Synthesis of Gd₂O₃:Eu nanoplatelets for MRI and fluorescence imaging

Abstract

We synthesized Gd₂O₃ and Gd₂O₃ doped by europium (Eu) (2% to 10%) nanoplatelets using the polyol chemical method. The synthesized nanoplatelets were characterized by X-ray diffraction (XRD), FESEM, TEM, and EDX techniques. The optical properties of the synthesized nanoplatelets were investigated by photoluminescence spectroscopy. We also studied the magnetic resonance imaging (MRI) contrast enhancement of T1 relaxivity using 3 T MRI. The XRD for Gd₂O₃ revealed a cubic crystalline structure. The XRD of Gd₂O₃:Eu³⁺ nanoplatelets were highly consistent with Gd₂O₃ indicating the total incorporation of the Eu³⁺ ions in the Gd₂O₃ matrix. The Eu doping of Gd₂O₃ produced red luminescence around 612 nm corresponding to the radiative transitions from the Eu-excited state ⁵D₀ to the ⁷F₂. The photoluminescence was maximal at 5% Eu doping concentration. The stimulated CIE chromaticity coordinates were also calculated. Judd-Ofelt analysis was used to obtain the radiative properties of the sample from the emission spectra. The MRI contrast enhancement due to Gd₂O₃ was compared to DOTAREM commercial contrast agent at similar concentration of gadolinium oxide and provided similar contrast enhancement. The incorporation of Eu, however, decreased the MRI contrast due to replacement of gadolinium by Eu.

Background

Gadolinium is a rare earth (RE) metal that has paramagnetic properties that enhance the magnetic resonance imaging (MRI) signal [1]. Gadolinium ions have seven unpaired electrons in the valence shell and hence have a high magnetic moment suitable for MRI. Gadolinium accelerates proton relaxation and hence shortens the T1 relaxation time. Gadolinium complexes such as Gd-DTPA and Gd-DOTA are some of the most commonly used clinical MRI contrast agents [2,3]. Gadolinium is a good host material for luminescence applications due to its thermal, chemical, and photochemical stability [4-6].

The gadolinium oxide doped with Eu³⁺ (Gd₂O₃:Eu³⁺) is paramagnetic with attractive photoluminescence (PL) properties. It is widely used in fluorescence lamps, television tubes, biological fluorescent labeling [5,7,8], MRI contrast [9-11], hyperthermia [12], immunoassays [13,14], and display applications [15-18]. Eu³⁺-doped Gd₂O₃ nanoparticles are red-emitting phosphors with bright luminescence and long-term photothermal stability [19]. Gd₂O₃:Eu³⁺ is also a very efficient X-ray and thermoluminescent phosphor [20]. Eu³⁺-doped CaF₂-fluorophosphate glass composites has intense IR fluorescence and is a promising candidate for IR lasers and amplifiers [21].

Gadolinium oxide and RE gadolinium oxide have been synthesized by many groups using different techniques such as sol-gel [22], polyol [23], flame-spray pyrolysis [24,25], laser ablation [26], hydrothermal [17,27,28], and direct precipitation [29].

In the present work, Gd₂O₃ and Gd₂O₃:Eu³⁺ nanoplatelets were synthesized using the simple and novel polyol chemical method. Detailed structural analysis such as field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and energy-dispersive X-ray EDX are reported. The photoluminescent properties of Eu³⁺-activated gadolinium oxide were investigated. Judd-Ofelt analysis was used to determine the radiative properties of the synthesized nanoparticles from their PL emission spectra. The attractive multifunctional Gd₂O₃ and Gd₂O₃:Eu³⁺ nanoplatelets were investigated form MRI contrast enhancement.

Methods

Synthesis of Gd₂O₃ and Gd₂O₃:Eu³⁺

All reagents were of analytical grade and were used without further purification in the experiment. In this experiment, 0.5 M gadolinium acetate (Gd(OAC)₃) was dissolved in ethanol under continuous stirring. Then 50 wt.% polyethylene glycol (mol. wt 600) was transferred in the solution under continuous stirring. After sometime, dropwise addition of 0.1 M diethylamine was carried out into the reaction solution. For the doping purpose, 2% Eu (EuCl₃) was transferred in the solution. The resultant solution was refluxed at 100°C for 48 h. After the reaction, the flask was cooled to room temperature. The precipitates of Gd₂O₃ were separated from the solution by centrifuging for 30 min with a rotation speed of 3,000 rpm and then washed using deionized water. The rinsing was repeated three to five times to totally remove organic and inorganic ions adsorbed on the surface of the product. The white grayish color product was dried in an oven at 80°C for 24 h. In order to obtain highly crystalline nature of Eu-Gd₂O₃, the product was further calcinated in ambient atmosphere at approximately 600°C for 12 h. Similar procedure was adopted for 5% and 10% europium (Eu) doping.

Characterization

The synthesized products were characterized using X-ray diffraction (XRD), FESEM, TEM, PL, and MRI. The crystal structure of the synthesized nanoparticles was investigated by XRD using a (XRD Shimadzu 6000; Shimadzu, Kyoto, Japan) advance X-ray diffractometer with Cu-Kα radiation source (λ = 1.5418 Å). The FESEM analysis was done using (FESEM JSM-6700F). TEM analysis was done on a high-resolution transmission electron microscope (HRTEM; JEOL, Tokyo, Japan). The PL spectrum was recorded using Shimadzu spectrofluorometer (Shimadzu). The excitation source was a 150-W Xenon lamp with excitation wavelength fixed at 350 nm, and the emission monochromator was scanned in the 450 to 900-nm wavelength range. The MRI contrast enhancement due to different Gd₂O₃ concentrations from a commercial contrast agent, Dotarem® (Guerbet LLC, Bloomington, IN, USA), was compared to the contrast due to Gd₂O₃ nanoparticles and Gd₂O₃ nanoparticles doped with Eu (2% to 10%). The different concentrations were placed in plastic 10 ml test tubes. The test tubes were placed in a plastic test tube holder and imaged in a 3 T MRI scanner (General Electric, Fairfield, CT, USA). A pulse echo T1 sequence was used with pulse repetition rates of 20, 30, 50, 100, 200, 300, 400, 500, and 1,000 ms. The images were then analyzed in order to determine the contrast enhancement due to the nanoparticles and to obtain the T1 relaxation times.

Results and discussion

Structural properties

XRD measurements were used to explore the phase and structure of Gd₂O₃ and Gd₂O₃:Eu³⁺ nanostructures. Figure 1a demonstrates the XRD pattern of Gd₂O₃ and 2%, 5%, and 10% Gd₂O₃:Eu³⁺, respectively. These results confirmed the cubic structure of Gd₂O₃ and Gd₂O₃:Eu³⁺ with spatial group Ia3 (JCPDS card No. 00-012-0797). No other peaks were observed in the XRD spectrum related to impurities. Due to Eu doping, a high-intensity (222) peak shift was observed as shown in Figure 1b. The presence of strong peaks indicates the highly crystalline nature of Gd₂O₃ nanostructures.

Figure 1.

XRD pattern of Gd₂O₃, 2% 5%, and 10% Eu:Gd₂O₃ (a) and high-intensity (222) plane resolved for different Eu concentrations (b).

Figure 2a,b,c,d shows the FESEM images of Gd₂O₃ and Gd₂O₃:Eu³⁺ with different doping concentrations of 2%, 5%, and 10%, respectively. Figure 2a shows fine nanoflakes of Gd₂O₃. It is interesting to note that the thickness of the nanostructures augmented when doped with 2% Eu. Figure 2b shows FESEM micrograph of 2% Gd₂O₃:Eu³⁺ nanoplatelets with some nanocrystals. When the concentration of Eu³⁺ increased to 5%, highly uniform nanoplatelets were formed. The thickness of each nanoplatelet is about 15 to 25 nm (Figure 2c). Figure 2d shows FESEM micrograph of 10% Gd₂O₃:Eu³⁺ irregularly thick nanoplatelets. It is observed that by further increasing the concentration of Eu, the thickness and diameter of nanoplatelets increased significantly. FESEM observation showed clear change in the morphology due to doping from Gd₂O₃ nanoflakes to thick Gd₂O₃:Eu³⁺ nanoplatelets.

Figure 2.

FESEM micrograph of (a) Gd₂O₃, (b) Gd₂O₃:Eu 2%, (c) Gd₂O₃:Eu 5%, and (d) Gd₂O₃:Eu 10%.

Figure 3a,b,c,d,e,f,g,h shows TEM HRTEM images of Gd₂O₃ with different Eu concentrations (2%, 5%, and 10%). The TEM analysis is in agreement with FESEM results in which the evolution of nanoplatelets is observed. The growth of Gd₂O₃:Eu³⁺ nanoplatelets is seen in TEM micrographs. From the HRTEM, the interspacing between the lattice fringes was found to be 0.316 nm which corresponds to growth plane (110) indicating the growth of nanoplatelets along the axis in [001] direction. The energy-dispersive spectrum (EDS) investigation (Figure 4) also confirmed that all the detected peaks are related to Gd, O, and Eu, indicating a chemically pure Gd₂O₃:Eu³⁺ phase. No other peak related to impurities was found in the samples.

Figure 3.

TEM micrographs of (a,b) Gd₂O₃, (c,d) Gd₂O₃:Eu 2%, (e,f) Gd₂O₃:Eu 5%, and (g,h) Gd₂O₃:Eu 10%.

Figure 4.

Energy dispersion spectrum (EDS) obtained from Gd₂O₃:Eu 2%.

Fluorescence properties

Figure 5 shows the PL spectra of Eu³⁺-doped Gd₂O₃ nanoparticles for different dopant concentrations (2%, 5%, and 10%) recorded in the 450 to 900-nm wavelength range. The spectra have five emission lines at 580, 593, 612, 652, and 708 nm corresponding to ⁵D₀ → ⁷F_J (J = 0, 1, 2, 3, 4) transitions, respectively. The two transitions corresponding to ⁵D₀ → ⁷FJ (J = 5, 6) are presented in the inset of Figure 5. We recorded a strong PL peak centered around 612 nm in addition to many smaller peaks for three different concentrations of Eu in Gd₂O₃. The high red luminescence signal intensity for Eu-doped samples around 612 nm corresponds to the radiative transitions from the Eu-excited state ⁵D₀ to the ⁷F₂ state (Figure 5). This sharp intense line indicates a complete incorporation of the dopant ions into Gd₂O₃ nanocrystals by replacing Gd³⁺ in a preferred C₂ site symmetry compared to the S₆ symmetry indicated by the ⁵D₀ to the ⁷F₁ transition [30]. In addition to the intense peak, numerous smaller peaks have been identified in the visible spectral range between 500 and 800 nm corresponding to the transitions from excited to the ground energy level of Eu. We also observed an increase of the emission intensities when the Eu³⁺ concentration increases to reach a maximal value at 5 mol%. Then the emission intensities decrease because of the concentration quenching. This emission behavior resembles exactly the fluorescence of Eu³⁺-doped phosphors [29,31]. Based on these measurements, we deduced an energy level scheme (Grotrian diagram) of the observed transition in PL spectra as shown in Figure 6 and Table 1.

Figure 5.

Photoluminescence spectrum of Gd₂O₃ and Eu (2% to 10%) doping of Gd₂O₃.

Figure 6.

Schematic presentation of photoluminescence observed energy transitions.

Table 1.

Photoluminescence transitions observed for Gd ₂ O ₃ :Eu ³⁺ nanoplatelets

label	Wavelength (nm)	Transition from	To
1	580	5D0 →	7F0
2	593	5D0 →	7F1
3	612	5D0 →	7F2
4	652	5D0 →	7F3
5	708	5D0 →	7F4
6	538	5D1 →	7F1
7	554	5D1 →	7F2

CIE chromaticity coordinates

The luminescent intensity of the emission spectral measurements has been characterized using the CIE1931 chromaticity diagram (Figure 7) to get information about the composition of all colors on the basis of color matching functions $\overline{x}\left(\lambda \right)$, $\overline{y}\left(\lambda \right)$, and $\overline{z}\left(\lambda \right)$ [32,33]. The (x, y) coordinates are used to represent the color and locus of all the monochromatic color coordinates. The values of the color chromaticity coordinates (x, y) were found to be (x = 0.6387; y = 0.3609) for Gd₂O₃:Eu³⁺ (2%), (x = 0. 6447; y = 0. 3550) for Gd₂O₃:Eu³⁺ (5%), and (x = 0. 6477; y = 0.3520) for Gd₂O₃:Eu³⁺ (10%) (Figure 7). The color coordinates are all in the pure red region of the chromaticity diagram. Indeed, the present nanoplatelets Gd₂O₃:Eu³⁺ give emission in the red region with appreciable intensity for fluorescence imaging.

Figure 7.

The CIE coordinate for Eu³⁺-doped Gd₂O₃ upon excitation at 365 nm.

Judd-Ofelt and radiative analysis

The Judd-Ofelt theory [34,35] is the most widely used and known theory in the analysis of spectroscopic properties of rare earth ions in different hosts. The great appeal of this theory is the ability to forecast the oscillator strengths in absorption and to give information about the luminescence branching ratios and lifetimes by using only three parameters, Ω_k (k = 2,4,6) [36-39].

For the particular Eu rare earth ion-doped materials, the J-O intensity parameters are calculated with two different methods. The first method is based on the optical absorption spectra. The second method is referred to the analysis of emission spectra at room temperature. It is noteworthy to mention that in the case of Eu³⁺-doped nontransparent hosts, we are not always able to measure the absorption spectra [40,41]. Therefore, for Gd₂O₃:Eu³⁺ nanoplatelets, the second method allows the calculation of J-O parameters.

Table 2 shows the type of transitions for Eu³⁺ ion. The transition ⁵D₀-⁷F₁ is the only allowed magnetic dipole transition. The transitions from ⁵D₀-⁷F_J′ (J′ = 0, 3, and 5) are forbidden according to electric and magnetic selection rules. In other words, their magnetic and electrics dipoles (A^ed and A^md) are zero. However, these states are not pure and are mixed with other states by crystal-field interaction, which allow these transitions to be observed as is shown in Figure 5. The transitions ⁵D₀-⁷F_J′ (J′ = 2, 4, and 6) are allowed electric dipole transitions and depend solely on Ω_k (k = 2, 4, 6).

Table 2.

Wavenumbers, transition rates, and branching ratio for ⁵ D ₀ → ⁷ F _J' ( J ' = 0 − 6) of Eu ³⁺ ions in Gd ₂ 0 ₃

Transition	Type	Wavenumber (cm −1 )	Transition rate (s −1 )	Branching ratio β (%)
5D0 → 7F0	Forbidden	17,241	19.1132	1.9109
5D0 → 7F1	Magnetic dipole	16,863.4	66.5612	6.6548
5D0 → 7F2	Electric dipole	16,339	876.9950	87.6820
5D0 → 7F3	Forbidden	15,337	10.0094	1.0007
5D0 → 7F4	Electric dipole	14,124	27.0115	2.7006
5D0 → 7F5	Forbidden	13,422	0.4321	0.0432
5D0 → 7F6	Electric dipole	12,422	0.0534	0.0053

Since it is well known that magnetic dipole transitions in rare earth ions are independent of the ion’s surroundings, the magnetic dipole radiative transition rates A^md can be evaluated using the following expression:

$$A_{J-J\text{'}}^{\mathrm{m}\mathrm{d}}=\frac{64{\pi }^4{\nu }_{\mathrm{m}\mathrm{d}}^3}{3h\left(2J+1\right)}{n}^3{S}_{\mathrm{m}\mathrm{d}}$$

Where n is the refractive index, (2J + 1) is the degeneracy of the initial state J and v_md is the transition energy of the ⁵D₀→⁷F₁ transition (cm⁻¹), h is Planck constant (6.63 × 10²⁷ erg s). S_md is the magnetic dipolar transition line strength, which is independent of host matrix and is equal to 11.26 × 10⁻⁴² (esu)² cm² [42]. From the definition of the $A_{J-J^{\prime }}^{\mathrm{m}\mathrm{d}}$, the refractive index can be calculated to be 1.58.

For a particular transition, the intensity (I) of an emission transition is proportional to the radiative decay rate $A_{{}_{}{}^7\mathit{F}_{\mathit{J}}\prime }$, of that transition, which equals the reciprocal of intrinsic lifetime τ₀. The intensity is also proportional to the area under that emission curve [43]. Thus, the intensity of an emission transition can be written as [44] follows:

$$I=\eta {\displaystyle \sum _{J^{\text{'}}=0,1\dots 6}}{A}_{{}_{}{}^7\mathit{F}_{\mathit{J}}\text{'}}$$

The fluorescence lifetime of the nanoparticles is approximately 1 ms [45,46]. The values of $A_{{}_{}{}^7\mathit{F}_{\mathit{J}}\prime }$, shown in Table 2 were determined by calculating the constant η. The radiative branching ratio shown in Table 2 was calculated using ${\beta }_{J-J\text{'}}=\frac{A_{J-J\text{'}}}{{\displaystyle {\sum }_{J^{\text{'}}=0,1\dots 6}}{A}_{J-J\text{'}}}$

The electric dipole transitions ⁵D₀-⁷F_J′ (J′ = 2, 4, and 6) can be represented by using the three J-O parameters Ω_k (k = 2, 4, 6) as follows [47,48]:

$$A_{J-J\text{'}}^{\mathrm{e}\mathrm{d}}=\frac{64{\pi }^4{e}^2{\nu }^{3}n\left(n^2+2\right)2}{27h\left(2J+1\right)}{\displaystyle \sum _{k=2,4,6}}{\mathrm{\Omega }}_k{\left|\psi J\left|U^{\left(k\right)}\right|\psi \text{'}J\text{'}\right|}^2$$

where h is the Planck’s constant, ν is the transition energy of electric dipole transition (in cm⁻¹) and e is the charge of an electron, and ${\left|〈{}_{}{}^{5}D_0^{}\left|U^{\left(k\right)}\right|F_{J^{\prime }}〉\right|}^2$ is the double-reduced matrix element. All of the matrix elements for ⁵D₀ → ⁷F_J′ transitions are zero [49-51], except those for the ⁵D₀-⁷F₂ transition (U⁽²⁾ = 0.0028), the ⁵D₀-⁷F₄ transition (U⁽⁴⁾ = 0.002) and the ⁵D₀ → ⁷F₆ transition (U⁽⁶⁾ = 0.0002). Thus, the values of Ω_k can be calculated using the emissions of ⁵D₀ → ⁷F_J' (J' = 2, 4, 6). The results of our calculations are shown in Table 3 together with the Ω_k values of Eu³⁺ ions in other hosts [41,51-57].

Table 3.

J-O parameters of Eu ³⁺ in several compounds

Compounds	Ω 2 (10 −20 cm 2 )	Ω 4 (10 −20 cm 2 )	Ω 6 (10 −20 cm 2 )	Reference
Gd2O3:Eu3+ nanoplatelets	28.07	1.87	0.05	This work
KLTB:Eu3+	14.20	~0	2.40	Saleem (2010) [54]
L4BE:Eu3+	17.56	~0	4.26	Babu (2000) [55]
LaOF:Eu3+	56.3	13.9	-	Grzyb (2011) [56]
Gd2O3:Eu3+ nanocrystals	5.61	1.57	-	Liu (2006) [57]
Eu0.08K0.075Ba0.845TiO3	6.92	1.84	-	Li (2008) [53]
Gd2(W0.5Mo0.5)O6:Eu3+	6.91	0.22	-	Yue (2011) [41]
Fluorosilicate glass ceramic	1.38	0.84	-	Zhao (2007) [52]
Fluorophosphate glass	3.24	5.11	2.89	Balda (1996) [51]

These intensity parameters follow the tendency Ω₂ > Ω₄ > Ω₆ found for other materials containing Eu³⁺ ions. It is well known that Ω₂ is most sensitive to the local structure and its value is indicative the higher asymmetry and higher covalence around the Eu³⁺ ions with their surrounding ligands [58]. However, the parameter Ω₆ is inversely proportional to the Eu-O band covalency, since it is more strongly affected by the overlap integrals of 4f and 5d orbitals than Ω₂ and Ω₄ [58].

The MRI contrast enhancement

We have tested MR image enhancement properties of the gadolinium nanoparticles and the Eu-doped nanoparticles using the MRI scanner at King Fahd Specialist Hospital. We also compared the MR images to commercially available MRI contrast agent (DOTAREM) using the same gadolinium concentrations (Gd molar concentrations 0.05, 0.1, 0.2 and 0.4 mM). The gadolinium oxide nanoparticles provided comparable MR image enhancement to the commercially used contrast agent DOTAREM (Figure 8). The addition of Eu reduced the MRI contrast due to the replacement of gadolinium atoms by the Eu atoms in the material structure. Figure 9 shows the contrast relative to water due to Dotarem, Gd₂O₃, and Gd₂O₃:Eu (2% to 10%) for Gd molar concentration from 0.05 to 0.4 mM. Figure 10 shows the variation of the T1 relaxation time for Dotarem, Gd₂O₃, and Gd₂O₃:Eu (2% to 10%) for Gd molar concentration from 0.05 to 0.2 mM.

Figure 8.

MRI of different concentrations (0.05 to 0.4 mM) of Gd₂O₃ and Gd₂O₃:Eu 2% to 10% compared to the same concentrations of commercial contrast agent (Dotarem).

Figure 9.

The contrast relative to water due to Gd₂O₃ and Gd₂O₃: Eu (2% to 10%) for Gd₂O₃ molar concentrations from 0.05 to 0.4 mM.

Figure 10.

MRI relaxation time (T1) for Gd₂O₃ and Gd₂O₃:Eu (2% to 10%) for molar concentrations from 0.05 to 0.2 mM.

Conclusions

We synthesized nanoplatelets of Gd₂O₃ and Gd₂O₃:Eu³⁺ (2%, 5%, and 10%). The doping with Eu preserved the crystalline cubic structure of the Gd₂O₃ matrix. The MRI contrast of the Gd₂O₃ was comparable to the commercial gadolinium-based contrast agent DOTAREM at the same gadolinium concentrations. Doping the Gd₂O₃ with Eu exhibits very strong PL spectra especially in the red region at 612 nm corresponding to the radiative transitions from the Eu-excited state ⁵D₀ to the ⁷F₂ state. The strongest red PL was obtained at 5% Eu doping concentration. The stimulated CIE chromaticity coordinates and Judd-Ofelt analysis were used to obtain the radiative properties of the sample from the emission spectra. However, doping with Eu has decreased the MRI contrast and increased the T1 relaxation time. The MRI contrast enhancement decreased with increasing Eu doping concentration due to the replacement of the gadolinium atoms with Eu. The synthesized nanoparticles can be used as a contrast agent for magnetic resonance imaging. The PL in the red region can be exploited in labeling biological materials for fluorescence microscopy applications. The synthesized nanoplatelets have to be coated or encapsulated in biocompatible material such as polyethylene glycol to be used for in vivo MRI of cancer tissues with or without targeting molecules.