Rare-earth doped radioluminescent hydrogel as a potential phantom material for 3D gel dosimeter

2.1 Materials

Gadolinium chloride hexahydrate (GdCl₃·6H₂O), europium chloride hexahydrate (EuCl₃·6H₂O), 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959), sodium diethyldithiocarbamate trihydrate (Na(ddtc)·3H₂O), oleylamine, 1-octadecene, and 1,10-phenanthroline (C₁₂H₈N₂) were purchased from Aladdin Reagent (Shanghai, China). Cyclohexane, chloroform, acrylamide (AAm), N,N′-methylenebisacrylamide (BIS), acetone, and absolute ethanol were purchased from Sinopharm Chemical Reagent (Shanghai, China). Oleic acid was obtained from Macklin Biochemical (Shanghai, China). DSPE-PEG_5k-Mal was bought from Yare Biotech (Shanghai, China). All chemicals were used as received without further purification. Nitrogen was obtained from Jinhong Gas (Suzhou, China). Deionized (DI) water was produced by a Milli-Q Plus system (USA).

2.2 Preparation of Gd₂O₂S:Eu nanoparticles

Synthesis of precursor Gd(ddtc)₃(Phen): in a 3-neck round bottom flask, Phen·H₂O (1 mmol, 40 mL) solution was stirred and heated to 100°C to which was added a solution of GdCl₃·6H₂O (1 mmol, 20 mL) under vigorous stirring. After that, Na(Dalkdtc)·H₂O (3 mmol, 40 mL) solution was added dropwise to the flask under constant stirring for 2 h. After the reaction, the precipitate was washed several times and dried in a vacuum for further use (14,15).

Synthesis of precursor Eu(ddtc)₃(Phen): the three raw materials, EuCl₃·6H₂O (1 mmol, 10 mL), Phen·H₂O (1 mmol, 40 mL), and Na(Dalkdtc)·H₂O (3 mmol, 20 mL) were used. The synthesis procedure was the same as Gd(ddtc)₃(Phen).

The Gd₂O₂S:Eu nanoparticles (the patterns match well with the standard Gd₂O₂S reflection, JCPDS No. 026-1422) were synthesized via a typical method with slight modification (16,17,18). In a typical procedure, 0.5 g of Gd(ddtc)₃(Phen) and 0.05 g of Eu(ddtc)₃(Phen) were added to a mixed solution of oleylamine (30 mmol, 9.84 mL), oleic acid (5 mmol, 1.6 mL), and 1-octadecene (30 mmol, 7.58 g) at room temperature under constant stirring. To remove air, nitrogen was continuously pumped into the 3-neck round bottom flask. The mixture was heated to 120°C and kept for about 30 min until a homogeneous, clear greenish-yellow solution was formed. Then, the nitrogen flow was stopped and the solution was rapidly heated to 290°C, over 5 min and kept for 2 h under constant stirring. The solution was cooled to room temperature and the Gd₂O₂S:Eu nanoparticles were precipitated by adding excess precipitant (hexane/acetone, 1:5). Then, the nanoparticles were washed and dried in a vacuum oven at room temperature for further use.

2.3 Modification of hydrophobic Gd₂O₂S:Eu nanoparticles

About 100 mg of DSPE-PEG_5k-Mal was added to 10 mL of chloroform to which was added 20 mg of Gd₂O₂S:Eu in 5 mL chloroform with ultrasonication. After stirring for 6 h at room temperature, the chloroform was evaporated by pumping nitrogen. Then, the residue was re-dispersed in 5 mL of DI water with the aid of sonication for 30 min. The resulting solution was filtered through a 0.2 μm membrane filter and water-dispersible Gd₂O₂S:Eu@PEG nanoparticles were obtained after centrifugation.

2.4 Synthesis of composite hydrogel

In a typical procedure, the precursor of composite hydrogel was obtained by mixing designated contents of AAm (0.4 g), BIS (0.8 mg), Gd₂O₂S:Eu@PEG (50 mg) and photoinitiator Irgacure 2959 (0.4 mg, relative to the concentration of AAm), and DI water (4 mL) in a glass vial with ultrasonication for 5 min to ensure homogeneous dispersion. After purging with nitrogen for 30 min, the vial was irradiated under 365 nm UV light (distance = 5 cm, intensity = 20 mW cm⁻²) for 1 h.

3.1 Transmission electron microscopy measurements

The morphology of nanoparticles was investigated by transmission electron microscopy (TEM, Tecnai F20, FEI, USA). The samples were diluted and then dripped on copper grids. Before TEM observation, the samples were dried at room temperature for 24 h and then heated under a mercury lamp for 15 min.

3.2 Particle size analysis

The hydrodynamic diameters of nanoparticles were determined by dynamic light scattering (DLS, Zetasizer Nano ZS90, Malvern, UK). The samples were dispersed in DI water and chloroform. Approximately 2 mL of the diluted solution after ultrasonication for 5 min was analyzed.

3.3 FT-IR spectra measurements

FT-IR spectra of the ground samples (Gd₂O₂S:Eu and Gd₂O₂S:Eu@PEG) were recorded on a Nicolet iS50 ATR FTIR spectrometer (Thermo Fisher Scientific, USA).

3.4 Thermal stability measurements

Thermogravimetric data were recorded on an SDT 2960 thermal gravimetric analyzer (TGA, TA Instruments, USA). The fully dried samples (5–10 mg) were added to an alumina crucible. The temperature range was 30–900°C and the samples were heated under a nitrogen atmosphere at a rate of 10°C min⁻¹.

3.5 Determination of luminescence property

The fluorescence emission spectra were obtained using an FLS 980 spectrofluorometer (Edinburgh Instruments, UK). Combined with the existing conditions of the laboratory, the Nova spectrometer (Fuxiang Optica, China) and the D8 Advance X-ray diffraction (Bruker, US) were used to measure the radioluminescence of the products. The ray energy (maximum energy is 40 kV) used in this experiment was kilovolt level radiation, which was different from the megavolt level radiation used in radiotherapy. The samples with a size of 1 cm³ were placed on the specimen stage directly without any container. The measurement voltage of the D8 XRD was set to 40 kV, the current range was 15–40 mA, and the interval was 5 mA. The dose rates of different tube currents were 0.67, 0.89, 1.11, 1.33, 1.56, and 1.78 cGy. A rough estimation of the dose can be calculated based on the dose rate and measurement time. The probe was fixed in a suitable position of D8 XRD and connected to a Nova spectrometer (out of the D8 XRD) through an optical fiber. For reflection mode measurement, the integration time of the spectrometer was 5,000 ms, and the CCD cooling temperature was −20℃.

4.1 Micromorphology of the nanoparticles

From the transmission electron microscopy (TEM) images and dynamic light scattering (DLS) data in Figures 1 and 2, neither obvious morphological change nor severe particle aggregation was observed, and the TEM images of Gd₂O₂S:Eu nanoparticles showed a platy structure with a hydrodynamic diameter of ∼27 nm, which was smaller than that of Gd₂O₂S:Eu@PEG (∼53 nm). These results intuitively indicated that the modification was successful.

Figure 1

TEM images of Gd₂O₂S:Eu before (a) and after modification (b).

Figure 2

Particle size of Gd₂O₂S:Eu before and after modification measured by DLS.

4.2 FT-IR spectra

FT-IR spectroscopy was performed to verify the chemical composition of the products. Figure 3 illustrates the FT-IR spectra of Gd₂O₂S:Eu and Gd₂O₂S:Eu@PEG. The Gd₂O₂S:Eu nanoparticles showed characteristic peaks at 2,921 and 2,851 cm⁻¹ that could be attributed to C–H stretching vibration; the absorption peaks at 1,596 and 1,420 cm⁻¹ could be attributed to the N–H stretching vibration and COO⁻ symmetric stretching, respectively; and the absorption peaks at 1,072 cm⁻¹ could be attributed to the C–N stretching vibration. These absorption peaks indicated that oleylamine and oleic acid were present in the unmodified nanoparticles as stabilizers (19). For Gd₂O₂S:Eu@PEG, the absorption peak at 1666.8 cm⁻¹ belonging to the C═O stretching vibration almost disappeared; and the modified material also had a broad, weak band stretching at 3,200–3,500 cm⁻¹, attributed to N–H. These two peaks were characteristic absorption peaks of secondary amine groups in PEG (20). The absorption peaks at 2,881 and 962 cm⁻¹ were attributed to the –CH₂ stretching vibration and the –CH out-of-plane bending vibration, respectively, and a strong absorption peak at 1,097 cm⁻¹ could be ascribed to the C–O stretching vibration; these three peaks belong to PEG. The results of FT-IR spectra confirmed that the modification of Gd₂O₂S:Eu was successful in terms of chemical composition (21).

Figure 3

FT-IR spectra of Gd₂O₂S:Eu before and after modification.

4.3 Thermogravimetric analysis

Figure 4 illustrates the TGA curves. For Gd₂O₂S:Eu, the residual weight percent of the sample was 66.5% and the curve could be divided into four main phases. The first phase occurred in the temperature range 100–350°C and was attributed to the decarboxylation of oleate groups. In the second phase (350–490°C), decomposition of the major part of organic-based ligands occurred, resulting in the major weight loss. In the third phase (490–720°C), the reaction between the free carbon and excess oxygen (formed by the decomposition of Gd₂O₂S) took place, which might produce CO₂ and CO (22). In the last phase (720–900°C), a slight weight loss was attributed to the removal of H₂S (formed by a limited degradation of the oxysulfide phase). For Gd₂O₂S:Eu@PEG, the total weight loss between 30°C and 900°C was 79.5%, corresponding to four-fifth of the sample that had been removed as volatile substances during the heating process. The major weight loss was observed in the temperature range of 370–430°C, and the main reason was the decomposition of a large amount of PEG. TGA analysis also indicated that the surface modification of nanoparticles was successful from another aspect.

Figure 4

Thermogravimetric analysis of Gd₂O₂S:Eu before and after modification.

4.4 Analysis of fluorescence property

As shown in Figure 5, the solutions of Gd₂O₂S:Eu and Gd₂O₂S:Eu@PEG were photographed under 254 nm UV light (tube 1, water; tube 4, chloroform). Both tube 2 and tube 3 are red, while the color is slightly lighter and the intensity is weaker of tube 2, which may result from the concentration and the optical quenching in water. The excitation spectrum has a wide range (200–400 nm), which is due to the charge transfer band between the anions and the Eu³⁺ ions. The excitation around 310 nm (Xe lamp as an excitation source) is attributed to the transition from the S²⁻ to Eu³⁺, which may yield an ideal intensity of emission. Figure 6b–d shows the emission spectra of the Gd₂O₂S:Eu, Gd₂O₂S:Eu@PEG, and the composite hydrogel. The significant emission peaks are at about 625 nm (due to the forced electric-dipole ⁵D₀ → ⁷F₂ transitions of the Eu³⁺) (18), which is consistent with the results observed in the above photograph. From these results, it can be seen that the modification of nanoparticles or blending into gel does not change the fluorescence property. As shown in Figure 7, the composite hydrogel (right) and control sample were photographed under daylight lamp and 254 nm UV light. The composite gel (Figure 7d) is red and clearly indicates that Gd₂O₂S:Eu@PEG nanoparticles were successfully incorporated into the hydrogel.

Figure 5

Photographs of water, Gd₂O₂S:Eu@PEG aqueous solution, Gd₂O₂S:Eu chloroform solution, and chloroform (under 254 nm UV).

Figure 6

(a) Excitation spectra of Gd₂O₂S:Eu. (b–d) Emission spectra of Gd₂O₂S:Eu, Gd₂O₂S:Eu@PEG, and the composite gel (λ _ex = 310 nm).

Figure 7

(a and b)Photographs of control sample (without Gd₂O₂S:Eu@PEG) and composite gel under daylight lamp. (c and d) Under 254 nm UV light.

4.5 Analysis of radioluminescence property

Figure 8 shows the emission spectrum of the composite gel excited by X-ray. The significant emission peak is located near 625 nm, and the result is consistent with that of the UV-excited emission peak. This may confirm that the composite gel has good radioluminescence properties.

Figure 8

The emission spectrum of the composite gel excited by X-ray.

Figure 9a shows the relationship between different tube currents and light intensity (excited by X-ray). This result indicates that the light intensity is proportional to the tube current when the tube voltage is constant. As shown in Figure 9b, the value of light intensity (Y) is proportional to the magnitude of the tube current (X) with good linearity (R ² = 0.9889). Quantitatively, the light intensity can be determined as a function of the tube current of X-ray (Eq. 1):

Figure 9

(a) The curves of light intensity with different tube currents and (b) the light intensity of the composite gel as a function of varying tube currents.

This may demonstrate that the composite gel features a good linear response to the dose of X-ray.

4.6 Discussion

Gd₂O₂S:Eu particles were chosen because they emit red light (625 nm) with good penetration ability. Among the commonly used rare earth luminescent materials, Tb-doped nanomaterials also have radioluminescence properties and emit green light (550 nm) with weak penetrating ability. In order to facilitate the research and be limited by the experimental conditions, the composite gel synthesized in the experiment had a small size (see Figure 7). The next research direction is to adjust the wavelength of the emitted light and to synthesize radioluminescent rare-earth nanomaterials, which can emit the second near-infrared (NIR-II) light. The NIR-II light has a wavelength ranging from 1,000 to 1,700 nm, which has the better penetrating ability and can reduce scattering and autofluorescence (23). The synthesis can be achieved by doping with Ln³⁺ (such as Yb³⁺, Er³⁺, Ho³⁺, and Nd³⁺).

In order to acquire the dose distribution information, the spatial and directional information of the optical signal from the composite gel can be recorded using a plenoptic camera (also called a light field camera). The Electronic Portal Imaging Device (EPID) integrated with linear accelerator can record the relative 2D beam’s eye view (BEV) projection of the incident dose distribution easily. The 3D emitted light pattern of the composite gel may be reconstructed by spatial and angular information. Using an iterative reconstruction algorithm, the optical signal received by the camera can be back-projected to the composite gel. The 3D dose distribution can be acquired from the 3D light pattern, as the intensity of the optical signal is proportional to the energy deposited in the composite gel. The reconstruction model is as follows:

where p → is the given plenoptic projection and D → is the relative emitted optical signal distribution discretized into voxels. “A” represents the system matrix that describes how the composite gel is imaged by the plenoptic camera. The constraints of Eq. 2 can be satisfied using the expectation-maximization algorithm and the reconstruction process is also constrained by the relative shape of the BEV dose projection and the depth in the composite gel (24).

Tissue equivalence and reusability: According to the above synthesis method, the mass of water in the composite gel accounts for 89.86% of the total mass. This conclusion is consistent with the water content in the BANG-1 polymer gel dosimeter (25). The reusability in this article is compared to the polymer gel dosimeter, Fricke gel dosemeter, and so on. Radioluminescence is an inherent property of the composite gel and it will not lose this property after irradiation.

The other important dosimetric features and detailed reconstruction of 3D dose distribution are the focus of the follow-up research.