Lanthanide-based Upconversion Nanoparticles Research Articles

Control of Luminescence and Interfacial Properties as Perspective for Upconversion Nanoparticles.

Near-infrared (NIR) light is highly suitable for studying biological systems due to its minimal scattering and lack of background fluorescence excitation, resulting in high signal-to-noise ratios. By combining NIR light with lanthanide-based upconversion nanoparticles (UCNPs), upconversion is used to generate UV or visible light within tissue. This remarkable property has gained significant research interest over the past two decades. Synthesis methods are developed to produce particles of various sizes, shapes, and complex core-shell architectures and new strategies are explored to optimize particle properties for specific bioapplications. The diverse photophysics of lanthanide ions offers extensive possibilities to tailor spectral characteristics by incorporating different ions and manipulating their arrangement within the nanocrystal. However, several challenges remain before UCNPs can be widely applied. Understanding the behavior of particle surfaces when exposed to complex biological environments is crucial. In applications where deep tissue penetration is required, such as photodynamic therapy and optogenetics, UCNPs show great potential as nanolamps. These nanoparticles can combine diagnostics and therapeutics in a minimally invasive, efficient manner, making them ideal upconversion probes. This article provides an overview of recent UCNP design trends, highlights past research achievements, and outlines potential future directions to bring upconversion research to the next level.

Plasmon Modulated Upconversion Biosensors

Over the past two decades, lanthanide-based upconversion nanoparticles (UCNPs) have been fascinating scientists due to their ability to offer unprecedented prospects to upconvert tissue-penetrating near-infrared light into color-tailorable optical illumination inside biological matter. In particular, luminescent behavior UCNPs have been widely utilized for background-free biorecognition and biosensing. Currently, a paramount challenge exists on how to maximize NIR light harvesting and upconversion efficiencies for achieving faster response and better sensitivity without damaging the biological tissue upon laser assisted photoactivation. In this review, we offer the reader an overview of the recent updates about exciting achievements and challenges in the development of plasmon-modulated upconversion nanoformulations for biosensing application.

Magnetic modification of lanthanide-based upconversion nanocrystals for fingerprint information recognition

The development of new magnetic fluorescent materials is of great significance for identification and criminal investigation. Since the photosensitive elements used in conventional cameras have exhibited the highest quantum efficiency in the range of 500–700 nm, lanthanide-based upconversion nanoparticles (UCNPs) with main emission peaks at 507–533 nm, 533–568 nm and 637–683 nm are suitable for constructing magnetic fluorescent materials. In this work, we demonstrate a type of magnetic upconversion nanoparticle (MUCNP) of NaGdF<sub>4</sub>:Yb,Er-Fe<sub>3</sub>O<sub>4</sub> by a ligand-linked method. After optimizing the reaction parameters, the composite particles possess remarkable magnetic properties and upconversion fluorescence intensity and achieve high contrast for latent fingerprint recognition on various substrates. The combination of upconversion luminescence and magnetism contributes to good fingerprint recognition sensitivity and universality.

Cubic upconversion nanoparticles used as the theranostic system for the treatment and diagnosis of angiogenesis-related diseases

Biocompatible nanostructures offer new pathways to overcome the obstacles in conventional anti-angiogenic therapy such as drug accumulation and therapeutic efficiency. However, current technology is limited by the bioavailability of therapeutics and the obstruction of imaging. Theranostic nanoparticles have been developed to bridge the gap between imaging and therapeutic delivery. In this paper, a theranostic system made of cubic lanthanide-based upconversion nanoparticles (UCNPs) has been developed. The average length of the cubic UCNPs is estimated at 53 ± 13 nm. The fluorescence intensity of the emission peaks of UNCPs in the visible range is dependent on the power of the excitation at a region of near-infrared (NIR), λex = 980 nm. In addition, cell imaging has demonstrated that the UNCPs conjugated with anti-VEGF antibodies show significant anti-angiogenic effects which are even stronger than their anti-VEGF counterpart. With the capabilities of both anti-angiogenic effects and cell imaging, the UCNPs-antiVEGF is a promising theranostic model at the nanoscale for the treatment and diagnosis of angiogenesis-related diseases .

A Facile Approach for the Ligand Free Synthesis of Biocompatible Upconversion Nanophosphors.

Upconversion nanophosphors, particles that can absorb low energy radiation and emit high energy light through multi-photon absorption processes, have gained augmented attention in recent years. Due to their admirable optical and chemical properties, these nanoparticles are finding wide range of applications in the field of bioimaging, light emitting devices and security printing. However, for any practical application, it is extremely important that a facile synthetic route is developed that can lead to the generation of nanophosphors exhibiting efficient upconversion luminescence under diverse experimental conditions. Herein, we report a new ligand-free approach for the synthesis of lanthanide-based upconversion nanoparticles by adopting a simple solid-state synthetic route. The reaction conditions such as temperature and time were optimized to obtain nanophosphors exhibiting enhanced upconversion luminescence. The synthesized nanoparticles, due to its ligand-free nature, could be well dispersed in both aqueous and organic media. The nanophosphors retained the upconversion luminescence under varying time, pH and temperature, indicating that the absence of ligand had least effect on their stability. The nanophosphors were found to exhibit good cell viability even under high concentrations, unveiling their potential as bioimaging agents in the biomedical research.

Microscale Self-Assembly of Upconversion Nanoparticles Driven by Block Copolymer.

Lanthanide-based upconversion nanoparticles can convert low-energy excitation to high-energy emission. The self-assembled upconversion nanoparticles with unique structures have considerable promise in sensors and optical devices due to intriguing properties. However, the assembly of isotropic nanocrystals into anisotropic structures is a fundamental challenge caused by the difficulty in controlling interparticle interactions. Herein, we report a novel approach for the preparation of the chain-like assemblies of upconversion nanoparticles at different scales from nano-scale to micro-scale. The dimension of chain-like assembly can be fine-tuned using various incubation times. Our study observed Y-junction aggregate morphology due to the flexible nature of amphiphilic block copolymer. Furthermore, the prepared nanoparticle assemblies of upconversion nanoparticles with lengths up to several micrometers can serve as novel luminescent nanostructure and offer great opportunities in the fields of optical applications.

Light-Emitting Diode Excitation for Upconversion Microscopy: A Quantitative Assessment

Lanthanide-based upconversion nanoparticles (UCNPs) generally require high power laser excitation. Here, we report wide-field upconversion microscopy at single-nanoparticle sensitivity using incoherent excitation of a 970 nm light-emitting diode (LED). We show that due to its broad emission spectrum, LED excitation is about 3 times less effective for UCNPs and generates high background compared to laser illumination. To counter this, we use time-gated luminescence detection to eliminate the residual background from the LED source, so that individual UCNPs with high sensitizer (Yb3+) doping and inert shell protection become clearly identified under LED excitation at 1.18 W cm-2, as confirmed by correlated electron microscopy images. Hydrophilic UCNPs are obtained by polysaccharide coating via a facile ligand exchange protocol to demonstrate imaging of cellular uptake using LED excitation. These results suggest a viable approach to bypassing the limitations associated with high-power lasers when applying UCNPs and upconversion microscopy to life science research.

Stretchable and upconversion-luminescent polymeric optical sensor for wearable multifunctional sensing.

Stretchable sensors with multiple sensory functions are in high demand for healthcare monitoring and artificial intelligence. Despite recent advances in wearable electronic sensors, it remains a significant challenge to achieve simultaneous sensing of both thermal and mechanical stimuli with a single sensor while integrating high stretchability. Herein, a stretchable and multifunctional optical sensor (SMOS) with simultaneous readout of temperature and strain is developed for wearable physiological monitoring of the human body. The SMOS primarily consists of a stretchable optical sensing fiber made from polymer nanocomposites containing lanthanide-based upconversion nanoparticles (UCNPs). Temperature measurements are achieved by ratiometric intensity measurements of the dual-emission UCNPs upon near-infrared excitation. By virtue of the ratiometric detection, the temperature readout of the SMOS is independent of strain deformations, enabling stable and continuous measurements of skin temperature during body motions. Furthermore, deformation of the SMOS by stretching leads to detectable and reversible changes in its light transmission, allowing tensile strains to be simultaneously measured. As a proof of concept, we demonstrate the capabilities of the SMOS in real time and simultaneous detection of both skin temperature and motion activities of the human body.

Surface Modifications for Photon-Upconversion-Based Energy-Transfer Nanoprobes.

An emerging class of inorganic optical reporters are near-infrared (NIR) excitable lanthanide-based upconversion nanoparticles (UCNPs) with multicolor emission and long luminescence lifetimes in the range of several hundred microseconds. For the design of chemical sensors and optical probes that reveal analyte-specific changes in their spectroscopic properties, these nanomaterials must be combined with sensitive indicator dyes that change their absorption and/or fluorescence properties selectively upon interaction with their target analyte, utilizing either resonance energy transfer (RET) processes or reabsorption-related inner filter effects. The rational development of UCNP-based nanoprobes for chemical sensing and imaging in a biological environment requires reliable methods for the surface functionalization of UCNPs, the analysis and quantification of surface groups, a high colloidal stability of UCNPs in aqueous media as well as the chemically stable attachment of the indicator molecules, and suitable instrumentation for the spectroscopic characterization of the energy-transfer systems and the derived nanosensors. These topics are highlighted in the following feature article, and examples of functionalized core-shell nanoprobes for the sensing of different biologically relevant analytes in aqueous environments will be presented. Special emphasis is placed on the intracellular sensing of pH.

Selective cellular imaging with lanthanide-based upconversion nanoparticles.

Upconversion nanoparticles (UCNPs) with sodium yttrium fluoride, NaYF4 (host lattice) doped with Yb3+ (sensitizer) and Er3+ (activator) were synthesized via hydrothermal route incorporating polyethyleneimine (PEI) for their long‐term stability in water. The cationic PEI‐modified UCNPs with diameter 20 ± 4 nm showed a zeta potential value of +36.5 mV and showed an intense, visible red luminescence and low‐intensity green emission with 976 nm laser excitation. The particles proven to be nontoxic to endothelial cells, with a 3‐(4,5‐dimethylthiazol‐2yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, showing 90% to 100% cell viability, across a wide range of UCNP concentrations (0.3 ng/mL‐0.3 mg/mL) were used in multiphoton imaging. Multiphoton cellular imaging and emission spectroscopy data reported here prove that the UCNPs dispersed in cell culture media are predominantly concentrated in the cytoplasm than the cell nucleus. The energy transfer from PEI‐coated UCNPs to surrounding media for red luminescence in the biological system is also highlighted with spectroscopic measurements. Results of this study propose that UCNPs can, therefore, be used for cytoplasm selective imaging together with multiphoton dyes (eg, 4′,6‐diamidino‐2‐phenylindole (DAPI)) that are selective to cell nucleus.

Strong upconversion emission in CsPbBr3 perovskite quantum dots through efficient BaYF5:Yb,Ln sensitization

An in situ growth method was proved to realize full sensitization efficiency of all-inorganic CsPbBr3 perovskite quantum dots from lanthanide-based upconversion nanoparticles, leading to intense emission intensity.

Upconversion nanoparticles with anti-Stokes luminescence as bioimaging agents

Lanthanide-based upconversion nanoparticles attach great attention in theranostics due to their unique physicochemical and optical properties. It is innovative platform possessing peculiar properties for luminescent imaging, temperature mapping, sensing, and therapy. In present work we demonstrate advantages of new luminescent agents based on upconversion nanoparticles and hydrophylic biocompatible polymer.

NIR-to-NIR UCL/T1-weighted MR/CT multimodal imaging by NaYbF4:Tm@NaGdF4:Yb-PVP upconversion nanoparticles

Multimodal imaging nanoprobes are urgently sought because they can integrate different imaging function into individual nanoplatform and provide more comprehensive and accurate information for the diagnosis of early-stage tumor. Lanthanide-based upconversion nanoparticles (UCNPs) are regarded as promising nanoplatforms to fabricate these probes. Herein, we firstly developed the active core-active shell structured NaYbF4:Tm@NaGdF4:Yb-PVP UCNPs with the average diameter of 13.23±0.96nm as multimodal imaging probes. These water-dispersible nanoprobes presented excellent near-infrared to near-infrared (NIR-to-NIR) upconversion luminescence (UCL) performance, which is favorable for optical bioimaging due to deeper tissue penetration and autofluorescence reduction. After coated with the NaGdF4:Yb active shell, the UCL emission intensity at 800nm increased by 7.2times. These nanoprobes exhibited a desirable longitudinal relaxivity (r1=3.58L/(mmols)) and strong X-ray attenuation property (58.84HUL/g). The cytotoxicity assessment, histology analysis and biodistribution study revealed that NaYbF4:Tm@NaGdF4:Yb-PVP UCNPs had relatively low cytotoxicity and negligible organ toxicity. These UCNPs were applied for NIR-to-NIR UCL imaging in vivo. More importantly, the detection of small tumor was successfully achieved under T1-weighted MRI and CT imaging modalities after intravenous injection of these UCNPs. These results revealed that NaYbF4:Tm@NaGdF4:Yb-PVP UCNPs could serve as promising NIR-to-NIR UCL/MRI/CT trimodal imaging probes.

Novel Fluorinated Polymer-Mediated Upconversion Nanoclusters for pH/Redox Triggered Anticancer Drug Release and Intracellular Imaging

This paper designs and synthesizes a novel amphiphilic fluorinated block copolymer, composed of oligo ethylene glycol methyl ether methacrylate, 2-(N,N-dimethylamino)ethyl methacrylate, and developing 2-((2-methacryloyloxy ethyl) disulfanyl) ethyl 3,5-bis(trifluoromethyl) benzoate, by reversible addition–fragmentation chain transfer polymerization. This amphiphilic block copolymer can self-assemble with hydrophobic lanthanide-based upconversion nanoparticles to form hybrid colloidal nanoclusters. The obtained nanoclusters exhibit not only good water-dispersibility, high biocompatibility, and strong stability in biological milieu, but excellent pH/redox-dual-responsive release in vitro behavior for doxorubicin (DOX). And the DOX-loaded nanoclusters have much better therapeutic effect than free DOX and can be uptaken by MCF-7 cells with evident upconversion luminescence signal for intracellular imaging.

Upconversion nanoparticle-decorated gold nanoshells for near-infrared induced heating and thermometry.

The present work involves the design of a multifunctional system based on gold nanoshells (AuNSs) decorated with lanthanide-based upconversion nanoparticles (UCNPs) intended as an optical heater and a temperature probe at the nanoscale. The synthesis of NaGdF4 UCNPs doped with ions Yb3+:Er3+ was performed via thermal decomposition of lanthanide fluoride precursors at high temperatures (>300 °C) in the presence of a coordinating ligand (oleic acid). UCNPs were synthesized at three different temperatures (310, 315 and 320 °C) and characterized in terms of morphological, structural and emission properties. In view of the intended biological applications, the surface of hydrophobic oleate-capped UCNPs was modified using a silica coating to achieve sufficient water dispersibility, through a modified Stöber process using a reverse micro-emulsion method. Monodisperse NaGdF4:Yb3+:Er3+ upconversion nanocrystals (∼25 nm dia.) were obtained in cubic (at 310, 315 °C) and hexagonal (at 320 °C) phases. The UCNPs in the hexagonal phase were shown to be more suitable as temperature sensors, due to their lower red-to-green emission ratios and higher thermal sensitivities. The emission spectrum of NaGdF4:Yb3+:Er3+ (oleate- or silica-coated) UCNPs was recorded at different temperatures in the vicinity of the physiological range (20-70 °C) and presented suitable properties for application as temperature sensors, such as excellent linearity (r2 > 0.99) and sensitivity (>3 × 10-3 K-1). The heating capacity of AuNSs@UCNPs was verified by monitoring the Er3+ emission, showing their potential for application as a hyperthermia agent controlled using a nanothermometer function.

Multimodal Cancer Imaging Using Lanthanide-Based Upconversion Nanoparticles

Multimodal nanoprobes that integrate different imaging modalities in one nano-system could offer synergistic effect over any modality alone to satisfy the higher requirements on the efficiency and accuracy for clinical diagnosis and medical research. Upconversion nanoparticles (UCNPs), particularly lanthanide (Ln)-based NPs have been regarded as an ideal building block for constructing multimodal bioprobes due to their fascinating properties. In this review, we first summarize recent advances in the optimizations of existing UCNPs. In particular, we highlight the applications of Ln-based UCNPs for multimodal cancer imaging in vitro and in vivo. The explorations of UCNPs-based multimodal nanoprobes for targeting diagnosis and imaging-guided therapeutics are also presented. Finally, the challenges and perspectives of Ln-based UCNPs in this rapid growing field are discussed.

Efficient gene delivery and multimodal imaging by lanthanide-based upconversion nanoparticles.

Nanoparticles have been explored as nonviral gene carriers for years because of the simplicity of surface modification and lack of immune response. Lanthanide-based upconversion nanoparticles (UCNPs) are becoming attractive candidates for biomedical applications in virtue of their unique optical properties and multimodality imaging ability. Here, we report a UCNPs-based structure with polyethylenimine coating for both efficient gene transfection and trimodality imaging. Cytotoxicity tests demonstrated that the nanoparticles exhibited significantly decreased cytotoxicity compared to polyethylenimine polymer. Further, in vitro studies revealed that the gene carriers are able to transfer the enhanced green fluorescence protein (EGFP) plasmid DNA into Hela cells in higher transfection efficiency than PEI. Gene silencing was also examined by delivering bcl-2 siRNA into Hela cells, resulting in significant downregulation of target bcl-2 mRNA. More importantly, we demonstrated the feasibility of upconversion gene carriers to serve as effective contrast agents for MRI/CT/UCL trimodality imaging both in vitro and in vivo. The facile fabrication process, great biocompatibility, enhanced gene transfection efficiency, and great bioimaging ability can make it promising for application in gene therapy.

Fabrication of versatile cyclodextrin-functionalized upconversion luminescence nanoplatform for biomedical imaging.

Lanthanide-based upconversion nanoparticles (UCNPs) are a new type of luminescent tags that show great application potential in biomedical fields. However, a major challenge when applying UCNPs in biomedical research is the lack of a versatile strategy to make water-dispersible and biocompatible UCNPs with high simplicity in functionalization. To address this problem, in the present work, we employed 6-phosphate-6-deoxy-β-cyclodextrin (βPCD) as the novel ligand to fabricate a versatile upconversion luminescent nanoplatform. Using βPCD as the surface ligand not only enhances the stability and biocompatibility of the UCNPs under physiological conditions but also enables simple conjugation with various functional molecules, such as organic dyes and biomolecules, via the host-guest interaction between those molecules and the cyclodextrin cavity. The conjugated upconversion nanoprobe then displays excellent capability in labeling the cancer cells and tumor tissue slices for luminescent imaging. These results demonstrate that the versatile cyclodextrin-functionalized upconversion nanoplatform appears particularly flexible for further modifications, indicating great potential for applications in biosensing and bioimaging.

Upconversion luminescence imaging of cells and small animals

Upconversion luminescence (UCL) is an anti-Stokes process whereby low-energy photons are converted to higher-energy ones. UCL imaging for cells and animal tissues has attracted substantial attention in recent years because of the unique abilities of upconversion materials, which can minimize the background interference from the autofluorescence of biosamples and enhance tissue penetration. This protocol describes a step-by-step guide for the fabrication of UCL probes, including lanthanide-based upconversion nanoparticles (Ln-UCNPs) with a particle size of ∼20 nm (NaYF4/NaLuF4: Yb, Er/Tm) and triplet-triplet annihilation-based UCNPs (TTA-UCNPs) with a particle size of ∼10 nm (palladium octaethylporphyrin as sensitizer and 9,10-diphenylanthracene as annihilator). We also describe the characterization of the UCL nanoprobes (via transmission electron microscopy and UCL emission spectroscopy) and functionalization (via silica coating and ligand exchange), as well as applications for UCL bioimaging of living cells (HeLa cells) and small animals (nude mice and Kunming mice). The setup of a laser-scanning UCL microscope and a UCL imaging system is also presented. Compared with a normal imaging setup, we adopted longer-wavelength excitation lasers and short-pass filters. The synthesis of hydrophilic UCNP for application in UCL bioimaging requires ∼15 d.

Highly-sensitive multiplexed in vivo imaging using pegylated upconversion nanoparticles

Lanthanide-based upconversion nanoparticles (UCNPs) have been widely explored in various fields, including optical imaging, in recent years. Although earlier work has shown that UCNPs with different lanthanide (Ln3+) dopants exhibit various colors, multicolor-especially in vivo multiplexed biomedical imaging-using UCNPs has rarely been reported. In this work, we synthesize a series of UCNPs with different emission colors and functionalize them with an amphiphilic polymer to confer water solubility. Multicolor in vivo upconversion luminescence (UCL) imaging is demonstrated by imaging subcutaneously injected UCNPs and applied in multiplexed in vivo lymph node mapping. We also use UCNPs for multicolor cancer cell labeling and realize in vivo cell tracking by UCL imaging. Moreover, for the first time we compare the in vivo imaging sensitivity of quantum dot (QD)-based fluorescence imaging and UCNP-based UCL imaging side by side, and find the in vivo detection limit of UCNPs to be at least one order of magnitude lower than that of QDs in our current non-optimized imaging system. Our data suggest that, by virtue of their unique optical properties, UCNPs have great potential for use in highly-sensitive multiplexed biomedical imaging.