Lanthanide-doped Nanoparticles Research Articles

Advances in near-infrared-activated lanthanide-doped optical nanomaterials: imaging, sensing, and therapy

As the population ages, cancer has become a major health concern. Although surgical treatment, chemoradiotherapy, and other clinical treatments have become dominant, their strong invasiveness and intolerable toxic side effects seriously affect patients' quality of life. Therefore, developing non-invasive optical therapy with high safety is of great significance. In the last two decades of development, great progress has been made in lanthanide doped nanoparticles on biomedical applications under near-infrared (NIR) light due to their unique properties. These nanomaterials have been used in a wide range of applications, including bioluminescence marker detection, in vitro and in vivo imaging, photodynamic therapy (PDT), photothermal therapy (PTT), and other therapeutic applications. These therapies have been rapidly developed in the profession involving oncology due to their non-invasive, spatiotemporal controllability, and high efficiency. For this key review, the applications based on lanthanide nanoparticles have been listed as follows: bioimaging, biosensors, PDT and PTT. Some emerging biological applications of lanthanide-doped nanoparticles currently at the forefront of the nano/biological interface are also discussed. Finally, this review summarizes the future opportunities and challenges of nanotechnology research based on lanthanide-doped nanoparticles.

Dual‐Wavelength Comparative Imaging Based on a Novel NIR‐II/IIb Emissive Rare Earth‐Doped Nanoparticle

AbstractThe second near‐infrared biological window two (NIR‐II, 1000–1700 nm) imaging has made remarkable achievements in fluorescence imaging of diseases. Here, this work takes advantage of the rich spectral properties of rare‐earth doped nanoparticles (RENPs) and their capability to present multiple emission peaks in different luminescence regions simultaneously; novel RENPs are synthesized that have emission peaks in the NIR‐II1000nm (1000–1300 nm) region and enhanced emission in the NIR‐IIb (1500–1700 nm) window and are named as NEU‐RENPs. These RENPs with new compositions enable a fair comparison to evaluate their imaging performance in NIR‐II1000nm and NIR‐IIb regions under the same conditions. The imaging abilities of the resulted nanoparticles in NIR‐II1000 nm and NIR‐IIb regions are investigated systematically for local blood vessels, tumor vessels, acute inflammatory vessels, arterial thrombosis, cerebrovascular inflammation, and brain injury models. The results indicate that imaging of NIR‐IIb shows higher resolution and sensitivity than that of NIR‐II1000nm, and it has a stronger ability to accurately distinguish normal and pathological tissues. Interestingly, the fuzzy image of NIR‐II1000nm reveals more information about the background structure of the target, which is difficult to be achieved in NIR‐IIb imaging. The results prove NEU‐RENPs based NIR‐IIb imaging is preferable for biomedical applications.

Correction Due to Nonthermally Coupled Emission Bands and Its Implications on the Performance of Y2O3:Yb3+ /Er3+ Single-Particle Thermometers

Lanthanide-doped single dielectric nanoparticles have been exploited toward the realization of temperature sensing in the nanoscale with high spatial, temporal, and thermal resolution. However, due to the relatively small number of emitters when compared with suspensions or powders, the luminescence readouts in individual nanocrystals usually require higher excitation power densities to keep an acceptable signal-to-noise ratio. Since in numerous cases these thermometers work by exploiting upconversion excitation pathways, higher excitation powers can lead to higher-order photon emissions that can overlap with the luminescent bands used to perform the temperature measurements. This work shows that the performance and the characterization of ∼400 nm Y2O3: Yb3+/Er3+ single-particle thermometers vary depending on the excitation irradiance if higher-order spectrally overlapping bands are not properly taken into account. We apply a recently developed method to separate these bands based on their different power-law, without the need for multiple wavelength excitation, resulting in a correction procedure that reduces the temperature readout uncertainty from 0.6 to 0.3 K in the specific case of the thermometer investigated in this work. Additionally, power-excitation-related thermal artifacts on the order of 10 °C were detected and corrected with the presented method.

In Vivo NIR-II Fluorescence Lifetime Imaging of Whole-Body Vascular Using High Quantum Yield Lanthanide-Doped Nanoparticles.

Second near infrared (NIR-II, 1000-1700nm) fluorescence lifetime imaging is a powerful tool for biosensing, anti-counterfeiting, and multiplex imaging. However, the low photoluminescence quantum yield (PLQY) of fluorescence probes in NIR-II region limits its data collecting efficiency and accuracy, especially in multiplex molecular imaging in vivo. To solve this problem, lanthanide-doped nanoparticles (NPs) β-NaErF4 : 2%Ce@NaYbF4 @NaYF4 with high PLQY and tunable PL lifetime through multi-ion doping and core-shell structural design, are presented. The obtained internal PLQY can reach up to 50.1% in cyclohexane and 9.2% in water under excitation at 980nm. Inspired by the above results, a fast NIR-II fluorescence lifetime imaging of whole-body vascular in mice is successfully performed by using the homebuilt fluorescence lifetime imaging system, which reveals a murine abdominal capillary network with low background. A further demonstration of fluorescence lifetime multiplex imaging is carried out in molecular imaging of atherosclerosis cells and different organs in vivo through NPs conjugating with specific peptides and different injection modalities, respectively. These results demonstrate that the high PLQY NPs combined with the homebuilt fluorescence lifetime imaging system can realize a fast and high signal-to-noise fluorescence lifetime imaging; thus, opening a road for multiplex molecular imaging of atherosclerosis.

Ecotoxicity of non- and PEG-modified lanthanide-doped nanoparticles in aquatic organisms

Various types of nanoparticles (NPs) have been widely investigated recently and applied in areas such as industry, the energy sector, and medicine, presenting the risk of their release into the environment. The ecotoxicity of NPs depends on several factors such as their shape and surface chemistry. Polyethylene glycol (PEG) is one of the most often used compounds for functionalisation of NP surfaces, and its presence on the surfaces of NPs may affect their ecotoxicity. Therefore, the present study aimed to assess the influence of PEG modification on the toxicity of NPs. As biological model, we chose freshwater microalgae, a macrophyte and invertebrates, which to a considerable extent enable the assessment of the harmfulness of NPs to freshwater biota. SrF2:Yb3+,Er3+ NPs were used to represent the broad group of up-converting NPs, which have been intensively investigated for medical applications. We quantified the effects of the NPs on five freshwater species representing three trophic levels: the green microalgae Raphidocelis subcapitata and Chlorella vulgaris, the macrophyte Lemna minor, the cladoceran Daphnia magna and the cnidarian Hydra viridissima. Overall, H. viridissima was the most sensitive species to NPs, which affected its survival and feeding rate. In this case, PEG-modified NPs were slightly more toxic than bare ones (non-significant results). No effects were observed on the other species exposed to the two NPs at the tested concentrations. The tested NPs were successfully imaged in the body of D. magna using confocal microscopy; both NPs were detected in the D. magna gut. The results obtained reveal that SrF2:Yb3+,Er3+ NPs can be toxic to some aquatic species; however, the structures have low toxicity effects for most of the tested species.

Time-resolved Fluorescence DNA-based Sensors for Reducing Background Fluorescence of Environment

The fluorescence assay is one of the popular methods that is applied for detection of different targets. However, this method may show low sensitivity and high background in biological samples due to the natural fluorescence of different compounds in complicated samples. In addition, it inevitably affects the detection results accuracy. A fundamental solution to this problem is the use of the time-resolved fluorescence technique (TRF). The main component of this technique is the use of long fluorescence lifetime reagents. In this review, various time-resolved fluorescent reagents such as complexes of lanthanide ions, lanthanide-doped inorganic nanoparticles; Mn-doped ZnS quantum dots (QDs) and pyrene excimer are introduced. Moreover, TRF sensors, especially TRF aptasensors (DNA-based sensors) are discussed. This review will give new ideas for researchers to develop novel high-sensitive TRF sensors that can remove or decrease background fluorescence and use them for the detection of various targets in complicated samples without treatment.

A ratiometric aptasensor for simultaneous determination of two estrogens based on multicolor upconversion nanoparticles

Different environmental estrogens (EEs) may coexist in the same foodstuff, necessitating the establishment of a simultaneous detection method. Although there are numerous studies on the detection of EEs, few was reported on the determination of two or more estrogens at the same time except HPLC. Our efforts have been made to develop a ratiometric aptasensor based on multicolor lanthanide-doped upconversion luminescence nanoparticles (UCNPs) to realize simultaneous and sensitive detection of two EEs (bisphenol A and 17β-estradiol). Three types of core-shell UCNPs with excellent luminous properties and distinct emitting colors were successfully synthesized via doping with various lanthanide ions, two of which were conjugated with specific aptamers and act as energy donors, while another one served as a reference. Because of their excellent luminescence quenching performance, ultra-thin metallic MoS2 nanosheets were selected as the energy acceptor. Thus, a ratiometric luminescence aptasensor was established and successfully used for the simultaneous detection of two estrogens in tap water and milk samples, demonstrating its considerable practical application value.

Clinical radiation dose verification by topographic persistent luminescence dosimetry

Radiation dose verification in radiotherapy is essential to determine the dose delivered to irradiated tissue while minimizing normal tissue toxicity. However, the challenge remains in determining topographic radiation dose profiles due to limitations in conventional dosimeters. Herein, we report a robust technique for visualizing and verifying clinical doses based on reusable, flexible scintillating films comprising lanthanide-doped persistent luminescent nanoparticles. These nanoparticle-based films outperform commercially available radiochromic films in terms of linear response to irradiation doses between 0 and 25 Gy. We demonstrate topographic persistent luminescence dosimetry for radiotherapy of mice and rabbits with malignant tumors. Our data show a higher signal-to-background ratio, especially at lower (<0.1 Gy) and higher (>10 Gy) X-ray doses. We also demonstrate that topographic persistent luminescence dosimetry can record complex clinical dose distributions for dose verification and radiotherapy planning.

Biodegradable near-infrared-IIb lanthanide-doped inorganic nanoparticles with red up-conversion luminescence for bioimaging and photodynamic therapy

Biodegradable near-infrared-IIb lanthanide-doped inorganic nanoparticles with red up-conversion luminescence for bioimaging and photodynamic therapy

Seeking Brightness in Molecular Erbium-Based Light Upconversion.

Whereas dye-sensitized lanthanide-doped nanoparticles represent an unquestionable advance for pushing linear near-infrared (NIR) to visible-light upconversion within the frame of applications, analogous improvements are difficult to mimic for related but intramolecular processes induced at the molecular level in coordination complexes. Major difficulties arise from the cationic nature of the target cyanine-containing sensitizers (S), which drastically limits their thermodynamic affinities for catching the lanthanide activators (A) required for performing linear light upconversion. In this context, the rare previous design of stable dye-containing molecular SA light-upconverters required large S···A distances at the cost of the operation of only poorly efficient intramolecular S → A energy transfers and global sensitization. With the synthesis of the compact ligand [L2]+, we exploit here the benefit of using a single sulfur connector between the dye and the binding unit for counterbalancing the drastic electrostatic penalty which is expected to prevent metal complexation. Quantitative amounts of nine-coordinate [L2Er(hfac)3]+ molecular adducts could be finally prepared in solution at millimolar concentrations, while the S···A distance has been reduced by 40% to reach circa 0.7 nm. Detailed photophysical studies demonstrate the operation of a three times improved energy transfer upconversion (ETU) mechanism for molecular [L2Er(hfac)3]+ in acetonitrile at room temperature, thanks to the boosted heavy atom effect operating in the close cyanine/Er pair. NIR excitation at 801 nm can thus be upconverted into visible light (525-545 nm) with an unprecedented brightness of Bup(801 nm) = 2.0(1) × 10-3 M-1·cm-1 for a molecular lanthanide complex.

NIR-II multiplexed fluorescence imaging of bacteria based on excitation-selective lanthanide-doped core-shell nanoparticles

Physiological processes and bacterial infection can be effectively monitored using multiplexed imaging in the second near-infrared region (NIR-II). In this study, we design two lanthanide-doped core-shell (cs) nanoparticles, NaYF4:Nd,Yb@NaYF4 (csNd,Yb) with 980 and 1060 nm emission under 808 nm excitation, and NaYF4:Yb,Er,Ce@NaYF4 (csYb,Er,Ce) with 1525 nm emission under 980 nm excitation. The NIR-II emission spectra of the two nanoparticles do not overlap. XRD characterization shows that the nanoparticles have good crystallinity. The nanoparticles are surface modified with vancomycin (Van) and polymyxin B (PMB), which can respectively target Gram-positive and Gram-negative bacteria for specific imaging and bacteria differentiation. In vitro experiments confirm that csNd,Yb-PMB and csYb,Er,Ce-Van can be used to detect different types of bacteria. In vivo simultaneous multiplexed NIR-II imaging of Gram-positive/negative bacterial infection is demonstrated. The good biocompatibility of the nanoprobes is demonstrated by MTT assay, monitoring the distribution in major organs at different times, and histological analysis.

Microwave-assisted hydrothermal synthesis of LaOF:Yb3+, Ho3+ nanorods with high thermoresponsive upconversion luminescence for thermometry

Non-contact thermometry based on upconversion luminescence from lanthanide-doped nanoparticles is the best choice when temperature probes with higher precision, accuracy, sensitivity, and spatial resolution are required. Here, LaOF:Yb3+,Ho3+ upconversion nanoparticles (UCNPs) were demonstrated to be thermometers with a high sensitivity and thermal stability within the temperature range of 303–673 K. Microwave-assisted hydrothermal synthesis was used to obtain these rod-shaped UCNPs with a trigonal crystal structure. LaOF:Yb3+,Ho3+ UCNPs displayed green emissions due to the thermally-coupled levels (5F4, 5S2) and red emissions from the Stark-split sublevels of the 5F5 energy level belonging to Ho3+ under 980 nm continuous-wave laser irradiation. The upconversion emission originating from these transitions were remarkably sensitive to the temperature variation. Their fluorescence intensity ratios were explored to evaluate their relative (SR) and absolute (SA) sensitivities. Optical heating induced by continuous laser irradiation was also examined to assess the degradation of the luminescence caused by laser exposure.

Efficient luminescence emission in both visible and NIR-II regions by Er3+ partitioning doping and interfacial energy transfer

Lanthanide-doped nanoparticles (LDNPs) are widely used in biophotonics due to their narrow emission band, long lifetime and broad-spectrum tunable luminescence properties. Usually, photosensitizers for biotherapeutic applications need to be triggered by visible light, while bioimaging requires near-infrared (NIR) light with better penetration. However, it is still challenging to achieve efficient luminescence emission in the visible to second near-infrared (NIR-II, 1000–1700 nm) range simultaneously for multifunctional nanoparticles excited at a single NIR wavelength. Here, a simple NaYF4:Er/Ce@NaYbF4:Er@NaYF4:Nd core-shell-shell nanoparticle with interfacial energy transfer by the Yb-sensitized shell and partition doping of Er3+ under 808 nm excitation, which allows the system to achieve visible and NIR-II luminescence emission from different partitions of Er3+. When Ce3+ is introduced into the core, the Er3+ in the Yb-sensitized shell is responsible for the emission in the visible region, while the core-doped Er3+ is mainly responsible for the emission at 1550 nm in the NIR-II. In addition, this core-shell-shell nanostructure has a long luminescence emission lifetime in the visible and NIR-II regions, especially the luminescence lifetime of Er3+ at 1550 nm is extended to 6.4 ms. More importantly, efficient 1O2 generation can be achieved by coupling core-shell-shell nanoparticles with photosensitizer. These results will provide previously unattainable opportunities for LDNPs in biotherapeutic and imaging applications.

Amplifying Photoluminescence of Lanthanide-Doped Nanoparticles by Iridium Phosphonate Complex

Amplifying the photoluminescence of lanthanide-doped nanoparticles by antenna materials can bridge the gap in properties between pristine nanoparticles and those required by practical applications. However, high-performance antennas with ideal stability are rather few. Here, we report a new type of iridium (Ir)-based phosphonate complex as an antenna to amplify the near-infrared luminescence of lanthanide-doped nanoparticles. Unlike conventional antennas, the Ir complex, with a quasi-spherical structure and pendent phosphonic groups, can resist the aggregation-caused quenching and firmly anchor on nanoparticles. Near-infrared luminescence of lanthanide-doped nanoparticles can be stably amplified up to 130 times by the complex, which should be due to short-range energy transfer from the triplet state of the complex to lanthanide ions. These findings may pave a new fundamental way to amplify the luminescence of lanthanide-doped nanoparticles and promote applications of the nanoparticles.

Surface Engineering of Lanthanide Nanoparticles for Oncotherapy.

Surface-modified lanthanide nanoparticles have been widely developed as an emerging class of therapeutics for cancer treatment because they exhibit several unique properties. First, lanthanide nanoparticles exhibit a variety of diagnostic capabilities suitable for various image-guided therapies. Second, a large number of therapeutic molecules can be accommodated on the surface of lanthanide nanoparticles, which can simultaneously achieve combined cancer therapy. Third, multivalent targeting ligands on lanthanide nanoparticles can be easily modified to achieve high affinity and specificity for target cells. Last but not least, lanthanide nanoparticles can be engineered for spatially and temporally controlled tumor therapy, which is critical for developing precise and personalized tumor therapy. Surface-modified lanthanide-doped nanoparticles are widely used in cancer phototherapy. This is due to their unique optical properties, including large anti-Stokes shifts, long-lasting luminescence, high photostability, and the capacity for near-infrared or X-ray excitation. Upon near-infrared irradiation, these nanoparticles can emit ultraviolet to visible light, which activates photosensitizers and photothermal agents to destroy tumor cells. Surface modification with special ligands that respond to tumor microenvironment changes, such as acidic pH, hypoxia, or redox reactions, can turn lanthanide nanoparticles into a smart nanoplatform for light-guided tumor chemotherapy and gene therapy. Surface-engineered lanthanide nanoparticles can include antigens that elicit tumor-specific immune responses, as well as immune activators that boost immunity, allowing distant and metastatic tumors to be eradicated. The design of ligands and surface chemistry is crucial for improving cancer therapy without causing side effects. In this Account, we classify surface-modified lanthanide nanoparticles for tumor therapy into four main domains: phototherapy, radiotherapy, chemotherapy, and biotherapy. We begin by introducing fundamental bioapplications and then discuss recent developments in tumor phototherapy (photodynamic therapy and photothermal therapy), radiotherapy, chemotherapy, and biotherapy (gene therapy and immunotherapy). We also assess the viability of a variety of strategies for eliminating tumor cells through innovative pathways. Finally, future opportunities and challenges for the development of more efficient lanthanide nanoprobes are discussed.

Development of Photoluminescent and Photochromic Polyester Nanocomposite Reinforced with Electrospun Glass Nanofibers.

A polyester resin was strengthened with electrospun glass nanofibers to create long-lasting photochromic and photoluminescent products, such as smart windows and concrete, as well as anti-counterfeiting patterns. A transparent glass@polyester (GLS@PET) sheet was created by physically immobilizing lanthanide-doped aluminate (LA) nanoparticles (NPs). The spectral analysis using the CIE Lab and luminescence revealed that the transparent GLS@PET samples turned green under ultraviolet light and greenish-yellow in the dark. The detected photochromism can be quickly reversed in the photoluminescent GLS@PET hybrids at low concentrations of LANPs. Conversely, the GLS@PET substrates with the highest phosphor concentrations exhibited sustained luminosity with slow reversibility. Transmission electron microscopic analysis (TEM) and scanning electron microscopy (SEM) were utilized to examine the morphological features of lanthanide-doped aluminate nanoparticles (LANPs) and glass nanofibers to display diameters of 7-15 nm and 90-140 nm, respectively. SEM, energy-dispersive X-ray spectroscopy (EDXA), and X-ray fluorescence (XRF) were used to analyze the luminous GLS@PET substrates for their morphology and elemental composition. The glass nanofibers were reinforced into the polyester resin as a roughening agent to improve its mechanical properties. Scratch resistance was found to be significantly increased in the created photoluminescent GLS@PET substrates when compared with the LANPs-free substrate. When excited at 368 nm, the observed photoluminescence spectra showed an emission peak at 518 nm. The results demonstrated improved hydrophobicity and UV blocking properties in the luminescent colorless GLS@PET hybrids.

NIR-II fluorescent nanoprobe-labeled lateral flow biosensing platform: A high-performance point-of-care testing for carcinoembryonic antigen

Fluorescent lateral flow immunoassay (LFA) is one of the most common analytical platforms for point-of-care testing (POCT), which is capable of facile and early screening of biomarkers. Notably, fluorescent probes play a decisive role in analytical performances of LFA. Herein, we report a novel LFA based on the rare earth doped nanoparticles (RENPs) emitting in the second near-infrared (NIR-II) window for the detection of biomarkers, such as carcinoembryonic antigen (CEA). Benefiting from the dual fluorescent emission at NIR-II window, strong fluorescent penetration, low autofluorescence and excellent photostability of RENPs, this proposed NIR-II LFA displays a good linear relationship ranging from 1 to 320 ng mL−1. The detection limit is as low as 0.37 ng mL−1, which is of 13.5 times lower than the clinical cutoff value. Overall, NIR-II LFA biosensing platform based RENPs not only exhibits high sensitivity, accuracy and specificity, but also have characteristics of rapidity, simplicity and low cost. It holds high potential for early diagnosis of tumor biomarkers in POCT.

Optimized core-shell lanthanide nanoparticles with ultrabright Ce3+-modulated second near-infrared emission for "lighting" plants.

Second near-infrared (NIR-II, 1000-1700 nm) photon-mediated fluorescence imaging has attracted extensive interest in the field of bioimaging. However, NIR-II fluorescent nanoprobes competent for plant imaging have been rarely developed. Herein, lanthanide-doped nanoparticle (LDNP) optimal core-shell structure and ultrabright NIR-II emission were developed for "lighting" plants. The Ce3+-doped active shell coated on the NaErF4:Tm core enables dual-mode red upconversion (UC) and NIR-II downconversion (DC) emission of LDNPs upon 980 nm laser excitation. Under the optimized doping content, the intensities of red UC and NIR-II DC emission were respectively boosted by 5- and 19-fold those of the core nanoparticles, which endowed LDNPs with ideal NIR-II emissive capabilities for optical imaging of plants. Significantly, the NIR-II fluorescent signal affords much higher signal-to-noise rate than the red UC. LDNPs were modified with polyethyleneimine to enable outstanding hydrophilicty and facilitate their uptake by plants. Arabidopsis thaliana and Nicotiana benthamiana were chosen as plant models for NIR-II imaging studies. The toxic effect of LDNPs after being transported into Brassica rapa chinensis was systematically studied on mice. The NIR-II imaging strategy offers a promising method for studying the uptake and transport of nanoparticles in plants.

Preparation of rare-earth doped NaYF4 luminescent nanoparticles by a high-energy ball milling process

An optimized scalable production of single-phase rare-earth doped β-NaYF4 nanoparticles is developed by the high-energy ball milling. This approach opens up prospects for the photoluminescent nanomaterials fabrication for biotechnology and photonics.

Enhancing upconversion via constructing local energy clusters in lanthanide-doped fluoride nanoparticles

By introducing local energy clusters within the NaGdF4 lattice, the optimal Er3+, Ho3+ and Tm3+ doping concentrations were increased to 8, 8, and 2 mol%, respectively. The UC intensity was enhanced approximately 54.3 times by doping Ca2+.