Journal of Nanomaterials

Journal of Nanomaterials / 2011 / Article

Research Article | Open Access

Volume 2011 |Article ID 531217 | 7 pages | https://doi.org/10.1155/2011/531217

Bimodal Fluorescence and Magnetic Resonance Imaging Using Water-Soluble Hexagonal NaYF4:Ce,Tb,Gd Nanocrystals

Academic Editor: Anukorn Phuruangrat
Received12 Jul 2011
Accepted13 Sep 2011
Published14 Dec 2011

Abstract

The present study explored the feasibility of using hexagonal-phase NaYF4:Ce,Tb,Gd nanocrystals as bimodal probes for fluorescence and magnetic resonance (MR) imaging. Using a facile and user-friendly strategy, the NaYF4:Ce,Tb,Gd nanocrystals were synthesized with good water dispensability, high quantum yield (26%), and decent MR relaxivity (  mM−1 s−1). The NaYF4:Ce,Tb,Gd NCs conjugated by folic acid presented great efficiency in fluorescence imaging of C6 glioma cells in vitro. Meanwhile, in in vivo MR experiments on rats, the NaYF4:Ce,Tb,Gd NCs also significantly increased signal in the liver, spleen, and kidney even with a low probe dose. The proposed NaYF4:Ce,Tb,Gd nanoprobes hold promise for simultaneous bimodal fluorescence and MR bioimaging.

1. Introduction

Multimodal bioimaging, which shows advantages over traditional single-imaging modality, has been regarded as a new research frontier in biological and medical sciences [13]. Among various imaging techniques, fluorescence imaging provides the highest sensitivity and spatial resolution for in vitro bioimaging. However, fluorescence imaging suffers from lacking of detailed anatomical and physiological information in vivo. Magnetic resonance imaging (MRI), a noninvasive diagnostic method in clinic, offers excellent anatomical and functional information for in vivo bioimaging, but it is limited due to the poor sensitivity and resolution for cell imaging [35]. Therefore, a probe with the combination of fluorescence and MR imaging could bridge gaps in resolution and depth of bioimaging and would provide a useful diagnostic tool for both in vitro and in vivo studies [4, 69]. By virtue of this bimodal combination, some applications have been exploited such as biological marking, photodynamic therapeutic intervention, tumors targeting, and drug delivering [1012]. Realization of such bimodal probes with high performance and good biocompatibility has aroused great research interests [13, 14], though it is still a great challenge now.

In recent years, nanocrystals (NCs) of rare-earth (RE) compounds have been proposed to be a promising new class of biological probes due to their unique optical and chemical features [1518]. Ascribed to their special electron configuration, lanthanide ions (such as Tb3+, Eu3+, Er3+, and Nd3+) exhibit sharp fluorescent emissions with long lifetime, superior photostability, and high resistance to photobleaching and photoblinking [19, 20]. In addition, other lanthanide ions including Gd3+ possess a large number of unpaired electrons, which could become a paramagnetic relaxation agent with positive contrast enhancement in -weighted MRI [21]. Among various RE compounds, hexagonal-phase NaYF4 has attracted increasing attention as a matrix for lanthanide ions, because it is considered to be one of the most efficient host materials for supporting fluorescence of lanthanide ions [2224]. What is more, at present high-quality NaYF4 nanocrystals have been synthesized by a user-friendly method [25], which makes this material more attractive on bioimaging applications. On the road to realize bimodal imaging, incorporation of fluorescence RE3+ ions and Gd3+ ions in NaYF4 nanocrystals have been demonstrated as an efficient route [4]. Nevertheless, the combination of the fluorescence and MR bioimaging for both in vitro and in vivo studies has rarely been studied.

In the present work, a bimodal nanoprobe was synthesized by codoping Ce3+, Tb3+, and Gd3+ ions in NaYF4. The synthesized hexagonal-phase NaYF4:Ce,Tb,Gd NCs exhibit good water solubility, low cytotoxicity and demonstrate both high fluorescence efficiency (26%) and high MR enhancement (58%). Using the NaYF4:Ce,Tb,Gd NCs as probes, we successfully demonstrate fluorescence imaging of C6 glioma cells in vitro and MR imaging for liver, spleen, and kidney of rat in vivo. These results provide an insight into this novel type of biological agent in multimodal bioimaging.

2. Experimental Section

2.1. Reagents and Materials

Branched polyethylenimine (PEI, Mw = 10000), folic acid, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), dimethyl sulfoxide (DMSO), NaCl, RECl3·6H2O (RE = Y, Gd, Ce, Tb), and NH4F were purchased from Sigma-Aldrich without further purification. PEI stock solution (5 wt %) was prepared by dissolving PEI in ultrapure water. NaCl, RECl3 stock solutions (0.5 M) and NH4F stock solution (1 M) were prepared in ultrapure water, respectively.

2.2. Synthesis

In a typical procedure to synthesize PEI-coated NaYF4:10%Ce,5%Tb,10%Gd, 5 mL of PEI solution, 1.0 mL of NaCl, 0.1 mL of GdCl3, 0.1 mL of CeCl3 and 0.05 mL of TbCl3, were added to 15 mL ethanol in sequence. After 5 min vigorous agitation, a stoichiometric amount of NH4F was charged. After another 15 min stirring, the resulting solution was transferred to a 50 mL Teflon-lined autoclave and eventually heated at 200°C for 3 h. After naturally cooling down, the product was collected by centrifugation, washed with ethanol and ultrapure water for several times, then dissolved in 20 mL of GdCl3 (0.1 M) and stirred for 3 h. Finally, the sample was obtained by centrifugation, washed with ethanol and ultrapure water several times, and dried in vacuum.

2.3. Characterization

The X-ray powder diffraction (XRD) analysis was carried out on a Bruker D8 ADVANCE X-ray diffractometer with Cu Kα1 irradiation (λ = 1.5406 Å). The transmission electron microscopy (TEM) measurements were performed with a JEOL 2010 HT microscope (operated at 200 kV).

2.4. In Vitro Cell Imaging

Folic acid (75 mg) and EDC (180 mg) were dissolved in 30 mL of DMSO. After a half-hour mild agitation, 3 mL of DMSO containing 15 mg NaYF4:Ce,Tb,Gd NCs was slowly added. The mixture was stirred at room temperature for 4 h. The products were collected using centrifugation, washed with DMSO and ultrapure water several times, and then dispersed in 3 mL of ultrapure water.

Prior to cell fluorescence imaging, live rat C6 glioma cells (obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China)) were incubated with folic acid conjugated by NaYF4:Ce,Tb,Gd NCs at the concentration of 1000 μg/mL at 37°C and 5% CO2 for 12 h. The living cell fluorescence was observed by an inverted fluorescence microscope (Olympus IX 70), coupled with a digital camera (Nikon Coolpix 5400) and Image-pro Plus 5.0 image analysis software.

2.5. MRI Relaxation Measurements

In order to evaluate the effectiveness of NaYF4:Ce,Tb,Gd NCs as an MRI contrast agent, the relaxation properties of NaYF4:Ce,Tb,Gd NCs solutions were examined on a 3T MR scanner (Siemens trio system, Huaxi MR Research Center, Chengdu, China) with a 12-channel phased array coil. Samples with concentration varying from 0.06 mg/mL to 1.67 mg/mL were prepared for -weighted MR imaging by diluting them in deionized water. Deionized water was used as the reference sample. All the samples were scanned using standard Spin-Echo (SE) sequence (TR = 500 ms; TE = 9.4 ms; FOV = 138 * 180; matrix = 170 * 384; slice thickness = 3 mm; number of signal averages = 2).

To further investigate the contrast effect of NaYF4:Ce,Tb,Gd NCs, specific relaxivity value was measured for each of the samples, respectively. Inversion recovery pulse sequence was used for the measurement of values (TR/TE = 15 ms/1.95 ms; 10 different inversion-recovery waiting delay values (TI) between 23 ms and 3 s; FOV = 160 * 160; matrix = 768 * 768; slice thickness = 3 mm). The signal intensity of each tube on MRI was measured by placing a circle region of interest (ROI) with voxel size of 200 pixels in the center of the tube. values of each tube were deduced from the following formula: by performing a nonlinear least-squares fit. A plot of versus Gd3+ concentration yielded a straight line with the slope defined as the NaYF4:Ce,Tb,Gd NCs relaxivity value .

2.6. In Vivo MRI Studies

In vivo experiments were performed on white Sprague-Dawley (SD) rats (3–60 g) under authorization of the Animal and Human Ethics Committee of the West China Hospital at Sichuan University. MR scanning was performed on a Philips Achieva 3.0 T system with a phased array coil for rat (Shanghai Chenguang Medical Technologies Co., Ltd). After intraperitoneal injection of 10% chloral hydrate 0.4 mL, the rat was placed pronely in the MR system with its abdomen at the center of the coil. The NaYF4:Ce,Tb,Gd NCs solution was injected intravenously, and dynamic MRI 3D images (TR/TE = 18 ms/8 ms, matrix = 148 * 124, slices = 30) were obtained before and 0.67, 1.5, 3, 9, 24, and 48 h after the administration of contrast agent for each animal (maintained at normal body temperature). Signal intensity was measured at the each time point by using Siemens Syngo software, and the relative signal intensity changes were plotted against time.

3. Results and Discussion

The characterization of the PEI-coated NaYF4:Ce,Tb,Gd NCs (Y : Ce : Tb : Gd = 75 : 10 : 5 : 10) was demonstrated in Figure 1. As indicated in Figure 1(a), the products took on a rod-like shape with an average diameter of approximately 30 nm. The XRD pattern in Figure 1(b) exhibited that peak positions were in good accordance with the data in the JCPDS standard card (28–1192) for hexagonal NaYF4 crystals. It was known that the NaYF4 nanocrystal in hexagonal-phase had been regarded as one of the most efficient host materials for RE fluorescence [2224].

The surface properties of the products were exhibited by using FTIR spectrum. As shown in Figure 2, two strong bands (3428 and 1635 cm−1), originating from O–H stretching and H–O–H bending modes of vibration, render the NCs water soluble. Furthermore, the absorption peaks from internal vibration of amide bonds (1382 cm−1) and CH2 stretching vibrations (2863 and 2927 cm−1) demonstrated the presence of PEI on the particle surface. The PEI-coated NCs could give a direct conjugation of biomolecules to the NCs.

Figure 3 showed the excitation and emission spectra of the NaYF4:Ce,Tb,Gd NCs in water solution. In the NaYF4:Ce,Tb,Gd NCs, the Ce3+ absorbed energy effectively from ultraviolet (UV) light and transferred it to the Tb3+ that emitted green light. Under a 254 nm UV lamp irradiation, the particle water solution exhibited bright green emissions (Figure 2). Monitored with the emission wavelength of 542 nm, excitation spectrum consisted of a broad and strong band with a peak at 249 nm, which corresponded to the transitions from the ground state 2F5/2 of Ce3+ to different components of the excited Ce3+ 5d stated split by the crystal field [26]. The emission spectrum showed the characteristic and strong emission of Tb3+ with the 5D4–7FJ (J = 6–3) transitions ranging from 475 to 650 nm. A broadband Ce3+ emission (5d–4f transition) between 300 and 400 nm, as well as a sharp line Gd3+ emission (6PJ−8S7/2 transition) at about 310 nm, could also be observed due to incomplete energy transfer [27].

The quantum yield of the NaYF4:Ce,Tb,Gd NCs was further determined by using quinine bisulfate in 0.5 M H2SO4 as the standard samples [28]. The quantum yield was calculated from the equation , in which referred to the absorption intensity and referred to the integral fluorescence intensity. The quantum yield of quinine bisulfate was 54.6% [29]. By measuring the luminescence of both terbium and cerium, for the NaYF4:Ce,Tb,Gd NCs dispersed in water, a quantum yield of 26% was found, which was higher than that of the LaF3:Ce,Tb NCs reported previously [30, 31].

In vitro bioimaging studies were conducted in live C6 glioma cells which were treated by folic acid conjugated with NaYF4:Ce,Tb,Gd NCs for 12 h. As shown in Figure 4, the comparison between fluorescence and bright field images suggested the signal distributions strongly correlated with the C6 glioma cells, proving the fine attachment of NCs on the surface of cells. No conspicuous cell death was observed, which further indicated that the NCs were not cytotoxic to the cells. The results demonstrated that the NaYF4:Ce,Tb,Gd NCs could be used as an efficient probe for fluorescence bioimaging.

In vitro, -weighted imaging for the NaYF4:Ce,Tb,Gd NCs was performed with the 4 different concentrations of Gd3+ varying from 0.03 to 0.82 mM (pure water for the background signal) on a 3T MR scanner. A significant dose-dependent positive enhancement was observed on MRI with increasing of Gd3+ (Figure 5(a)). The solution with maximum concentration (0.82 mM Gd3+) presented the most effective positive MR signal enhancement which is about 200%. To further evaluate these properties, we calculated the MR relaxivity value of the NaYF4:Ce,Tb,Gd NCs by fitting a linear relationship between the relaxation rates and the Gd3+ concentration (Figure 5(b)). The of NaYF4:Ce,Tb,Gd NCs, 2.87 mM−1 s−1, was higher than those of 0.14 mM−1 s−1 of NaYF4:Yb,Er,Gd NCs [4] and 1.4 mM−1 s−1 of NaGdF4:Er,Yb/NaGdF4 NCs [16]. Furthermore, the of our products was only slightly lower than that of commonly used Gd-DTPA (3.7 mM−1 s−1) [32, 33]. The results suggested that the NaYF4:Ce,Tb,Gd NCs could be a decent contrast agent for MRI application.

In vivo, MRI experiments were carried out on a Philips Achieva 3.0 T MR system. Health SD rats were injected with NaYF4:Ce,Tb,Gd NCs (4.17 mg/kg) through tail veins. Three-dimensional -weighted images were acquired at the time points of 1.5, 3, and 48 hours after injection of the probes. Signal alteration was defined using “enhancement” (ENH) from the equation: , according to previous studies [34]. In order to quantitatively assess the enhanced effect of NCs, Siemens Syngo software was used to measure the signal intensity of the liver, spleen, and kidney of rats. As shown in Figure 6(c), obvious enhancement of the MR signal intensity was observed within 1.5 h after injection. The maximum relative enhancements were 58%, 36%, and 37% in the liver, spleen, and kidney, respectively. After 3 h after injection, the MR signal decreased gradually. After 48 h after injection, few probe MR signals were observed only in the intestinal tract, indicating the almost clearance of the injected probes [35]. All the treated rats had survived for more than two months without any obvious toxicity response. Considering that the injected probe dosage was much lower than conventional clinical dosage and well tolerated by the animals, the results demonstrated that the probes were effective contrast agent for noninvasive MR imaging. In clinical applications, they would show good performance in indicating organ lesions, evaluating atherosclerosis, and labeling tumors [36, 37].

4. Conclusions

In summary, a convenient and green route has been established for synthesizing water-soluble hexagonal-phase NaYF4:Ce,Tb,Gd NCs, which demonstrated high efficiency for both fluorescence imaging and -positive contrast-enhanced MRI. Compared with previously reported bioprobes, the NaYF4:Ce,Tb,Gd NCs provided the dual-modality bioimaging, in which the fluorescence imaging could provide cellular- or molecular-level information with near single-molecule sensitivity, while MRI images could provide noninvasive in vivo imaging to clearly show organ lesions. Due to the combined presence of efficient optical and MR imaging capabilities, the proposed NaYF4:Ce,Tb,Gd nanoprobes held great promise for simultaneous bimodal fluorescence and MR bioimaging.

Acknowledgments

The authors acknowledge financial support from the Natural Science Foundation of China (10875092, 10904119, 81030027, 30871432) and the China Postdoctoral Science Special Foundation (201003498). This work is also funded by Open Research Fund Program of the State Key Laboratory of Virology of China.

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Copyright © 2011 Wen Ting Ren et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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