shows higher CT value at 80 KVp than other metal elements (such as Au, Pt, Ta), which indicates bismuth has good X-ray CT imaging at low voltage.33 In addition, bismuth is the only heavy metal that is nontoxic. Thus, the Bicontaining nanoparticles have the potential to be used as safe contrast agent for CT imaging.34,35 Bismuth oxide (Bi2O3) is the most significant member of bismuth-based compounds, which exhibits five main polymorphs, including α-Bi2O3 (monoclinic), β-Bi2O3 (tetragonal), ω-Bi2O3 (triclinic), δ-Bi2O3 (face-centered cubic), and γ-Bi2O3 (body-centered cubic).36,37 It has been reported that the Bi2O3/HSA core-shell nanoparticles have been applied for CT imaging.38 Moreover, the UCL of Ln3+ (Ln3+ = Er3+, Tm3+, Ho3+) could be greatly enhanced by doping Bi3+ ion in the NaYF4:20% Yb3+/2% Ln3+ (Ln3+ = Er3+, Tm3+, Ho3+) crystals.39 In addition, UCL properties in bismuth oxide glasses were studied.40-43 However, to our best knowledge, there is no report on combining UCL and CT imaging based on pure Bi2O3 matrix materials. In the present work, we report a facile strategy to synthesis water-soluble Yb3+/Er3+ codoped Bi2O3 nanospheres with dual modality of UCL and CT imaging. By simply changing the Yb3+ ions doping concentration, multicolor UC emissions (from green to red) has been achieved under 980 nm near-infrared irradiation, which offer the in vivo UCL imaging modality. The binary contrast agent Bi2O3:20% Yb3+/2% Er3+ nanospheres also provide high contrast in vitro and in vivo CT imaging modality due to Bi3+ and Yb3+ possess good X-ray attenuation properties and high K-edge value. In addition, Bi has advantage at low voltage and Yb shows good signal at high voltage, the complementary strengths of Bi and Yb elements expand its application at a variety of voltage. So, the in vitro/in vivo CT signals are stronger than iodine-based contrast agent at equivalent concentrations, regardless of the voltage setting. Therefore, we have successfully integrate optical and CT imaging modalities into a hybrid system. After grafting


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citric acid molecules on the surface, Bi2O3:20% Yb3+/2% Er3+ nanospheres show good biocompatibility through the MTT assay on HeLa cells and CCK-8 assay on osteoblasts. Thus, binary contrast agent Bi2O3:Yb3+/Er3+ nanospheres could be employed as promising single-phase multifunctional nanoprobe for UCL bioimaging and computed tomography imaging applications. 2. EXPERIMENTAL SECTION 2.1. Materials. Analytical grade Bi(NO3)3·5H2O (99%), CO(NH2)2 (99%) and Na3C6H5O7 (99%) were purchased from Aladdin Reagents (Shanghai, China). Yb(NO3)3·5H2O (99.99%) and Er(NO3)3·5H2O (99.99%) were purchased from Alfa. Ethylene glycol (EG) was obtained from Beijing Chemical Reagents (Beijing, China). All the above chemicals were used directly without further purification. 2.2. Preparation of Monodisperse Bi2O3:Yb3+/Er 3+ Nanospheres. In a typical procedure, Bi (NO3)3·5H2O (0.78 mmol), Yb(NO3)3·5H2O (0.20 mmol) and Er(NO3)3·5H2O (0.02 mmol) were dissolved in 6 mL of ethylene glycol under vigorous stirring. Then, a certain quantity of CO(NH2)2 dissolved in 7 mL of ethylene glycol were added to the above solution. The mixture were stirred for another 30 min at room temperature and then transferred to a 20 mL Teflon-lined autoclave, and subsequently heated at 180 °C for 9 h. After the reaction, the system was naturally cooled to room temperature. The precursor was collected by centrifugation, and washed with deionized water and anhydrous ethanol respectively, in sequence three times, and then dried at 80 °C for 8 h under vacuum. Bi2O3:20% Yb3+/2% Er3+ were obtained by annealing the precursor at 700 °C for 2 h in air with a heating rate of 10 °C min−1. Other samples were prepared by the similar procedure, except for different amounts of Yb3+ ions. 2.3. Preparation of Citrate-coated Bi2O3:20% Yb3+/2% Er3+ Nanospheres. To obtain citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres, 20 mg ligand-free Bi2O3:20% Yb3+/2% Er3+


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nanospheres were dispersed in the aqueous solution of trisodium citrate (60 mg/mL). After continuously stirring for 3 h at room temperature, the products were collected by centrifugation, and washed with deionized water to remove redundant solvents. And then the citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres were obtained. 2.4. Characterization. The crystal structures and phase purities of the samples were investigated by powder X-ray diffraction (XRD) with a D8 Focus diffractometer (Bruker) with Cu Kα radiation ( λ = 1.5418 Å) with an operation voltage and current maintained at 40 kV and 40 mA. The morphology and composition of the samples were studied using a field-emission scanning electron microscope (FE-SEM, S-4800, Hitachi) equipped with an energy-dispersive Xray (EDX) spectrometer. Low-/high-resolution transmission electron microscopy (TEM) were carried out on a FEI Tecnai G2S-Twin instrument with a field-emission gun operating at 200 kV. Fourier transform infrared spectroscopy (FT-IR) was recorded on a Perkin-Elmer 580B IR spectrophotometer using the KBr pellet technique. The UCL spectra were recorded by using a 980 nm laser diode and a triple grating monochromator (Spectra Pro-2758, Acton Research Corporation, USA) equipped with a photomultiplier (Hamamatsu R928). All the measurements were performed at room temperature (RT). 2.5. Cell Lines and Cell Culture. HeLa cell lines were purchased from the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China. Human osteoblast cell lines were purchased from the Institute of Translational medicine, Nanchang University. Cells were cultured in Dulbecco's modified Eagle's medium (DMEM, GIBCO) supplemented with 10% fetal bovine serum (FBS) in a humidified incubator at 37 °C and 5% CO2, and the culture medium was replaced once very day.


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2.6. In Vitro Cytotoxicity of Citrate-coated Bi2O3:20% Yb3+/2% Er3+ Nanospheres. In vitro cytotoxicity of citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres were tested by using the typical methyl thiazolyl tetrazolium (MTT) reduction assay on HeLa cells and the CCK-8 assay on osteoblasts. HeLa cells harvested in a logarithmic growth phase were seeded in 96-well plates at a density of 105 cells per well and were cultured at 37 °C and 5% CO2 for 24 h. Subsequently, serial dilutions of different nanospheres formulations (0, 15.63, 31.25, 62.5, 125, 250, 500, 1000 µg/mL) were added to the culture medium. The cells were incubated for 24 h. Then, 20 µL of MTT solution in PBS with the concentration of 5 mg/mL was added to each well and the plates were incubated for an additional 4 h at 37 °C, followed by removal of the culture medium containing MTT and 150 µL of DMSO was added to each well to dissolve the MTT formazan crystals formed. Finally, the plates were shaken for 10 min, and the absorbance of formazan product was measured at 490 nm by a microplate reader. The cell viability was calculated by the following formula: Cell viability (%) = (mean of absorbance value of treatment group/mean of absorbance value of control) × 100%. Osteoblasts suspension solution (100 µL) were seeded into a 96-well cell culture plate and cultured at 37 °C under air containing 5% CO2 for 24 h. Then, 10 µL of different concentrations of citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres suspension (0, 15.63, 31.25, 62.5, 125, 250, 500 and 1000 µg/mL) were added into the wells and cultured for 6 h. CCK-8 reagent was subsequently added to the wells followed by an incubation for 2 h. The optical density at 450 nm (OD450) of each well was measured on a microplate reader. 2.7. Animal Experiments. Kunming mice were purchased from Laboratory Animal Center of Jilin University (Changchun, China). Animal care and handing procedures were in agreement


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with the guidelines of the Regional Ethics Committee for Animal Experiments. The tumor models were established by subcutaneous injection of H22 cells in the left axilla of each mouse. The mice were used for experiments when the tumors had grown to reach the size of around 200 mm3. 2.8. In Vivo UCL Imaging. The tumor-bearing mice with average weight of 20 g were first anesthetized by intraperitoneal injection (with 10% chloral hydrate 100 µL) and intratumorally injection with PBS solution with citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres. Then, the mouse was imaged on an in vivo Maestro whole-body imaging system equipped with an external 980 nm laser as the excitation source. 2.9. In Vitro and In Vivo X-ray CT Imaging. To assess CT contrast efficacy, citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres and iobitridol were dispersed in deionized water with different (Bi+Yb) and I concentrations over the range from 0 to 120 mM, respectively. For in vivo CT imaging, the tumor-bearing mice was anesthetized by intraperitoneal injection of 100 µL 10% chloral hydrate and scanned to get the CT imaging before injection of the contrast agent. After intratumorally injection of 50 µL citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres solution (0.12 M), the same mice was scanned again in the CT imaging system. In vitro and in vivo CT images were collected using a Philips 256-slice CT scanner. Imaging parameters were as follows: 80 KVp, 100 KVp, 120 KVp, and 140 KVp, 300 mA; thickness, 0.9 mm; pitch, 0.99; field of view, 350 mm; gantry rotation time, 0.5 s; table speed, 158.9 mm s-1. 3. RESULTS AND DISCUSSION 3.1. Phase and Morphology. XRD patterns of the 20% Yb3+/2% Er3+-codoped precursor and the final products with different Yb3+ ions concentrations are shown in Figure 1. Before calcination, the diffraction peaks of the precursor could be well indexed in accordance with


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tetragonal Bi2O2CO3 crystals (JCPDS No. 41-1488), which indicates a pure phase acquired after the solvothermal reaction. After calcination at 700 °C, the phase of the sample without Yb3+ doping matches well with the standard monoclinic Bi2O3 (α-Bi2O3) (JCPDS No. 71-2274). Increasing the Yb3+ ions concentration to 5%, the phase transforms from monoclinic (α-Bi2O3) to tetragonal (β-Bi2O3) obviously. The diffraction peaks are in agreement with those of the standard data (JCPDS No. 27-0050).41 When Yb3+ ions concentration reached to 10%, new well-defined strong diffraction peaks appear, suggesting high crystallinity of the product, which can be assigned exactly to the cubic phase of Bi2O3 (δ-Bi2O3) (JCPDS No. 52-1007) and belongs to the CaF2-type structure. Even Yb3+ ions concentration increasing to 30 %, the pure cubic phase remains unchanged. Similar results were observed in the previous report. The structure transforms from β-Bi2O3 to δ-Bi2O3, which is a displacement phase transition resulting from order to disorder of the atoms.44 In addition, the diffraction peaks shift slightly to the higherangle side in the Figure S1, which due to the substitution of Bi3+ ions (r = 1.17 Å) by Yb3+ ions with smaller size (r = 1.125 Å) in the host lattice. To further study the conversion process from Bi2O2CO3 precursor to Bi2O3, FT-IR spectra were employed for both the 20% Yb3+/2% Er3+-codoped precursor and the final products, as displayed in Figure 2. For the precursor, four typical internal vibration modes for CO32- groups are observed, including ν1 (1070 cm-1), ν2 (848 cm-1), ν3 (1394 cm-1), and ν4 (670 cm-1).45 The weak absorption peaks at 2927 cm-1 and 2850 cm-1 are attributed to the asymmetric and symmetric stretching vibrations of the C–H bond of the surface adsorbed ethylene glycol molecules, respectively.46 Likewise, the broad absorption band at 3326 cm-1 corresponds to the O–H stretching vibration of chemisorbed and/or physisorbed water molecules on the surface.47 After calcination of the precursor at 700 °C for 2 h, the characteristic peaks of the CO32- groups


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disappeared, indicating that the CO2 molecules were removed completely from Bi2O2CO3 precursor.48 Moreover, a band located at 546 cm–1, which attributed to Bi–O–Bi absorption band, indicating the well-defined crystallization of Bi2O3.49 In addition, the EDX spectra show in the Figure S2a confirm the presence of Bi, Yb, Er, C and O elements in the precursor. The element C almost disappears in the final products and the sample mainly consists of Bi, Yb, Er, and O, which is consistent with the results of XRD and FT-IR (Figure S2b). Figure 3a and d show the SEM of the 20% Yb3+/2% Er3+-codoped precursor and the final products. It is clearly observed that the precursor mainly composed of numerous monodispersed nanospheres with diameter about 350 nm (Figure 3a). Figure 3d reveals that Bi2O3 still maintains the nanospheres morphology at high temperature, which suggests the nanospheres with high thermal stability. The microstructure and morphologies of the nanospheres were also confirmed by TEM and HRTEM. Figure 3b and e show the typical TEM images of the as-synthesized precursor and the final products, which are consistent with the SEM results. Moreover, the corresponding HRTEM image (Figure 3c) of Bi2O2CO3 particle exhibits the obvious lattice fringes, which confirm the high crystallinity of the sample. The distance of the adjacent lattice fringes is 0.273 nm, which is in good agreement with the d-spacing values of the (110) plane of Bi2O2CO3. The HRTEM images (Figure 3f) of a single Bi2O3 nanospheres exhibit clear lattice fringes with observed d-spacing of 0.320 nm corresponding to the lattice planes of (111) in δBi2O3. 3.2. Upconversion Luminescence Properties. Generally, Yb3+ is commonly chosen as the co-dopant with Er3+, because of its large absorption cross-section at 980 nm (the Yb3+ absorption is an order of magnitude stronger than that of Er3+) and much longer excited-state lifetime. In this work, we investigate the UCL of Bi2O3:Yb3+/Er3+ which were synthesized at 700 °C. Figure


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4a shows the typical UCL spectra of Bi2O3:x% Yb3+/2% Er3+ with various Yb3+ ions doping levels (x = 0, 5, 10, 15, 20, 30). When x = 0, some weak emission bands appear in the green emission region (505-565 nm), which assigned to 2H11/2-4I15/2 and 4S3/2-4I15/2 transitions of Er3+, respectively. The red emission band (635-690 nm) corresponds to 4F9/2-4I15/2 transitions of Er3+. It is obvious that the intensity of the green emission is much stronger than that of the red ones. Codoping with sensitizer ions can not only increase the luminescence intensity and efficiency but also induce the variation of the emission colors.50,51 With increasing the concentration of Yb3+ ions from 5 to 20%, more sensitizer Yb3+ ions become available to be excited and transfer the energy to the activator Er3+ ions, leading to the drastically enhancement of red emission. The intensity of the red emission achieves the maximum when the Yb3+ concentration reached to 20%. The green emission increases slowly but weaker than that of without Yb3+ ions. Furthermore, the intensities of both the red and green emissions intensity decrease when Yb3+ ion concentration is increased to 30%. Figure 4c and d show the intensities of green (2H11/2, 4S3/2– 4

I15/2) and red (4F9/2–4I15/2) emission, and the ratio of red/green of Bi2O3:Yb3+/Er3+ as a function of

the Yb3+ ions concentration. The value of red/green gradually increases from 0.46 to 92.20. The variation of the Commission International de L’Eclairage (CIE) chromaticity coordinates of Bi2O3:x% Yb3+/2% Er3+ nanospheres with different doping contents of Yb3+ ions are calculated based on the corresponding UCL spectrum under 980 nm irradiation and plotted in Figure 4b, and the results are summarized in Table S1. The corresponding CIE coordinates of Bi2O3:x% Yb3+/2% Er3+ nanospheres change from (0.361, 0.630 ） to (0.700, 0.299), which further proves that the emission color shift from green to red. The schematic energy level diagram for Yb/Er system and possible UCL mechanism of Bi2O3:Yb3+/Er3+ are shown in Figure 5. Firstly, the 4I15/2 level of Er3+ ion can be populated to the


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I11/2 level by absorbing a photon from Yb3+. Subsequent non-radiative relaxations of 4I11/2-4I13/2

also populate the 4I13/2 level. Then, transfer to the 4F7/2 levels of the Er3+ ions from 4I11/2 state or populate 4F9/2 energetic state from 4I13/2 of the Er3+ ions by a second transfer photon from Yb3+.5253

With increasing Yb3+ ions concentration, the interatomic distance of Yb3+ and Er3+ will

decrease, which can efficiently accelerate the back-energy transfer process from Er3+ to Yb3+ ions 4

F7/2(Er3+) + 2F7/2(Yb3+) - 4I11/2(Er3+) + 2F5/2(Yb3+).51,54 This energy back-transfer suppresses the

population of Er3+ ions in levels 2H11/2 and 4S3/2 by depopulating the excited state 4F7/2 (Er3+), resulting in the decrease of green (2H11/2,4S3/2–4I15/2) emission. Besides, the intrinsic lifetime of the 4I13/2 level being much longer than that of 4I11/2,which makes the energy transfer of 2

F5/2(Yb3+) + 4I13/2(Er3+) - 2F7/2(Yb3+) + 4F9/2(Er3+) more favorable than the 2F5/2(Yb3+) +

4

I11/2(Er3+) -

2

F7/2(Yb3+) +

4

F7/2(Er3+), leading to the red emission (4F9/2–4I15/2) improve

significantly.54-57 As a result, the main emission peaks appear in the red region. To further understand the UCL mechanism, the UCL intensity was measured as a function of the pump power density. For the general UC process, the UCL intensity (I) depends on the power of the excitation power (P), which could be expressed by the following formula: I∝Pn, where n is the number of pump photons absorbed for per UC emission, the value of n can be determined by the slope of the fitted line of log (I) versus log (P).58-59 As shown in Figure S3, the fitted slopes of n values for the red and green emissions of the Er3+ ions are 2.42 and 2.29, respectively, illustrating involvement of the two- or three-photon processes in generation of the UCL in the Bi2O3:Yb3+/Er3+ nanospheres. 3.3. In Vitro Cytotoxicity. In order to evaluate the biocompatibility of UCNPs and their potential in vivo imaging applications, the cytotoxicity of the citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres were investigated by a standard methyl thiazolyl tetrazolium (MTT) assay. As


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shown in Figure 6, the cell viability of HeLa cells was maintained at >90% after 24 h of incubation with citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres. Furthermore, the cytotoxicity of the nanospheres was tested through CCK-8 assay on osteoblasts, the cell viability was still more than 95% after 6 h treatment (Figure S4). The results demonstrated that the low cytotoxicity and good biocompatibility of the citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres, implying their safety for in vivo imaging applications. 3.4. In Vivo UCL Imaging. To investigate the feasibility of the in vivo UCL imaging, citratecoated Bi2O3:20% Yb3+/2% Er3+ nanospheres were injected into the tumor site of a mouse without shaving the hair. The UCL images of the mouse collected by the in vivo Maestro wholebody imaging system equipped with an external 980 nm laser as the excitation source. Due to the high ratio of red/green, the emission color is almost red, which falls within the “tissue optical window”. It could be expected that Bi2O3:20% Yb3+/2% Er3+ nanospheres with intense red UC emission display high tissue penetration depth. As demonstrated in Figure 7, upon excitation at 980 nm, the strong UCL signal was observed at the tumor site, whereas no UCL signal could be detected around the tumor area without injection. The overlay image (Figure 7c) also confirmed that the UCL signal appear at the injection site. The high-contrast photoluminescence images between the background and UCL imaging area suggest that the prepared UCNPs are suitable to be employed for UCL imaging in vivo. 3.5. In Vitro and In Vivo X-ray CT Imaging. X-ray CT imaging with its deep penetration tissues and organs and high resolution, has been regarded as one of the most popular diagnostic imaging techniques. It should be note that different kinds of patients will require different CT scanning voltages, such as 80 KVp for children and 140 KVp for overweighted people. However, a single contrast element (such as Au) cannot provide high contrast efficacy to meet


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the needs of different operating voltages. Thus, it is important to explore a suitable material that has much higher contrast efficacy for all kinds of clinical voltages (such as 80, 100, 120, and 140 KVp). As known, high atomic number elements usually have high contrast efficacy because of high X-ray attenuation coefficient. For instance, noble metals-based contrast agents with higher atomic number are new class of CT contrast media. However, the cost will essentially limit their clinical application. Bismuth is nontoxic and inexpensive, which possesses high K-edge value and good X-ray attenuation properties.11,34,60 The X-ray attenuation property of bismuth is higher than I-based contrast agent at low voltage, which could provide better contrast efficacy at low voltage. In addition, the K-edge values of Yb (61 KeV) located within the higher-energy region of the X-ray spectrum, which is more suitable for X-ray CT imaging at high operating voltage (120 KVp) than currently available I-based contrast agent. Thus, it could be expected that Bi2O3:Yb3+/Er3+ nanospheres perform good imaging ability in X-ray CT imaging at different voltage setting. To assess in vivo CT contrast efficacy of citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres, we first compared the in vitro contrast efficiency of citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres to that of iobitridol (a traditional iodine-based clinical CT contrast agent) in solution. As shown in Figure 8a, the two contrast agents exhibit signal enhancement as the increase of contrast agent concentration at different voltage setting. Figure 8b shows a good linear correlation between the Hounsfield units (HU) value and the concentration of Bi+Yb (or iodine-based agent). In addition, as the increase of the voltage, the CT values of both citratecoated Bi2O3:20% Yb3+/2% Er3+ nanospheres and iobitridol decreased. However, the citratecoated Bi2O3:20% Yb3+/2% Er3+ nanospheres always produce higher contrast than iobitridol at equivalent concentrations at different voltage setting, indicating the good X-ray CT imaging ability and its potential as a CT imaging contrast agent. In order to further verify the citrate-


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coated Bi2O3:20% Yb3+/2% Er3+ nanospheres in vivo imaging capability, citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres were intratumorally injected into a mouse. The CT signal is very weak before injection. After 30 minutes, the obvious CT signal at the tumor injection site is observed at 80 KVp, as shown in Figure 8c. In addition, clear contrast enhancement could be detected from the tumor site after 30 minutes injection at other voltage settings (such as 100, 120, and 140 KVp) (Figure S5). 4. CONCLUSION In summary, we have synthesized uniform high-quality Yb3+/Er3+ codoped pure Bi2O3 UC nanospheres via a solid-state-chemistry thermal decomposition process. The relationship between the UCL intensity and the concentration of Yb3+ ion has been investigated. The MTT assay on HeLa cells and CCK-8 assay on osteoblasts reveal the UCL materials exhibit excellent stability and biocompatibility. The citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres employed as optical contrast in vivo animal imaging have been realized. Furthermore, positive contrast enhancement by Bi3+ and Yb3+ ions in vitro/in vivo at different voltage setting also verified in CT imaging. Therefore, bioprobe based on Yb3+/Er3+ codoped Bi2O3 nanospheres could serve as a safe multifunctional platform for UCL and CT imagings. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Figures S1-S5, Table S1. AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]


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*E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS The authors are grateful for the financial aid from the National Natural Science Foundation of China (Grant Nos. 21371165, 51372242, 21221061, 91122030, 21210001, and 21501167), Science and Technology Cooperation Special Project of Hong Kong, Macao and Taiwan (Grant no. 2014DFT10310), the National Key Basic Research Program of China (No. 2014CB643802), the Youth Innovation Promotion Association of Chinese Academy of Sciences (No. 2015181). REFERENCES (1)

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Figure Captions Figure 1. XRD patterns of 20% Yb3+/2% Er3+-codoped precursor and the final products of Bi2O3:x% Yb3+/2% Er3+ (x = 0, 5, 10, 15, 20, 30). Figure 2. FT-IR spectra of 20% Yb3+/2% Er3+-codoped precursor and the final product of Bi2O3:20% Yb3+/2% Er3+. Figure 3. SEM images of 20% Yb3+/2% Er3+-codoped precursor (a) and the final product of Bi2O3:20% Yb3+/2% Er3+ (d). TEM/HRTEM images of 20% Yb3+/2% Er3+-codoped precursor (b and c) and the final product of Bi2O3:20% Yb3+/2% Er3+ (e and f) Figure 4. (a) UCL spectra of Bi2O3:x% Yb3+/2% Er3+ (x = 0, 5, 10, 15, 20, 30) nanospheres. (b) The CIE chromaticity diagram of Bi2O3:x% Yb3+/2% Er3+ (x = 0, 5, 10, 15, 20, 30). (c) The green and red UCL intensities of Bi2O3:x% Yb3+/2% Er3+ as a function of Yb3+ ions concentration (Inset: the amplification of the green UCL intensity). (d) The intensity ratio of red/green as a function of Yb3+ ions concentration. All the samples were excited with a 980 nm laser (1.5 W). Figure 5. Proposed energy transfer mechanism of Bi2O3:Yb3+/Er3+. Figure 6. In vitro cell viability of Hela cells after incubation with citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres for 24 h using standard MTT colorimetric assay. Figure 7. In vivo UCL imaging of the mouse after intratumorally injection of citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres. (a) bright field, (b) upconversion luminescence, and (c) overlay images.


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Figure 8. (a) In vitro CT images of citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres and iobitridol with different concentration at clinical voltages 80, 100, 120, and 140 KVp. (b) CT value (HU) of citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres and iobitridol as a function of the concentration at clinical voltages 80, 100, 120, and 140 KVp. (c) In vivo CT images of a tumor-bearing mouse pre-injection and after intratumoral injection of citrate-coated Bi2O3:20% Yb3+/2% Er3+ nanospheres at 80 KVp. The tumor site was marked by red circles.


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Figure 1

Figure 2


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Figure 3

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Figure 5

Figure 6


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Figure 8


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TOC

Yb3+/Er3+-codoped Bi2O3 nanospheres as probe for upconversion luminescence imaging and binary contrast agent for computed tomography imaging.


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Er3+-Codoped Bi2O3 Nanospheres: Probe for Upconversion

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