Highly Doped Upconversion Nanoparticles for In Vivo Applications Under Mild Excitation Power.

One of the major challenges in using upconversion nanoparticles (UCNPs) is to improve their brightness. This is particularly true for in vivo studies, as the low power excitation is required to prevent the potential photo toxicity to live cells and tissues. Here, we report that the typical NaYF4:Yb0.2,Er0.02 nanoparticles can be highly doped, and the formula of NaYF4:Yb0.8,Er0.06 can gain orders of magnitude more brightness, which is applicable to a range of mild 980 nm excitation power densities, from 0.005 W/cm2 to 0.5 W/cm2. Our results reveal that the concentration of Yb3+ sensitizer ions plays an essential role, while increasing the doping concentration of Er3+ activator ions to 6 mol % only has incremental effect. We further demonstrated a type of bright UCNPs 12 nm in total diameter for in vivo tumor imaging at a power density as low as 0.0027 W/cm2, bringing down the excitation power requirement by 42 times. This work redefines the doping concentrations to fight for the issue of concentration quenching, so that ultrasmall and bright nanoparticles can be used to further improve the performance of upconversion nanotechnology in photodynamic therapy, light-triggered drug release, optogenetics, and night vision enhancement.

A single-particle enumeration method for the detection of Fe2+ based on a near-infrared core-shell upconversion nanoparticle and IR-808 dye composite nanoprobe.

Ferrous ion (Fe2+) is an important component of hemoglobin and plays a role in transporting O2 to human tissues. If iron deficiency is present, iron deficiency anemia may occur, so it is critical to develop sensitive and accurate methods to detect Fe2+. Herein, a novel luminescence energy transfer (ET) system has been designed for the sensitive detection of Fe2+ by a single-particle enumeration (SPE) method in the near-infrared (NIR) region through combining NIR-to-NIR ß-NaGdF4:Yb,Tm@NaYF4 upconversion nanoparticles (UCNPs) and IR-808 dye. IR-808 dye can quench the luminescence of the UCNPs because of the efficient overlap between the absorption spectrum of IR-808 and the emission spectrum of the UCNPs. When Fe2+ and H2O2 are added to the system, the Fenton reaction produces hydroxyl radicals (˙OH). The generated ˙OH reacts with IR-808 and the structure of IR-808 is destroyed. As a result, the ET process is suppressed, causing recovery of the luminescence of the UCNPs, which is reflected as an increase in the number of luminescent particles. Accurate quantification of Fe2+ is achieved by statistically counting the target concentration-dependent luminescent particles. Under the optimal conditions, the linear detection range of Fe2+ is 5-10 000 nM, which is much wider than the ensemble luminescence spectra measurements in bulk solution. Moreover, this strategy can be applied to detection in serum samples with satisfactory results.

A paper-supported sandwich immunosensor based on upconversion luminescence resonance energy transfer for the visual and quantitative determination of a cancer biomarker in human serum.

In this paper, a paper-supported analytical device based on a sandwich immunoreaction and luminescence resonance energy transfer (LRET) was reported for the visual and quantitative determination of a cancer biomarker, in which upconversion nanoparticles (UCNPs) were located on the surface of the paper as energy donors and gold nanoparticles (AuNPs) were used as energy acceptors. Upon the recognition of the cancer biomarker by two rationally selected antibodies, the upconversion luminescence was quenched by the AuNPs in a biomarker concentration-dependent manner. As a model target, CEA was detected using this immunosensor, and a linear relationship within 0.5-30 ng mL-1 was obtained in buffer solution, with a detection limit of 0.21 ng mL-1. The immunosensor was also applicable in 20-fold diluted human serum with a linear range of 0.5-30 ng mL-1 and a detection limit of 0.36 ng mL-1. This technique also realized the qualitative judgment of the critical concentration of CEA in serum samples by the naked eye. This approach displays great application potential for point-of-care testing in clinical applications, as well as the potentiality to be extended to other kinds of disease-related biomolecules.

Upconversion luminescence-infrared absorption nanoprobes for the detection of prostate-specific antigen.

Aiming to the ongoing challenge of accurate and sensitive detection for cancer biomarkers, antibody-functionalized NaYF4:Yb3+, Er3+@SiO2 nanorods were developed as upconversion luminescence (UCL)-infrared absorption (IRA) nanoprobes. Benefiting from the shielding effect of the SiO2 shell, an enhanced UCL was achieved. Additionally, an IRA detection signal was introduced by the Si-O-Si bonds of SiO2. Its mutual verification with UCL signal was favorable for ensuring the accuracy of the assay. A UCL-IRA sandwich detection method was established for the detection of the prostate-specific antigen. The UCL intensity at 542 nm and IRA at 1095 cm-1 were chosen for quantitative assay. The method has high sensitivity (0.05 pg mL-1) and selectivity. The range of detection (200 fg mL-1-200 ng mL-1) was singnificantly broadened compared with that of single-readout UCL or IRA detection. The assay performance of human serum samples demonstrated the practicability of the method in clinical cancer diagnosis. Graphical abstract.

NaGdF4:Yb,Er-Ag nanowire hybrid nanocomposite for multifunctional upconversion emission, optical imaging, MRI and CT imaging applications.

The effect of novel silver nanowire encapsulated NaGdF4:Yb,Er hybrid nanocomposite on the upconversion emission and bioimaging properties has been investigated. The upconvension nanomaterials were synthesised by polyol method in the presence of ethylene glycol, PVP and ethylenediamine. The NaGdF4:Yb,Er-Ag hybrid was formed with upconverting NaGdF4:Yb,Er nanoparticles of size ~ 80 nm and silver nanowires of thickness ~ 30 nm. The surface plasmon induced by the silver ion in the NaGdF4:Yb,Er-Ag nanocomposite resulted an intense upconversion green emission at 520 nm and red emission at 660 nm by NIR diode laser excitation at 980 nm wavelength. The UV-Vis-NIR spectral absorption at 440 nm and 980 nm, the intense Raman vibrational modes and the strong upconversion emission results altogether confirm the localised surface plasmon resonance effect of silver ion in the hybrid nanocomposite. MRI study of both NaGdF4:Yb,Er nanoparticle and NaGdF4:Yb,Er-Ag nanocomposite revealed the T1 relaxivities of 22.13 and 10.39 mM-1 s-1, which are larger than the commercial Gd-DOTA contrast agent of 3.08 mM-1 s-1. CT imaging NaGdF4:Yb,Er-Ag and NaGdF4:Yb,Er respectively showed the values of 53.29 HU L/g and 39.51 HU L/g, which are higher than 25.78 HU L/g of the CT contrast agent Iobitridol. The NaGdF4:Yb,Er and NaGdF4:Yb,Er-Ag respectively demonstrated a negative zeta potential of 54 mV and 55 mV, that could be useful for biological application. The in vitro cytotoxicity of the NaGdF4:Yb,Er tested in HeLa and MCF-7 cancer cell line by MTT assay demonstrated a cell viability of 90 and 80 %, respectively. But, the cell viability of NaGdF4:Yb,Er-Ag slightly decreased to 80 and 78%. The confocal microscopy imaging showed that the UCNPs are effectively up-taken inside the nucleolus of the cancer cells, and it might be useful for NIR laser-assisted phototherapy for cancer treatment. Graphical abstract.

Lateral flow immunostrips for the sensitive and rapid determination of 8-hydroxy-2'-deoxyguanosine using upconversion nanoparticles.

Lateral flow immunostrips were newly designed and a sensitive and rapid fluorometric method for the determination of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a model target of small biomarker molecules was developed. The upconversion nanoparticles (UCNPs, NaYF4:Yb/Er core, and polyacrylic acid (PAA)-modified shell, size ~ 39 nm, excitation wavelength = 980 nm; emission wavelength = 540 nm) were employed as fluorescence signal material. The 8-OHdG antibody (Ab) was taken as the recognition probe while UCNP-labeled Ab was taken as the signal probe. Bovine serum albumin (BSA) was designed as carrier protein for 8-OHdG to form 8-OHdG-BSA conjugate as the capture probe. The lateral flow immunostrips were prepared by laminating a sample pad (glass fiber membrane), a test pad (nitrocellulose membrane), and adsorption pad (filter paper) on PVP backing. The capture probe was immobilized on the test zone while an IgG antibody taken as the control probe was immobilized on the control zone. When the signal probe and the sample were in sequence loaded on the sample pad, 8-OHdG analyte bound with the signal probe, and then the excess of the signal probe move along the strip and is collected by the capture probe on the test zone while the remnant signal probe is collected by the control probe on the control zone. The signal probe and capture probe were synthesized and characterized. The fluorescence intensity on the test zone was inversely proportional to the concentration of 8-OHdG for the quantitative determination while the fluorescence emission on the control zone was observed to validate the assay. The developed method showed a wide linear range from 0.10 to 10 nM, a quite low detection limit of 0.05 nM, small sample volume requirement (100 µL), short assay time (15 min), and good method reproducibility (RSD = 4.4%, nine immunostrips). Graphical abstract Schematic illustration of the configuration and measurement principle of lateral flow fluorescence immunostrip for 8-OHdG: (a) configuration; (b) preparation: load of capture probe (BSA-8-OHdG, 2 µL) on test zone; load of control probe (IgG Ab, 2 µL) on control zone; load of signal probe (UCNP-Ab, 16 µL) on sample pad; (c) measurement: load of sample (8-OHdG, 100 µL) on sample pad, collection, and measurement.

A Turn-On Luminescence Method for Phosphate Determination Based on Fast Green-Functionalized ZrO2:Yb,Er@ZrO2 Core@Shell Upconversion Nanoparticles.

The development of practical and sensitive tools for detecting phosphate deficiency could facilitate engineering approaches to enhance crop yield and quality in phosphate-stressed environments, reducing the misuse of nonrenewable fertilizers and their consequent ecological impact. Herein, a 975 nm-activated method based on ZrO2:Yb,Er@ZrO2 core@shell upconversion nanoparticles is presented for rapid visualization and determination of the phosphate ions in aqueous solutions and extracts. At optimized thickness, the nondoped ZrO2 shell not only enhances the emission of the ZrO2:Yb,Er but also provides an active surface for the intense interaction with the phosphate group, allowing a "label-free" determination that avoids the use of additional phosphate-recognizing elements like ligands or antibodies. According to the experimental evidence, the optical output of the ZrO2:Yb,Er@ZrO2 nanoparticles specifically matches with the absorption spectrum of the fast green alimentary dye (FG) electrostatically attached to the nanoparticle surface, activating the Förster resonance energy transfer (FRET) and thereby the upconversion luminescence quenching. Upon addition of the phosphate ions and the covalent interaction with the ZrO2:Yb,Er@ZrO2-FG nanocomplex, the FG is gradually removed, displaying a fast and reproducible "turn-on" luminescence which allows measurements in a few minutes. This rapid response is due to the stronger coordination between the ZrO2 shell and the phosphate compared to the FG molecules (-31.97 and -5.99 eV, respectively). The detection method was then effectively modulated in a 20-1000 nM linear response range without interfering effects of commonly coexisting ions, achieving a detection limit up to 15 times lower than that obtained with the conventionally used colorimetric methods.

Near-Infrared-to-Ultraviolet Light-Mediated Photoelectrochemical Aptasensing Platform for Cancer Biomarker Based on Core-Shell NaYF4:Yb,Tm@TiO2 Upconversion Microrods.

Titanium dioxide (TiO2; as a potential photosensitizer) has good photocurrent performance and chemical stability but often exhibits low utilization efficiency under ultraviolet (UV) region excitation. Herein, we devised a near-infrared light-to-UV light-mediated photoelectrochemical (PEC) aptasensing platform for the sensitive detection of carcinoembryonic antigen (CEA) based on core-shell NaYF4:Yb,Tm@TiO2 upconversion microrods by coupling with target-triggered rolling circle amplification (RCA). The upconversion microrods synthesized through the hydrothermal reaction could act as a photosensing platform to convert the near-infrared (near-IR) excitation into UV emission for generation of photoinduced electrons. The target analyte was determined on a functional magnetic bead by using the corresponding aptamers with a sandwich-type assay format. Upon target CEA introduction, a complex was first formed between capture aptamer-1-conjugated magnetic bead (Apt1-MB) and aptamer-2-primer DNA (Apt2-pDNA). Thereafter, the carried primer DNA by the aptamer-2 paired with linear padlock DNA to trigger the RCA reaction. The guanine (G)-rich product by RCA reaction was cleaved by exonuclease I and exonuclease III (Exos I/III), thereby resulting in the formation of numerous individual guanine bases to enhance the photocurrent of core-shell NaYF4:Yb,Tm@TiO2 upconversion microrods under near-IR illumination (980 nm). Under optimal conditions, the near-IR light-mediated PEC aptasensing system could exhibit good photoelectrochemical response toward target CEA and allowed for the detection of target CEA as low as 3.6 pg mL-1. High reproducibility and good accuracy were achieved for analysis of human serum specimens. Importantly, the near-IR-activated PEC aptasensing scheme provides a promising platform for ultrasensitive detection of other biomolecules.

Photochemical Ligation to Ultrasensitive DNA Detection with Upconverting Nanoparticles.

In this work, we explore a photochemical ligation reaction to covalently modify oligonucleotide-conjugated upconverting nanoparticles (UCNPs) in the presence of a specific target DNA sequence. The target sequence acts as a hybridization template, bringing together a biotinylated photoactivatable oligonucleotide probe and the oligonucleotide probe that is attached to UCNPs. The illumination of the UCNPs by NIR light to generate UV emission internally or illuminating the photoactivatable probe directly by an external UV light promotes the photochemical ligation reaction, yielding covalently biotin functionalized UCNPs that can be selectively captured in streptavidin-coated microwells. Following this strategy, we developed a DNA sensor with a limit of detection of 1 × 10-18 mol per well (20 fM). In addition, we demonstrate the possibility to create UCNP patterns on the surface of solid supports upon NIR illumination that are selectively formed under the presence of the target oligonucleotide.

Optically Monitoring Mineralization and Demineralization on Photoluminescent Bioactive Nanofibers.

Bone regeneration and scaffold degradation do not usually follow the same rate, representing a daunting challenge in bone repair. Toward this end, we propose to use an external field such as light (in particular, a tissue-penetrating near-infrared light) to precisely monitor the degradation of the mineralized scaffold (demineralization) and the formation of apatite mineral (mineralization). Herein, CaTiO3:Yb(3+),Er(3+)@bioactive glass (CaTiO3:Yb(3+),Er(3+)@BG) nanofibers with upconversion (UC) photoluminescence (PL) were synthesized. Such nanofibers are biocompatible and can emit green and red light under 980 nm excitation. The UC PL intensity is quenched during the bone-like apatite formation on the surface of the nanofibers in simulated body fluid; more mineral formation on the nanofibers induces more rapid optical quenching of the UC PL. Furthermore, the quenched UC PL can recover back to its original magnitude when the apatite on the nanofibers is degraded. Our work suggests that it is possible to optically monitor the apatite mineralization and demineralization on the surface of nanofibers used in bone repair.

Q-switched operation of a pulsed-laser-deposited Yb:Y(2)O(3) waveguide using graphene as a saturable absorber.

The first, to the best of our knowledge, Q-switched operation of a pulsed-laser-deposited waveguide laser is presented. A clad Yb:Y(2)O(3) waveguide was Q-switched using an output coupling mirror coated with a single layer of graphene deposited by atmospheric pressure chemical vapor deposition. During continuous-wave operation, a maximum power of 83 mW at a slope efficiency of 25% was obtained. During Q-switched operation, pulses as short as 98 ns were obtained at a repetition rate of 1.04 MHz and a central wavelength of 1030.8 nm.

Optical temperature sensing based on the near-infrared emissions from Nd³âº/Yb³âº codoped CaWO4.

Under a 980 nm diode laser excitation, the near-infrared (NIR) emissions from Nd3+:4F7/2, 4F5/2, and 4F3/2 states in Nd3+/Yb3+ codoped CaWO4 powder were studied at temperatures ranging from 303 to 873 K. As the temperature increased, the NIR luminescence intensity was significantly enhanced and nearly 190-fold enhancement was achieved at 873 K compared with that at 303 K. By using the fluorescence intensity ratio technique, the thermometry behaviors through the NIR emissions were investigated. The results illustrate that the sensitivity and the accuracy achieved here are much higher than temperature sensors based on other rare earth ion doped materials.

Spectral and lasing investigations of Yb:YSGG crystal.

We report on a systematic study of the absorption and emission spectral properties of (Yb(0.1)Y(0.9))(3)(Sc(1.5)Ga(0.5))Ga(3)O(12) (Yb:YSGG) crystals. The broad fluorescence spectral lines indicate great potential of Yb:YSGG for tunable and ultrafast laser applications. Efficient continuous-wave (cw) laser oscillation was also demonstrated at room temperature (RT), generating an output power of 6.11 W with an optical-to-optical efficiency of 64.2%, and a slope efficiency of 80.1% with respect to absorbed pump power. The laser emission spectrum shifts to shorter wavelengths as the transmission of the output coupler varies from 3% to 20%, a result that can be explained based on the effective gain cross-sections of Yb:YSGG.

Intense ultra-broadband down-conversion in co-doped oxide glass by multipolar interaction process.

We report that Eu(2+) can be an efficient sensitizer for Yb(3+) and a broadband absorber for blue solar spectra in the host of oxide glass. The greenish 4f → 5d transition of Eu(2+) and the characteristic near-infrared emission of Yb(3+) were observed, with the blue-light of xenon lamp excitation. The 5d energy can be adjusted by the host and the energy transfer efficiency can be enhanced. The quantum efficiency is up to 163.8%. Given the broad excitation band, high absorption coefficient and excellent mechanical, thermal and chemical stability, this system can be useful as down-conversion layer for solar cells.

Upconversion-nanoparticle-functionalized Janus micromotors for efficient detection of uric acid.

We report enzyme-powered upconversion-nanoparticle-functionalized Janus micromotors, which are prepared by immobilizing uricase asymmetrically onto the surface of silicon particles, to actively and rapidly detect uric acid. The asymmetric distribution of uricase on silicon particles allows the Janus micromotors to display efficient motion in urine under the propulsion of biocatalytic decomposition of uric acid and simultaneously detect uric acid based on the luminescence quenching effect of the UCNPs modified on the other side of SiO2. The efficient motion of the motors greatly enhances the interaction between UCNPs and the quenching substrate and improves the uric acid detection efficiency. Overall, such a platform using uric acid simultaneously as the detected substrate and motion fuel offers considerable promise for developing multifunctional micro/nanomotors for a variety of bioassay and biomedical applications.

Dual-Responsive and ROS-Augmented Nanoplatform for Chemo/Photodynamic/Chemodynamic Combination Therapy of Triple Negative Breast Cancer.

Integrating chemodynamic therapy (CDT) and photodynamic therapy (PDT) into one nanoplatform can produce much more reactive oxygen species (ROS) for tumor therapy. Nevertheless, it is still a great challenge to selectively generate sufficient ROS in tumor regions. Meanwhile, CDT and PDT are restricted by insufficient H2O2 content in the tumor as well as by the limited tumor tissue penetration of the light source. In this study, a smart pH/ROS-responsive nanoplatform, Fe2+@UCM-BBD, is rationally designed for tumor combination therapy. The acidic microenvironment can induce the pH-responsive release of doxorubicin (DOX), which can induce tumor apoptosis through DNA damage. Beyond that, DOX can promote the production of H2O2, providing sufficient materials for CDT. Of note, upconversion nanoparticles at the core can convert the 980 nm light to red and green light, which are used to activate Ce6 to produce singlet oxygen (1O2) and achieve upconversion luminescence imaging, respectively. Then, the ROS-responsive linker bis-(alkylthio)alkene is cleaved by 1O2, resulting in the release of Fenton reagent (Fe2+) to realize CDT. Taken together, Fe2+@UCM-BBD exhibits on-demand therapeutic reagent release capability, excellent biocompatibility, and remarkable tumor inhibition ability via synergistic chemo/photodynamic/chemodynamic combination therapy.

A CORM loaded nanoplatform for single NIR light-activated bioimaging, gas therapy, and photothermal therapy in vitro.

Carbon monoxide (CO) can cause mitochondrial dysfunction, inducing apoptosis of cancer cells, which sheds light on a potential alternative for cancer treatment. However, the existing CO-based compounds are inherently limited by their chemical nature, such as high biological toxicity and uncontrolled CO release. Therefore, a nanoplatform - UmPF - that addresses such pain points is urgently in demand. In this study, we have proposed a nanoplatform irradiated by near-infrared (NIR) light to release CO. Iron pentacarbonyl (Fe(CO)5) was loaded in the mesoporous polydopamine layer that was coated on rare-earth upconverting nanoparticles (UCNPs). The absorption wavelength of Fe(CO)5 overlaps with the emission bands of the UCNPs in the UV-visible light range, and therefore the emissions from the UCNPs can be used to incite Fe(CO)5 to control the release of CO. Besides, the catechol groups, which are abundant in the polydopamine structure, serve as an ideal locating spot to chelate with Fe(CO)5; in the meantime, the mesoporous structure of the polydopamine layer improves the loading efficiency of Fe(CO)5 and reduces its biological toxicity. The photothermal effect (PTT) of the polydopamine layer is highly controllable by adjusting the external laser intensity, irradiation time and the thickness of the polydopamine layer. The results illustrate that the combination of CO gas therapy (GT) and polydopamine PTT brought by the final nanoplatform can be synergistic in killing cancer cells in vitro. More importantly, the possible toxic side effects can be effectively prevented from affecting the organism, since CO will not be released in this system without near-infrared light radiation.

Nonlinear spectroscopic properties of Yb3+-doped sesquioxides Lu2O3 and Sc2O3.

We report on the measurements of near-UV excited-state absorption (ESA) spectra and refractive index changes (RICs) in the two ytterbium doped laser crystals Yb:Lu2O3 and Yb:Sc2O3. ESA is assigned to ligand-to-metal charge transfer (LMCT) absorption transitions and RICs to the polarizability changes experienced by the Yb3+ ions due to these strong electric-dipole allowed absorption bands.

Lanthanide Sensitizers for Large Anti-Stokes Shift Near-Infrared-to-Visible Triplet-Triplet Annihilation Photon Upconversion.

The upconversion of near-infrared (NIR) to visible (vis) photons is of interest for display technologies and energy conversion. Although triplet-triplet annihilation (TTA) offers a mechanism for upconversion that works efficiently at low incident irradiance flux densities, current strategies for NIR-vis upconversion based on TTA have fundamental limitations. Herein, we report a strategy for NIR-vis TTA based on lanthanide-containing complexes to sensitize the upconversion. We demonstrate a ß-diketonate complex of Yb3+ paired with rubrene that emits yellow (λem = 559 nm) under NIR excitation (λexc = 980 nm). This corresponds to an exceptional anti-Stokes shift of just less than 1 eV. Thus, lanthanide complexes could unlock high-performance NIR-vis upconversion, with lanthanide sensitizers overcoming the energy loss, reabsorption, and short triplet lifetime that fundamentally limit porphyrin, nanocrystals, and direct S0-T1 sensitizers.

Aptamer-modified sensitive nanobiosensors for the specific detection of antibiotics.

The overuse or abuse of quinolone antibiotics such as enrofloxacin (ENR) in veterinary medicine results in the presence of their residues in food and environment. Thus, a sensitive method is needed to detect them. Herein, we demonstrate a fluorescence resonance energy transfer (FRET) based aptasensor for ENR detection, using core-shell upconversion nanoparticles (CSUNPs) as an energy donor and graphene oxide (GO) as an energy acceptor. The core-shell structure and Gd3+ doping significantly increased the fluorescence intensity of CSUNPs and the FRET efficiency. The ENR aptamer was conjugated to CSUNPs through ligand exchange, and the π-π stacking between the aptamer and GO brought the aptamer-modified CSUNPs to the surface of the GO sheets, resulting in the formation of a CSUNP-GO complex and the subsequent quenching of CSUNP fluorescence. As a result, an aptasensor was established with the fluorescence of CSUNPs correlated with the ENR concentration within the range of 0.976 ng mL-1 to 62.5 ng mL-1, allowing ENR to be detected at a limit of 0.47 ng mL-1. This method reduced the detection limit by approximately 13-fold in 2 h compared to the commercial enzyme-linked immunosorbent assay (ELISA) kit. The aptasensor could also be applied to detect ENR from commercial milk powder samples with a detection limit of 1.59 ng mL-1, which was far below the regulated maximum residue limit of ENR in milk. The aptasensor could not detect other antibiotics, suggesting its good specificity towards ENR. Our work demonstrates a highly selective, sensitive and cost-effective method for detecting antibiotic residues in veterinary medicine. Since the aptamer can be switched to one recognizing another antibiotic, the aptasensors are used as a plug-and-play platform that can detect a variety of antibiotics.