1. Introduction

In medicine, addressing cancer with efficient and sensible solutions remains a significant challenge. Over the years, researchers have developed a variety of treatments. Among them, photodynamic therapy (PDT), a non-invasive cancer therapy with high specificity, has been growing rapidly [1]. Conventional photosensitizers for PDT are usually activated by UV-vis or near-infrared (NIR) light, but the penetration depth of these lights are both limited, thus narrowing their applications in deep disease treatment [2]. Another method of using X-rays and nanoscintillators to excite fluorescence and activate photosensitizers (PSs) has been proposed, which is called X-rays induced photodynamic therapy (X-PDT) [3]. Due to its high energy and strong penetration capacity, the introduction of X-rays can break the depth limitation of conventional PDT and facilitate deep-seated tissue therapy [4].

As the key component of X-PDT, scintillation nanocrystals with response to X-ray have been developed in recent years [5]. Rare-earth doped nanocrystals are classical photoconverters, and their participation in the PDT process is feasible [6]. Ce³⁺ doped lutetium silicates bulk crystals own high stability, strong absorption for X-ray and γ-ray, and high luminescence efficiency, which benefit to their application in computerized tomography (CT), positron emission tomography (PET), and high-energy physics (HEP) areas [7,8]. Hence it is worth wondering if such typical scintillation crystal could be reduced to micro-nano size and have excellent properties for use in X-PDT. Xie et al. synthesized Ce³⁺-doped lutetium oxyorthosilicate low temperature phase A-Lu₂SiO₅@SiO₂ (A-LSO:Ce³⁺@SiO₂) core-shell nanospheres [9]. A broad absorption band centered at about 450 nm under X-rays excitation was observed, indicating that lutetium silicate nanoparticles doped with Ce³⁺ were expected to be constructed and applied to X-PDT.

For expanding the application scenarios, the modification of nanoscintillators has been of interest to researchers [2]. It would be interesting to construct a particle that activates several PSs at the same time, so that the type of X-ray converters required can be reduced and the efficiency of the PDT process can be increased to some extent when multiple PSs are used for combination therapy. Generally, different PSs have their own strong absorption band. Thus it is feasible to extend the emission band of the X-rays convertors by co-doping rare-earth ions for the achievement of the simultaneous activation. In biological tissues, red light has stronger penetration than blue light [10] and is more favorable to activating proper PSs in the vicinity of the nanoscintillators, so it would be beneficial to consider introducing red light into the previously prepared blue-emitting LSO:Ce [9] for X-PDT. The trivalent samarium ion Sm³⁺ possesses characteristic emission in red region which can be used for an extra red light. Ce³⁺/Sm³⁺ co-doped luminescent materials and the contained ET mechanism have been currently revealed [11–13]. Compared with red-emitting Eu³⁺, Ce³⁺/Sm³⁺ pairs avoid metal-metal charge transfer (MMCT) that occurs in Ce³⁺/Eu³⁺ pairs [14], allowing for required light conversion. Existing discussions, however, have mostly been based on the spectra excited by UV-vis, few work involves the presence of ET in Ce³⁺/Sm³⁺ pairs under X-rays excitation. In other words, the practicability of LSO co-doped with Ce³⁺ and Sm³⁺ in X-PDT has not yet been demonstrated.

Coating outer layers on luminescent nanoparticles to construct core-shell structures is a common approach for surface modification. Silica has been used as coating shell due to its high chemical stability and optical transparency. Especially, for biological applications, the silica is non-toxic and biocompatible [15,16], and its surface can be further functionalized [17–20]. In this work, in order to explore their potential applications in X-PDT, Ce³⁺/Sm³⁺ co-doped A-Lu₂SiO₅@SiO₂ (LSO:xCe³⁺, ySm³⁺@SiO₂) core-shell nanoparticles were prepared, and the energy transfer mechanism between Ce³⁺ and Sm³⁺ was revealed under UV excitation. Moreover, the presence of ET in Ce³⁺/Sm³⁺ under X-ray excitation was verified, while the light yield of nanoscintillators has been further investigated.

2. Experimental

2.1 Materials

All chemical reagents including absolute ethanol (Analytical Reagent, A.R.,GHTECH), nitric acid (A.R.,Guangzhou), tetraethyl orthosilicate (TEOS, 98%, Aladdin), ammonia hydroxide (A.R.,Guangzhou), urea (99.5%, Aladdin), lutetium(III) oxide (99.99%, A&C Rare Earth Materials Center), samarium acetate hydrate (99.9%, Aladdin), cerium acetate hydrate (99.9%, Aladdin) were used as starting materials without further purification. Commercial LYSO:Ce bulk crystal (Qiandong Rare Earth Group Co., Ltd.), which are ground to powder, will be used as the reference powder for light yield estimation.

2.2 Preparation of the Lu(NO₃)₃ solution

Solution of 0.1 mol/L Lu(NO₃)₃ were prepared by dissolving 4.9732 g of Lu₂O₃ in 15 ml nitric acid, then the superfluous nitric acid was evaporated under constant heating and stirring, and followed by dissolving the obtained solid products into 250 ml volumetric flasks with distilled water.

2.3 Preparation of Ce³⁺ and Ce³⁺/Sm³⁺ doped Lu(OH)CO₃ precursors

Lu(OH)CO₃:Ce³⁺ precursors were synthesized via coprecipitation route using urea as precipitators. Firstly, a certain volume of 0.1 mol/L Lu(NO₃)₃, 0.02 mol/L Ce(Ac)₃ and 0.02 mol/L Sm(Ac)₃ were added into 250 ml single-neck round-bottom flask with 100 ml distilled water according to the stoichiometric ratio of target sample. Then, 3.0 g of urea was dissolved into the solution. With constantly stirring, the mixture was thermally treated at 80 °C in an oil bath pan for 7 h. After reaction, the as-prepared products were collected by centrifugation and washed with distilled water and ethanol four times respectively. Finally, the doped Lu(OH)CO₃ nanospheres were obtained after being dried at 75 °C for one night.

2.4 Preparation of Ce³⁺ and Ce³⁺/Sm³⁺ doped Lu₂SiO₅ @SiO₂ core-shell nanospheres

Typical Stöber method was used to prepare doped Lu₂SiO₅@SiO₂ core-shell nanospheres. 0.0603 g of the doped Lu(OH)CO₃ precursors was ultrasonically dispersed in 50 ml of ethanol in a 100 ml flask for 20 minutes, followed by adding 10 ml distilled water. Next, with mild stirring, 2.0 ml of NH₃·H₂O as catalyst and 0.2 ml of TEOS were added into the solution dropwise in sequence. After that, the mixture was heated at 35 °C and stirred for 12 h. The core-shell nanospheres were collected by centrifugation and washed with water and ethanol for four times dried at 75 °C overnight. Lastly, the obtained nanospheres were annealed at 1000 °C for 14 h in a muffle furnace in atmosphere to form the doped Lu₂SiO₅ @SiO₂.

2.5 Characterizations

The crystal phases of the samples were characterized by powder X-ray diffraction (XRD, RIGAKU, D-MAX 2200 VPC) with a step of 0.02° and a scanning rate of 10°/min, and the scanning angle ranged from 10° to 80° with Cu Kα radiation. The data for Rietveld refinement were collected by BRUKER D8 ADVANCE powder diffractometer(Cu Kα) at room temperature (RT). Morphologies of the obtained samples were characterized by scanning electron microscope (SEM, field-emission SEM, Gemini 500) with an energy dispersive X-ray spectrometer (EDS, Bruker Flat QUAD). The photoluminescence (PL) emission spectra of the obtained core-shell nanospheres were measured by Edinburgh Instruments FLS1000 spectrometer with 450W xenon lamp as excitation source. The decay curves were obtained using a 150W nF920ns flash lamp with a pulse width of 1.0-1.5 ns and pules repetition rate of 0.1-40 kHz. X-ray excited emission spectra were recorded at RT with an X-ray tube with Cu anode operating at 50 kV and 100 µA (Moxtek).

3. Results and discussion

3.1 Crystal structure and morphology

Rietveld refinement result based on the XRD data of the synthesized Lu₂SiO₅@SiO₂ is shown in Fig. 1(a). The XRD is well agreement with that of A-Lu₂SiO₅ (JCPDS 70-3281) with the reliability factors R_wp= 6.821%, R_p =3.520% and R_b= 4.420%, proving the phase purity of the as-prepared sample. The A-LSO@SiO₂ compound is crystallized in a monoclinic structure with space group P2₁/c, and the lattice parameters are a = 8.9418 Å, b = 6.7252 Å, c = 6.5898 Å, β = 104.1800°, V = 384.21ų. The crystal structure of A-LSO@SiO₂ was depicted in Fig. 1(b). It should be noted that the polyhedra in blue are [SiO₄]^4- while the inside atoms are Si. The oxygen atoms that make up these silicon tetrahedra are displayed in smaller forms due to the automatic adjustment of the software Diamond. Considering the ionic radii and valence states factors, doped ions would tend to occupy the Lu³⁺ sites.

 

Fig. 1. Crystal structure of A-LSO@SiO₂. (a) XRD pattern and rietveld refinement results. (b) Projection of the crystal structure.

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The phase purity of doped Lu₂SiO₅@SiO₂ samples has been judged by XRD measurements, as shown in Fig. 2. The most diffraction peaks of obtained representative Sm³⁺ and Ce³⁺/Sm³⁺ doped samples were consistent with A-Lu₂SiO₅ (JCPDS 70-3281) while the remaining peaks probably belong to Lu₂Si₂O₇ (e.g. JCPDS 35-0326, JCPDS 31-0777), which imply that the doped ions does not significantly affect crystal structure. The existence of Lu₂Si₂O₇ possibly may be caused by the unevenness of temperature field in heat treatment and the local aggregation of silica around the precursors. After comparing the relative intensity of diffraction peaks for the Lu₂Si₂O₇ and Lu₂SiO₅, it is reasonable to consider the synthesized samples as their main phase A-LSO.

 

Fig. 2. XRD patterns of the prepared samples at RT.

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The morphologies of the expected core-shell structure were displayed in TEM image (Fig. 3(a)), the obtained products own a uniform core-shell structure with a diameter of about 300 nm and the thickness of the SiO₂ shell is about 20 nm, while inside crescent-shaped voids are also can be observed. The EDS in Fig. 3(b) proves the presence of the elements Lu, Si, and O. In the element mapping of the core-shell particles (Fig. 3(b) inset), the elements of Si were distributed outside the shell and elements of Lu were distributed in the core, certifying the formation of A-LSO@SiO₂ core-shell nanospheres.

 

Fig. 3. TEM image, EDS spectra and elemental mapping of Lu₂SiO₅@SiO₂ core-shell nanospheres. (a) TEM image, (b) EDS spectra. The Cu and Al element signal in EDS are result from the holding foil. Inset: elemental mapping of Si, O and Lu.

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3.2 Luminescence properties and energy transfer mechanism of LSO:0.01Ce³⁺,ySm³⁺@SiO₂ nanospheres

The excitation and emission spectra of LSO:0.01Ce³⁺@SiO₂, LSO:0.01Sm³⁺@SiO₂ nanospheres and the excitation spectrum of Ce³⁺/Sm³⁺ co-doped sample were measured respectively (Fig. 4). An overlap in the 400-475 nm range was observed between the excitation spectrum of Sm³⁺ ions and the emission of Ce³⁺ ions. The peak at 355 nm is attributed to the 4f-5d excitation band of Ce³⁺, while Sm³⁺ has extremely weak absorption at the same wavelength, thus we hypothesize that if the possible emission peak of Sm³⁺ ions can be detected under the excitation at 355 nm, it would be one of the strong evidences for the existence of energy transfer from Ce³⁺ to Sm³⁺ in the co-doped LSO@SiO₂ nanospheres.

 

Fig. 4. The excitation-emission spectra of LSO:0.01Ce³⁺@SiO₂ (blue) and LSO:0.07Sm³⁺@SiO₂ (red); the excitation spectra of LSO:0.01Ce³⁺,0.07Sm³⁺@SiO₂ (green). The excitation spectra were drawn in short dash dot lines.

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The emission spectra of the Ce³⁺/Sm³⁺ co-doped Lu₂SiO₅@SiO₂ nanospheres under 355 nm excitation were measured (Fig. 5). The spectra are mainly composed of emission due to ⁴G_5/2 - ⁶H_J (J = 5/2-11/2) transitions of Sm³⁺ and 4f-5d transitions within Ce³⁺. Compared with the emission of co-doped sample, when the sample without Ce³⁺ was excited, an extremely weak emission with apparent background occurred, which indicates the presence of energy transfer in Ce³⁺/Sm³⁺ pairs. As depicted in Fig. 5(a), the concentration quenching effect of Sm become stronger than the energy transfer effect of Ce³⁺/Sm³⁺ pairs when the doped concentration of Sm exceeds 3%. As a result, the intensity of the band peak at 603 nm exhibits a weakening trend, while that of the Ce³⁺ emission around 420 nm continues to decrease. Additionally, the position of emission peak locates at the 350-550 nm slightly moves towards longer wavelengths when increasing the content of Sm³⁺ ions continuously (Fig. 5(b)). This phenomenon can be explained in two ways: on the one hand, Sm³⁺ ions absorb the emission of Ce³⁺ in 400-425 nm and 455-490 nm band efficiently while the absorption in 425-455 nm is much weaker, which may lead to the difference in the degree of luminescence decline in these three wavelength ranges of Ce³⁺. On the other hand, Sm³⁺ has larger ionic radius than Lu³⁺, raising the Sm³⁺ concentration may compress the volume of Lu³⁺ sites occupied by Ce³⁺ when Ce³⁺ doping remains unchanged, causing a red shift in Ce³⁺ emission.

 

Fig. 5. (a) The emission spectra of the LSO:0.01Ce³⁺,ySm³⁺@SiO₂ (y = 0.01-0.09) under 355 nm excitation wavelength. Inset: Integrated emission intensity dependence on Sm³⁺ concentration. (b) Enlargement of the normalized emission spectra.

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To quantitatively analyze the energy transfer process, the luminescence decay curves of the LSO:0.01Ce³⁺,ySm³⁺@SiO₂ (y = 0.01-0.09) samples were determined (λ_em= 430 nm, λ_ex= 360 nm). As displayed in Fig. 6(a), the decay curves deviating from single-exponential one with the ascending value of the Sm³⁺ doped concentration and the Ce³⁺ life time of each sample were estimated (Fig. 6(b)). A monotonically decreasing can be seen, which also demonstrate the presence of ET process from Ce³⁺ to Sm³⁺. ET efficiency $\mathrm{\eta }$ from the sensitizer Ce³⁺ to the activator Sm³⁺ were calculated [21], whose results are depicted in Fig. 6(b) inset. The ET efficiency increases gradually and reaches over 45% when the Sm³⁺ doping level y = 0.09.

 

Fig. 6. (a) Luminescence decay curves and (b) corresponding lifetimes $\mathrm{\tau }$ of LSO:0.01Ce³⁺,ySm³⁺@SiO₂ (y = 0.01-0.09) at RT. Inset: energy transfer efficiency η versus Sm³⁺ concentration.

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Furthermore, if only considered the energy transfer from Ce³⁺ to Sm³⁺, the characteristic of luminescence decay could be described by Inokuti-Hirayama(I-H) model. The decay equation of LSO:0.01Ce³⁺,ySm³⁺@SiO₂ nanospheres would be obtained by mathematical treatment as follows [22]:

 

Fig. 7. (a) Luminescence decay curves of the LSO:0.01Ce³⁺,ySm³⁺@SiO₂ (y = 0.01 and 0.09) at RT and the fitting results via the I-H model. (b) Energy level diagram of Ce³⁺ and Sm³⁺.

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The calculated energy transfer micro-parameter C_DA is 7.58 × 10⁻⁴⁸ m⁶·s^-1, and the critical energy transfer distance R_c is about 8.09 Å, indicating that energy of Ce³⁺ could transfer to Sm³⁺ efficiently when Sm³⁺ doping level y = 0.01. For other samples, their corresponding C_DA and R_c could be estimated in the same way. Moreover, the energy level diagram and the proposed energy transfer mechanism has been schematically shown in Fig. 7(b).

3.3 Radio-luminescence properties of LSO:Ce³⁺,Sm³⁺@SiO₂ nanospheres

The X-rays excitation luminescence spectrum of the reference powder (commercial LYSO:Ce³⁺) and the prepared samples were measured at RT (Fig. 8). It was obvious that the intensity of the obtained LSO@SiO₂ nanoparticles were significantly weaker than that of the reference, which can be attributed to the quenching caused by the small size effect and surface effect of nanocrystals and the less quantity of samples compared to the reference. Additionally, the characteristic emission of Sm³⁺ in the co-doped sample is almost twice that of the singly Sm-doped sample, while the Ce³⁺ emission band also occurs in the LSO:Ce,Sm sample. Thus, this observed energy transfer from Ce³⁺ to Sm³⁺ under X-ray excitation, whose inclusive energy transfer mechanism can be similarly illustrated by Fig. 7(b), suggests the possibility of constructing nanoscintillators capable of stimulating both blue and red activated PSs.

 

Fig. 8. X-ray excited area-normalized emission spectra of LSO:0.01Ce³⁺,0.03Sm³⁺@SiO₂, and commercial LYSO:Ce³⁺ powder at RT.

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The X-rays excited light yield of the LSO:0.01Ce³⁺,0.03Sm³⁺@SiO₂ was estimated from the ratio of the integrated intensity (${\textrm{I}_{\textrm{sample}}}$) from the sample (powder pellets) with that of the reference (${\textrm{I}_{\textrm{reference}}}$) (powder pellet) multiplied with the absolute light yield of the reference. From the tested absolute total light yield of 36000 ph/MeV for the commercial LYSO:Ce reference powder, the LY of the nanospheres can be estimated by Equation (3) [23]:

The calculated X-ray excitation light yield of the obtained LSO:0.01Ce³⁺,0.03Sm³⁺@SiO₂ sample is ∼ 6200 ph/MeV, which is close to the light-yield of BaF₂ with 8880 ph/MeV. This relatively low light yield may be caused by the quantity of obtained sample used in the test is less than that of the LYSO:Ce reference powder.

4. Conclusions

In summary, A-LSO:Ce³⁺,Sm³⁺@SiO₂ core-shell nanospheres were synthesized by a facile two-step coprecipitation process with subsequent heat treatment. The luminescence properties of LSO:0.01Ce³⁺,ySm³⁺@SiO₂ (y = 0.01-0.09) have been discussed in detailed. Both the excitation-emission spectra and decay curves provide strong evidence for the presence of energy transfer from Ce³⁺ to Sm³⁺ under UV excitation. Moreover, the ET efficiency exceeds 45% in 9% Sm³⁺ co-doped sample. Based on the I-H model, the mechanism of the energy transfer was fitted to be electric dipole-dipole interaction. Finally, the radio-luminescence spectra were also measured. Both relatively strong blue and red light were observed in the co-doped sample. The intensity of the Sm³⁺ derived emission in the co-doped sample was ∼2 times higher than that in the singly Sm-doped sample, confirming the ET in Ce/Sm under X-ray excitation. And the light yield of LSO:0.01Ce³⁺,0.03Sm³⁺@SiO₂ has been estimated to be about 6200 ph/MeV. The above discussion suggests a potential application of the obtained A-LSO:Ce³⁺,Sm³⁺@SiO₂ core-shell nanospheres for the simultaneous activation of blue and red activated PSs in X-PDT.