Xingjun Zhu

Fluorine-18-labeled Gd3+/Yb3+/Er3+ co-doped NaYF4 nanophosphors for multimodality PET/MR/UCL imaging

Molecular imaging modalities provide a wealth of information that is highly complementary and rarely redundant. To combine the advantages of molecular imaging techniques, (18)F-labeled Gd(3+)/Yb(3+)/Er(3+) co-doped NaYF(4) nanophosphors (NPs) simultaneously possessing with radioactivity, magnetic, and upconversion luminescent properties have been fabricated for multimodality positron emission tomography (PET), magnetic resonance imaging (MRI), and laser scanning upconversion luminescence (UCL) imaging. Hydrophilic citrate-capped NaY(0.2)Gd(0.6)Yb(0.18)Er(0.02)F(4) nanophosphors (cit-NPs) were obtained from hydrophobic oleic acid (OA)-coated nanoparticles (OA-NPs) through a process of ligand exchange of OA with citrate, and were found to be monodisperse with an average size of 22 × 19 nm. The obtained hexagonal cit-NPs show intense UCL emission in the visible region and paramagnetic longitudinal relaxivity (r(1) = 0.405 s(-1)·(mM)(-1)). Through a facile inorganic reaction based on the strong binding between Y(3+) and F(-), (18)F-labeled NPs have been fabricated in high yield. The use of cit-NPs as a multimodal probe has been further explored for T(1)-weighted MR and PET imaging in vivo and UCL imaging of living cells and tissue slides. The results indicate that (18)F-labeled NaY(0.2)Gd(0.6)Yb(0.18)Er(0.02) is a potential candidate as a multimodal nanoprobe for ultra-sensitive molecular imaging from the cellular scale to whole-body evaluation.

Core-shell Fe3O4@NaLuF4:Yb,Er/Tm nanostructure for MRI, CT and upconversion luminescence tri-modality imaging.

Core-shell Fe(3)O(4)@NaLuF(4):Yb,Er/Tm nanostructure (MUCNP) with multifunctional properties has been developed using a step-wise synthetic method. The successful fabrication of MUCNP has been confirmed by transmission electron microscopy, powder X-ray diffraction, energy-dispersive X-ray analysis and X-ray photoelectron spectroscopy. The MUCNP exhibits superparamagnetic property with saturation magnetization of 15 emu g(-1), and T(2)-enhanced magnetic resonance (MR) effect with an r(2) value of 21.63 s(-1) mM(-1) at 0.5 T, resulting from the Fe(3)O(4) cores. Moreover, the NaLuF(4)-based MUCNP provides excellent X-ray attenuation and upconversion luminescence (UCL) emission under excitation at 980 nm. In vivo MR, computed tomography (CT) and UCL images of tumor-bearing mice show that the MUCNP can be successfully used in multimodal imaging. In vitro tests reveal that the MUCNP is non-cytotoxic. These results suggest that the developed MUCNP could be served as an MR, CT and UCL probe for tri-modality imaging.

Core–Shell Lanthanide Upconversion Nanophosphors as Four-Modal Probes for Tumor Angiogenesis Imaging

Multimodality imaging overcomes the shortage and incorporates the advantages of different imaging tools. Lanthanide-based nanoprobes are unique and have rich optical, magnetic, radioactive, and X-ray attenuation properties; however, simple doping of different lanthanide cations into one host can result in a material with multifunction but not the optimized properties. In this study, using NaLuF4:Yb,Tm as the core and 4 nm of (153)Sm(3+)-doped NaGdF4 (half-life of (153)Sm = 46.3 h) as the shell, we developed a lanthanide-based core-shell nanocomposite as an optimized multimodal imaging probe with enhanced imaging ability. The lifetime of upconversion luminescence (UCL) at 800 nm and relaxation rate (1/T1) were at 1044 μs and 18.15 s(-1)·mM(-1), respectively; however, no significant decrease in the attenuation coefficient was observed, which preserved the excellent X-ray imaging ability. The nanomaterial NaLuF4:Yb,Tm@NaGdF4((153)Sm) was confirmed to be effective and applicable for UCL imaging, X-ray computed tomography (CT), magnetic resonance imaging, and single-photon emission computed tomography (SPECT) in vivo. Furthermore, the NaLuF4:Yb,Tm@NaGdF4((153)Sm) nanoparticles were applied in tumor angiogenesis analysis by combining multimodality imaging of CT, SPECT, and confocal UCL imaging, which shows its value of multifunctional nanoparticles NaLuF4:Yb,Tm@NaGdF4((153)Sm) in tumor angiogenesis imaging.

Temperature-feedback upconversion nanocomposite for accurate photothermal therapy at facile temperature.

Photothermal therapy (PTT) at present, following the temperature definition for conventional thermal therapy, usually keeps the temperature of lesions at 42–45 °C or even higher. Such high temperature kills cancer cells but also increases the damage of normal tissues near lesions through heat conduction and thus brings about more side effects and inhibits therapeutic accuracy. Here we use temperature-feedback upconversion nanoparticle combined with photothermal material for real-time monitoring of microscopic temperature in PTT. We observe that microscopic temperature of photothermal material upon illumination is high enough to kill cancer cells when the temperature of lesions is still low enough to prevent damage to normal tissue. On the basis of the above phenomenon, we further realize high spatial resolution photothermal ablation of labelled tumour with minimal damage to normal tissues in vivo. Our work points to a method for investigating photothermal properties at nanoscale, and for the development of new generation of PTT strategy.

NIR photothermal therapy using polyaniline nanoparticles.

Developing a biocompatible and efficient photothermal coupling agent with appropriate size is a prerequisite for the development of near-infrared (NIR) light-induced photothermal therapy (PTT). In the present study, polyaniline nanoparticles (PANPs) with a size of 48.5 ± 1.5 nm were fabricated and exhibited excellent dispersibility in water by a hydrothermal method and further surface functionalization by capping with F127. The developed F127-modified PANPs (F-PANPs) had a high molar extinction coefficient of 8.95 × 10(8) m(-1) cm(-1), and high NIR photothermal conversion efficiency of 48.5%. Furthermore, combined with NIR irradiation at 808 nm and injection of F-PANP samples, in vivo photothermal ablation of tumor with excellent treatment efficacy was achieved. In vitro transmission electron microscopy (TEM) images of cells, methyl thiazolyl tetrazolium (MTT) assay, histology, and hematology studies revealed that the F-PANPs exhibit low toxicity to living systems. Therefore, F-PANPs could be used as PTT agents for ablating cancer, and the concept of developing polyaniline-based nanoparticles can serve as a platform technology for the next generation of in vivo PTT agents.

Water-stable NaLuF4-based upconversion nanophosphors with long-term validity for multimodal lymphatic imaging

Multimodal imaging is rapidly becoming an important tool for biomedical applications because it can compensate for the deficiencies of individual imaging modalities. Herein, multifunctional NaLuF(4)-based upconversion nanoparticles (Lu-UCNPs) were synthesized though a facile one-step microemulsion method under ambient condition. The doping of lanthanide ions (Gd(3+), Yb(3+) and Er(3+)/Tm(3+)) endows the Lu-UCNPs with high T(1)-enhancement, bright upconversion luminescence (UCL) emissions, and excellent X-ray absorption coefficient. Moreover, the as-prepared Lu-UCNPs are stable in water for more than six months, due to the protection of sodium glutamate and diethylene triamine pentacetate acid (DTPA) coordinating ligands on the surface. Lu-UCNPs have been successfully applied to the trimodal CT/MR/UCL lymphatic imaging on the modal of small animals. It is worth noting that Lu-UCNPs could be used for imaging even after preserving for over six months. In vitro transmission electron microscope (TEM), methyl thiazolyl tetrazolium (MTT) assay and histological analysis demonstrated that Lu-UCNPs exhibited low toxicity on living systems. Therefore, Lu-UCNPs could be multimodal agents for CT/MR/UCL imaging, and the concept can be served as a platform technology for the next-generation of probes for multimodal imaging.

Hollow silica nanoparticles loaded with hydrophobic phthalocyanine for near-infrared photodynamic and photothermal combination therapy.

Owing to the convenience and minimal invasiveness, phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is emerging as a powerful technique for cancer treatment. To date, however, few examples of combination PDT and PTT have been reported. Phthalocyanine (Pc) is a class of traditional photosensitizer for PDT, but its bioapplication is limited by high hydrophobicity. In this present study, hollow silica nanospheres (HSNs) were employed to endow the hydrophobic phthalocyanine with water-dispersity, and the as-prepared hollow silica nanoparticles loaded with hydrophobic phthalocyanine (Pc@HSNs) exhibits highly efficient dual PDT and PTT effects. In vitro and in vivo experimental results clearly indicated that the dual phototherapeutic effect of Pc@HSNs can kill cancer cells or eradicate tumor tissues. This multifunctional nanomedicine may be useful for PTT/PDT treatment of cancer.

High-Contrast Visualization of Upconversion Luminescence in Mice Using Time-Gating Approach.

Optical imaging through the near-infrared (NIR) window provides deep penetration of light up to several centimeters into biological tissues. Capable of emitting 800 nm luminescence under 980 nm illumination, the recently developed upconversion nanoparticles (UCNPs) suggest a promising optical contrast agent for in vivo bioimaging. However, presently they require high-power lasers to excite when applied to small animals, leading to significant scattering background that limits the detection sensitivity as well as a detrimental thermal effect. In this work, we show that the time-gating approach implementing pulsed illumination from a NIR diode laser and time-delayed imaging synchronized via an optical chopper offers detection sensitivity more than 1 order of magnitude higher than the conventional approach using optical band-pass filters (S/N, 47321/6353 vs 5339/58), when imaging UCNPs injected into Kunming mice. The pulsed laser illumination (70 μs ON in 200 μs period) also reduces the overall thermal accumulation to 35% of that under the continuous-wave mode. Technical details are given on setting up the time-gating unit comprising an optical chopper, a pinhole, and a microscopy eyepiece. Being generally compatible with any camera, this provides a convenient and low cost solution to NIR animal imaging using UCNPs as well as other luminescent probes.

Highly Enhanced Cooperative Upconversion Luminescence through Energy Transfer Optimization and Quenching Protection

Upconversion luminescence nanomaterials have shown great potential in biological and physical applications because of their unique properties. However, limited research exists on the cooperative sensitization upconversion emission in Tb(3+) ions over Er(3+) ions and Tm(3+) ions because of its low efficiency. Herein, by optimizing the doping ratio of sensitizer and activator to maximize the utilization of the photon energy and introducing the CaF2 inert shell to shield sensitizer from quenchers, we synthesize ultrasmall NaYbF4:Tb@CaF2 nanoparticles with a significant enhancement (690-fold) in cooperative sensitization upconversion emission intensity, compared with the parent NaYbF4:Tb. The lifetime of Tb(3+) emission in NaYbF4:Tb@CaF2 nanoparticles is prolonged extensively to ∼3.5 ms. Furthermore, NaYbF4:Tb@CaF2 was applied in in vitro and in vivo bioimaging. The presented luminescence enhancement strategy provides cooperative sensitization upconversion with new opportunities for bioapplication.

Energy Transfer Highway in Nd3+-Sensitized Nanoparticles for Efficient near-Infrared Bioimaging

Despite the large absorption cross-section of Nd3+ dopant as a sensitizer in lanthanide doped luminescence system, the strong cross-relaxation effect of it impedes the promotion of doping concentration and thus reduces the utilization of excitation light. In this work, we introduce a highly efficient acceptor, Yb3+ ion, which can quickly receive energy from Nd3+ ions, to construct an energy transfer highway for the enhancement of near-infrared emission. By using the energy transfer highway, the doping amount of Nd3+ ions in our NaYF4:Yb,Nd@CaF2 core/shell nanoparticles (CSNPs) can be markedly elevated to 60%. The quantum yield of CSNPs was determined to be 20.7%, which provides strong near-infrared luminescence for further bioimaging application. Remarkably, deep tissue penetration depth (∼10 mm) in in vitro imaging and high spatial resolution of blood vessel (∼0.19 mm) in in vivo imaging were detected clearly with weak autofluorescence, demonstrating that probes can be used as excellent NIR biosensors.