1. Introduction

At present, the interest in investigating Gd₂O₃ and Gd₂O₂S has increased notably in the biomedical field [2,3]. This is due to the excellent optical response of both compounds that can be syntonized in a wide spectral range, from high energy photons (X-ray) to radiation considered transparent to the biological window (750–950 nm) [4]. Moreover, the Gd₂O₃ and Gd₂O₂S have excellent physicochemical properties related to their high optical response, high thermal and chemical stability, and their capacity to be produced in different shapes, particle sizes, and textures. These attributes make them superior compared to other particles for applications in the biomedical field [5] since they allow us to have particles with a large surface area that can be functionalized with ligands to target specific biomolecules [6]. Their production in the micro or nanoscale is a constant challenge. Therefore, numerous synthesis and functionalization strategies have been approached to enhance both systems’ intrinsic properties in recent years. The synthesis methods for their preparation include techniques such as sonochemical reaction [7], solid-state reaction [8], the sol-gel method [9], polyol method [10], microwave-assisted synthesis [11], the hydrothermal method [12], and combustion synthesis method [13]. These techniques are widely used to produce well-shaped nano- or micro-particles doped with different ions. However, differences in the quantum efficiency or optical responses among the reports have also been observed [1,3,14]. Moreover, some of these synthesis routes also produce samples with low crystallinity, defects on the particle surface, and the generation of organic by-products that are difficult to remove and limit their application in the biological field [15].

Recently, a variety of novel biomedical applications for Gd₂O₃ and Gd₂O₂S have been discovered, which include their use as antimicrobial agents [16], transport vehicles [17], therapeutic agents [18], and nanovaccines [19]. These applications have emerged because of particle surface functionalization and by obtaining particles with specific sizes and shapes. However, the appropriate selection of Gd₂O₃ and Gd₂O₂S for use in these applications is not yet clear. Recent reports suggest that Gd₂O₂S is more promising due to its superior quantum efficiency than Gd₂O₃ [20]. In this regard, our work presents a compilation of the recent studies of gadolinium-based oxides and oxysulfides to establish a critical analysis and prospects for their use in the biomedical field.

2. Optical Properties of Gadolinium-Based Oxide and Oxysulfide Materials

2.1. Gadolinium-Based Oxide

Rare-earth oxides are advanced materials widely used as host lattices to develop sensors and luminescent materials [21]. They are recognized for their excellent chemical and thermal stability [22], low phonon energy (~300–600 cm⁻¹), and the facility on which they can be doped with lanthanide ions [23,24]. Gadolinium oxide (Gd₂O₃) is considered one of the most promising materials for developing contrast agents for magnetic resonance and fluorescence imaging [25]. This is due to the trivalent state of gadolinium inside the matrix that induces a highly stable 4f shell with seven unpaired spins, making it strongly paramagnetic [26]. Likewise, the intrinsic optical properties of Gd₂O₃ render them the ability to producing sharp wavelength absorptions and photostability, which make them useful for imaging applications. The optical properties of Gd-based materials can be enhanced by doping the matrix with other lanthanide ions. Thus, a good selection of doping-ions makes it possible to obtain photoluminescent materials with high Stokes shifts, sharp emission spectra (in the visible or NIR regions), long lifetimes, minimized photobleaching, and multiphoton absorption [27]. Besides, the tuning of the excitation and emission wavelength, as desired. Because of these properties, gadolinium-oxide lattices are considered excellent materials for photoluminescence applications, including not only the technological approach but the biomedical field as well [28].

2.2. Down- and Up-Conversion Emission Processes

Lanthanide ions share a similar electronic configuration, but unlike gadolinium, most of them can exhibit luminescence due to intraconfigurational 4f-4f transitions when excited with UV-Vis or NIR wavelengths [29]. The crystal field might alter lanthanide ions’ electronic structure to access this impressive phenomenon [30]. Therefore, to achieve photoluminescence through downconversion (DC) or upconversion (UC) processes, lanthanide ions are placed in minimum quantities into the gadolinium host lattices.

The most common process to obtain a photoluminescence emission is by DC [31]. In this process, high-energy photons are used to excite electrons from their ground state to a higher energy level inside the host lattice. After that, the energy is transferred to a luminescent ion, and the energy dissipates by radiative relaxation (a luminescent emission occurs) [32]. In this case, the host lattice’s gadolinium acts as a sensitizer (which absorbs the excitation energy), and the other lanthanide ions act as an activator (which usually releases radiative energy).

On the other hand, the UC phenomenon occurs when low-energy photon absorption is transformed into a high-energy photon emission [33]. Three mechanisms can explain this phenomenon: (1) the energy transfer (UC-ETU), (2) the cross-relaxation (UC-CR), and (3) the energy state absorption (UC-ESA). A schematic representation of each mechanism is shown in Figure 1. The UC-ETU is the most common path to obtain UC photoluminescence [34]. In this process, both the sensitizer and activator must be in the crystal lattice as doping ions. The sensitizer should be selected for its multiphoton absorption capacity of NIR wavelengths, and the activator must have coupled energy levels with the sensitizer’s excited state [35,36]. Two or more photons absorbed by the sensitizer can create a virtual energy level paired with the activator’s energy level during the absorption process. Then, the sensitizer transfers the absorbed energy to the activator, making a radiative relaxation to the ground state (see Figure 1).

Figure 1. Lanthanide photoluminescence phenomena achieved in gadolinium oxide and oxysulfide materials. The most common mechanisms that involve photoluminescence include the following: (a) downconversion (DC), (b) energy transfer upconversion (UC-ETU), (c) cross-relaxation (UC-CR), (d) energy state absorption (UC-ESA) graphically explained in energy level diagrams.

The UC-CR takes place when several energy levels exist with a similar energy gap. Most of the time, the cross-relaxation is undesired for the luminescence because it decreases the emission intensity by phonons; however, it can be managed to obtain luminescent emission under specific excitation conditions. This process is achieved by using a sensitizer and an activator. Both must have two or more energy levels with a similar energy gap. After the sensitizer has absorbed the excitation energy, some relaxation transitions release energy, which is used to excite certain energy levels of the activator, resulting in multiple excitations within the activator and high energy emission wavelengths [37].

The energy state absorption (UC-ESA) can be accomplished by using lanthanide ions with a ladder-like energy level configuration. In this process, the same ion can act as a sensitizer and activator. Because of the ladder-like arrangement, an absorbed photon after NIR excitation can promote an electron to the first excited state. Still, a successive second absorption can excite the same electron to a higher energy level, from which a radiative transition to the ground state occurs [13].

Due to these mechanisms, the lanthanide-doped gadolinium oxides and sulfides can virtually absorb the whole electromagnetic spectrum from UV to NIR. Moreover, the energy can be transformed into visible luminescence, which is very attractive for contrast, imaging, and sensing applications [38].

2.3. Dopants and Their Effect on the Photoluminescence Emission of Gd₂O₃

Gadolinium-based oxide and oxysulfide host lattices are highly compatible with other lanthanide ions. Therefore, photoluminescence can be tuned with the desired color emission under a required wavelength excitation through their appropriate selection. Over the past ten years, different photoluminescent materials based on lanthanide-doped gadolinium oxide have been widely studied. Figure 2a–c depict the analysis of a careful search of Gd₂O₃ materials doped with varying lanthanide ions. For this analysis, 131 published studies were collected from Google Scholar© under the search “gadolinium oxide photoluminescent materials” and “Gd₂O₃ doped photoluminescent materials”.

Figure 2. General features of photoluminescent processes by downconversion and upconversion in gadolinium oxide lattices. (a) Percentage of publications in the last ten years on the design of gadolinium-based matrices for upconversion or downconversion phenomena. (b,c) The most widely used lanthanide dopant. (d) Excitation and emission spectra of Eu-doped gadolinium matrices. (e) Excitation and emission spectra of Tb-doped gadolinium matrices. (f) Energy level diagram and luminescent emission processes in Eu-doped gadolinium matrices. (g) Emission lines of Er, Tm, and Ho were used as dopants in Gadolinium matrices. (h) Photograph of the photoluminescent emission by upconversion of Gd-based particles with different dopants in colloidal suspension. (i) Energy levels diagram describing the radiative and non-radiative processes in Gd-based lattices by upconversion using Yb, Er, and Tm as dopants.

Europium (Eu) is the most common activator ion used to study and recognize the photoluminescence in gadolinium lattices (see Figure 2b). Figure 2d shows the excitation and emission spectra of an Eu-doped gadolinium oxides material. After a 255 nm excitation, an intense red color can usually be detected even by the naked eye [39]. The red color is attributed to the ⁵D₀→⁷F₂ transition, which appears at ~613 nm, as shown in the energy level diagram of Figure 2f. The UV radiation (~250 nm) absorbed by the gadolinium from the host lattice promotes the electrons from its ground state to the ⁵L_J energy levels of the europium ion, from which several non-radiative transitions occur up to the ⁵D₀ energy level, finally the characteristic radiative transitions ⁵D₀→⁷F_J take place. Terbium (Tb), on the other hand, gives a bright green color luminescence after UV excitation of the gadolinium lattices [40]. As it can be seen in Figure 2e, this color corresponds to the transition ⁵D₄→⁷F₅ which lies in 545 nm. The color can be noted in the inset of Figure 2e.

Regarding the upconversion (UC) luminescence, the most used lanthanide ions are depicted in Figure 2c, with ~40% frequency for both Ytterbium (Yb) and Erbium (Er), which are the most used doping ions to obtain UC. Yb is an excellent sensitizer for NIR radiation. After being excited at 980 nm, Yb can efficiently transfer the harvested energy to Er [41], Tm [42], Ho [43], or other lanthanides, and the photoluminescence can be detected, as shown in Figure 2g. The characteristic colors obtained under NIR radiation can be observed in Figure 2h, which shows how the upconversion luminescence can be tuned depending on the activator ion used. The versatility of Yb to be paired with other activator ions makes it possible to obtain gadolinium-based lattices with different color emissions. This versatility can be explained by the energy level diagram in Figure 2i, where Yb is the sensitizer that, after multiple photon absorption, can transfer its energy (UC-ETU) to several energy levels of the paired activator ions whose radiative transitions lay in different sections of the visible spectrum. Following this outcome, the Yb/Er combination is the most common to obtain a successful gadolinium oxide upconverting material. However, using Yb as a sensitizer makes it possible to bring other luminescent colors upon 980 nm excitation [44].

2.4. Dopants and Their Effect on the Photoluminescence of Gd₂O₂S

Another advantage of gadolinium oxide material is the possibility of obtaining gadolinium oxysulfide phosphors by using them as precursors in a solid-state sulfidation reaction [45]. Gadolinium oxysulfide shares some properties with its precursors, such as high thermal and chemical stability, insolubility in water, and high absorption of light [46]. However, some properties are enhanced with respect to other materials. Gadolinium oxysulfides are better luminescent materials than their precursor oxides or sulfides and exhibit high quantum yield efficiency compared with fluorides [47]. These properties make oxysulfides promising materials in the bioimaging field [48,49]. The luminescent mechanisms are not affected despite the host lattice used to contain the selected lanthanide ions.

Gadolinium oxysulfides, on the other hand, are less studied than oxides. In the last ten years, only 27% of the 179 retrieved publications referred to lanthanide-doped gadolinium oxides, and oxysulfides belonged to studies related to oxysulfide luminescent materials (see Figure 3). The main reason is the complicated processes required to obtain oxysulfide materials [50,51] that might compromise the precursors’ initial morphology, affecting the materials’ luminescence properties [25]. Nonetheless, novel strategies are being explored nowadays to avoid the stringent processes to obtain oxysulfides without compromising the optical properties. Another issue is the frequent requirement of toxic precursors; thus, the synthesis should proceed in environmentally controlled conditions.

Figure 3. State of the art for gadolinium-based oxide and oxysulfide luminescent materials. Comparison of the preferential research between oxides and oxysulfides over a total of 179 publications from the last ten years.

In Figure 4, some relevant examples of gadolinium oxysulfide materials used as a host lattice for luminescent phosphors are depicted. The synthesis of oxysulfide materials mainly focuses on three luminescent phenomena, as shown in Figure 4a, where the radioluminescence is an alternative application of oxysulfides apart from DC and UC. DC is still the most studied process upon lanthanide-doped oxysulfides, highlighting europium and terbium as the most utilized lanthanide dopants to obtain photoluminescence (see Figure 4b). The europium-doped gadolinium oxysulfide excitation-emission spectra are depicted in Figure 4d. Although the emission color corresponding to the transition ⁵D₀→⁷F₂ is the same as in the oxide, there is an important difference in the emission spectrum structure. In the europium-doped oxide material, the ⁵D₀→⁷F₂ transition has a maximum peak at 613 nm, whereas in the oxysulfide, the maximum peak is located at 623 nm. This difference is due to the crystal field environment and provides information about the doping ions’ position in the host lattice [50]. Despite this difference, europium-doped oxysulfide materials are recognized as red phosphors applied in technological applications.

Figure 4. Gadolinium oxysulfide materials and their general applications: (a) main applications of gadolinium oxysulfides in the last ten years, (b) lanthanides employed as dopants to achieve downconversion processes, (c) most employed lanthanide dopants for gadolinium oxysulfide upconversion materials, (d) fluorescence excitation/emission spectra of a Gd₂O₂S:Eu material where the principal excitation-emission is detected at 622 nm, (e) fluorescence emission spectrum of a Gd₂O₂S:Tb material and (f) the corresponding energy level diagram representing the main transitions that make possible the green coloration at room temperature, (g)visible upconversion emission of a Gd₂O₂S:Yb/Er material under different Yb concentrations, the excitation energy employed was 980 nm at room temperature, (h) upconversion luminescence spectra of gadolinium oxysulfide materials with different concentrations of Er upon excitation at 1510 nm and (i) energy level diagram of a Gd₂O₂S:Er material showing all the processes involved in the luminescence phenomena.

Another recognized phosphor is the terbium-doped oxysulfide, which is characterized by its bright green color often used in radioluminescence applications [14,51]. Figure 4e shows the photoluminescence emission spectra of terbium doped oxide and oxysulfide materials, where the intensity of oxysulfides is up to fifteen times greater than its oxide precursor. This study has highlighted the importance of more research related to photoluminescent oxysulfides. Moreover, the downconversion mechanism is depicted in Figure 4f. The host lattice absorbs the UV radiation (~290 nm) and is transferred to the terbium ions that release the energy in several radiative transitions resulting in a visible green color.

Although studied in a minor proportion, upconverting gadolinium oxysulfides are exciting and valuable materials. The most used lanthanides to achieve this phenomenon are depicted in Figure 4c. It can be seen that Yb and Er are still the most used ions to develop upconverting materials. Figure 4g shows a set of experiments carried out to find the optimum Yb/Er composition. The luminescence of the materials is depicted in the inset. A green-yellowish coloration is observed after irradiation with a 980 nm diode laser. The UC-ETU is the mechanism that explains this coloration, as described before.

Figure 4h shows another approach. In a series of experiments where only Er is used as the dopant ion, the optimum concentration to obtain the most intense luminescence was 10%. The UC-ESA was the primary mechanism leading these results, which is explained in Figure 4i. Erbium ion possesses a ladder-like energy level structure that can promote electrons to higher energy levels in the UV region after multiple photon absorption. As it can be observed in the picture, after successive absorption of 980 nm or 1150 nm excitation energy, the ⁴I_13/3 energy level is reached, from which the electrons are promoted to ⁴I_9/2, and ⁴S_3/2, energy levels. A further energy transfer between erbium ions can lead to high energy emissions in the blue color (~450 nm).

Additionally, cross-relaxation processes can occur (labeled in a–d), which leads to exciting ⁴S_3/2 energy levels. The radiative transitions to the ground state give the characteristic green coloration (~540 nm). Finally, the red color is attributed to the ⁴F_9/2→⁴I_15/2 transition, which is a consequence of cross-relaxation processes followed by some non-radiative transitions from ⁴S_3/2 to ⁴F_9/2.

For the case of oxysulfides, erbium is mainly used as a sensitizer comparing with ytterbium. There is no specific reason for this trend. Erbium has the same versatility as ytterbium, with the difference that erbium can absorb different wavelengths in the NIR infrared spectrum, while ytterbium is limited only to 980 nm energy absorption.

3. Biological Applications on Gadolinium-Based Particles

Gadolinium-based particles have been reported for promising bio-applications (Figure 10) due to their interesting optical properties, highlighted physicochemical characteristics, combined with low cytotoxicity and high photosensitivity [103]. Because of their high longitudinal relaxivities and small r₂/r₁ ratios, Gd₂O₃ and Gd₂O₂S NPs are used for magnetic resonance imaging (MRI), dual-modal imaging, tissue labeling, immunosensing, and photodynamic therapy (PDT) [17,104,105]. Moreover, the surface of upconverting nanoparticles can be functionalized and then conjugated with biological molecules (such as proteins, peptides, antibodies, drugs, and genes) to be delivered in target cells. Gadolinium-based nanoparticle systems are currently under evaluation for several biological applications. Table 1 summarizes some relevant works published on this topic.

Figure 10. Main biological applications of gadolinium-based oxides. Created with https://biorender.com/ (accessed on 7 September 2021).

Table 1. A summary of the most used gadolinium-based nanoparticles in the biomedical field.

Particle	Synthesis Strategy	Size and Morphology	Biological Application	Results	Ref.
Gd2O3	Modified polyol protocol	Nanospheres	Imaging	Longitudinal proton relaxivities higher than the contrast agents commonly used for MRI	[99]
Gd2O3:Eu3+	Polyol	Nanoplatelets	Imaging	Doping with Eu exhibits strong PL spectra, especially at 612 nm	[100]
Gd2O3	One-pot	Ultrasmall nanospheres	Imaging	NPs showed high longitudinal relaxivities. These allowed the visualization of labeled cells implanted in vivo	[101]
Gd2O3:Eu3+	Spray pyrolysis	Quasi-spherical	Imaging and immunosensing	Excellent matrix for antibody immobilization	[102]
Gd2O3 doped with Tb3+, Dy3+, Eu3+	Gas-phase condensation	Fluffy morphology	Imaging and immunosensing	Strong emission lines and long lifetimes. Dy3+ was the most sensitive to concentration quenching	[31]
Gd2O3:Tb3+	Spherical	Spherical	Imaging	Cellular fluorescence imaging in S18 cells clearly showed the green fluorescence from Gd2O3:Tb intracellular	[8]
Gd2O3:Eu3+	Spray pyrolysis	Nearly-spherical	Imaging	NPs do not suffer any photobleaching and show significant excitation times	[103]
Gd2O3	Organic synthesis	Ultrasmall nanospheres	Imaging	Improved longitudinal relaxivity r1 of 12.1 mM−1 s−1 at 7 T	[104]
Gd2O3	Organic synthesis	Spherical	Imaging	NPs exhibited a longer longitudinal relaxation time (T1) and better biocompatibility with macrophage cell line	[105]
Gd2O3	Polyol	Spherical	Theranostic sensitizers	The sensitizer enhancement ratio at the 10% survival level and elicited an increase in hydroxyl radical production, which led to DNA damage and cell cycle arrest.	[114]
Gd2O3	Simple precipitation	Spherical	Antimicrobial agents	NPs had a potent antimicrobial effect against gram-negative and gram positives bacteria	[16]
Gd2O3	Sonication technique	Spherical	Antimicrobial agents	NPs had antimicrobial and antifungal effects	[108]
Gd-NGO	Organic synthesis	Dendrimer	Drug and micro RNA delivery	NPs were able to deliver EPI and Let-7g miRNA into cells to destroy the DNA and then inhibited the cancer cell growth	[109]
Gd2O3	Fungus based approach	Quasi-spherical	Drug delivery	Bioconjugation with taxol was potent in killing tumor/cancer cells	[70]
Gd2O3:Eu3+	High temperature solvothermal	Small triangular nanoplates	Drug delivery	Efficient delivery of drugs to the nuclei of cancer cells (HeLa and KB) with a high cytotoxic effect	[111]
Gd2O3:Eu3+	Sol-gel process	Nanospheres	Drug delivery	The nanocomposite system exhibited more significant cytotoxicity compared to Dox free	[112]
Gd2O3	Simple wet-chemical route	Rod-shaped	Drug delivery and imaging	Nanorods were internalized by cells more quickly than the control (DOX free) and displayed more cell cytotoxicity. Furthermore, these can serve as contrast agents for MRI	[17]
Gd2O3:Eu3+	Flame pyrolysis	Spherical	Deposition studies	The dose of deposited particles was significantly greater in the juvenile rats at 2.22 ng/g body weight. The NPs did not show toxicity in any organ.	[18]
Gd2O3:Eu3+	Spray flame pyrolysis	Quasi-spherical	Deposition, clearance, and translocation	NPs were detected in all the studied organs at low ppb levels; 59% of the particles remained in the lung.	[113]
Gd2O3:Tb3+/Er3+	Hydrothermal	Spherical	Vaccines	Microparticles have shown an enhanced humoral (with a Th2-polarization) response compared with the control groups.	[19]
Gd2O3	Polyol	Spherical	Imaging	The combination of NPs with CPC gives an injectable material that allowed the visualization of the implanted cement up to 8 weeks after implant	[115]
Gd2O2S: Er3+:Yb3+	Hydroxycarbonate precursor precipitation.	Spherical	Imaging	NPs under infrared excitation (λex = 980 nm) show mainly red emission (≈650–680 nm). Consequently, they are more specifically designed for in vivo deep fluorescence imaging	[45]
Gd2O2S:Eu3+	Hydroxycarbonate precursor precipitation	Spherical	Imaging	NPs demonstrated no toxic effects on whole organisms and their long-lasting tracking aptitude as well as their potential use as multimodal cell trace	[101]
Gd2O2S: Eu3+, Ti4+, Mg2+	Hydrothermal	Nanoprobes	Imaging	NPs exhibited both persistent luminescence and paramagnetic properties.	[50]
Gd2O2S:Tb3+	Urea homogenous precipitation	Hexagonal structure	Imaging	Emitting of green light from phosphor layer confirms its luminescence property.	[14]

 

 

This entry is adapted from the peer-reviewed paper 10.3390/cryst11091094