A Multifunctional Nanocrystalline CaF2:Tm,Yb@mSiO2 System for Dual‐Triggered and Optically Monitored Doxorubicin Delivery

Daunting challenges in investigating the controlled release of drugs in complicated intracellular microenvironments demand the development of stimuli‐responsive drug delivery systems. Here, a nanoparticle system, CaF₂:Tm,Yb@mSiO₂, made of a mesoporous silica (mSiO₂) nanosphere with CaF₂:Tm,Yb upconversion nanoparticles (UCNPs) is developed, filling its mesopores and with its surface‐modified with polyacrylic acid for binding the anticancer drug molecules (doxorubicin, DOX). The unique design of CaF₂:Tm,Yb@mSiO₂ enables us to trigger the drug release by two mechanisms. One is the pH‐triggered mechanism, where drug molecules are preferentially released from the nanoparticles at acidic conditions unique for the intracellular environment of cancer cells compared to normal cells. Another is the 808 nm near infrared (NIR)‐triggered mechanism, where 808 nm NIR induces the heating of the nanoparticles to weaken the electrostatic interaction between drug molecules and nanoparticles. In addition, luminescence resonance energy transfer occurs from the UCNPs (the energy donor) to the DOX drug (the energy acceptor) in the presence of 980 nm NIR irradiation, allowing us to monitor the drug release by detecting the vanishing blue emission from the UCNPs. This study demonstrates a new multifunctional nanosystem for dual‐triggered and optically monitored drug delivery, which will facilitate the rational design of personalized cancer therapy.     

Highly Bright and Photostable Li(Gd,Y)F4:Yb,Er/LiGdF4 Core/Shell Upconversion Nanophosphors for Bioimaging Applications

Intense green‐emitting Li(Gd,Y)F₄:Yb,Er/LiGdF₄ core/shell (C/S) upconversion nanophosphors (UCNPs) with a tetragonal bipyramidal morphology are synthesized. The morphology and UC luminescence of the Li(Gd,Y)F₄:Yb,Er UCNPs are significantly affected by the Li precursors, and bright UC green‐emitting Li(Gd,Y)F₄:Yb,Er UCNPs with a tetragonal bipyramidal shape, i.e., UC tetragonal bipyramids (UCTBs), are synthesized using LiOH·H₂O as a Li precursor. A LiGdF₄ shell is grown on the Li(Gd,Y)F₄:Yb,Er UCTBs, and the C/S UCNPs exhibit 4.7 times higher luminescence intensity than core UCTBs. The C/S UCNPs show a high absolute UC quantum yield of 4.6% under excitation with 980 nm near infrared (NIR) light, and the UC luminescence from the C/S UCNPs is stable under continuous irradiation with the 980 nm NIR laser for 1 h. The hydrophobic surfaces of the as‐synthesized C/S UCNPs are modified to hydrophilic surfaces by using poly(acrylic acid) (PAA) for bioimaging applications. They are applied to human cervical adenocarcinoma (HeLa) cell imaging and SK‐MEL‐2 melanoma cell imaging and in vivo imaging, including subcutaneous and intramuscular imaging, and UC luminescence images with high signal‐to‐noise ratio are obtained. Furthermore, sentinel‐lymph‐node imaging is successfully conducted with the PAA‐capped Li(Gd,Y)F₄:Yb,Er/LiGdF₄ C/S UCNPs under illumination with NIR light.     

Recent Advancements in Ln‐Ion‐Based Upconverting Nanomaterials and Their Biological Applications

Upconversion nanoparticles (UCNPs) convert low‐energy infrared (IR) or near‐infrared (NIR) photons into high‐energy emission radiation ranging from ultraviolet to visible through a photon upconversion process. In comparison to conventional fluorophores, such as organic dyes or semiconductor quantum dots, lanthanide‐ion‐doped UCNPs exhibit high photostability, no photoblinking, no photobleaching, low cytotoxicity, sharp emission lines, and long luminescent lifetimes. Additionally, the use of IR or NIR for excitation in such UCNPs reduces the autofluorescence background and enables deeper penetration into biological samples due to reduced light scattering with negligible damage to the samples. Because of these attributes, UCNPs have found numerous potential applications in biological and medicinal fields as novel fluorescent materials. Different upconversion mechanisms commonly observed in UCNPs, various methods that are used in their synthesis, and surface modification processes are discussed. Recent applications of Ln‐UCNPs in the biological and medicinal fields, including in vivo and in vitro biological imaging, multimodal imaging, photodynamic therapy, drug delivery, and antibacterial activity, are also presented.     

Construction of a Dual Drug Carrier on the Basis of Hollow Structured Upconversion Nanoparticles for pH‐Responsive Drug Delivery and UCL/MRI Dual Mode Imaging

A series of Gd³⁺ doping hollow upconversion nanoparticles NaYF₄:Yb,Gd,Tm (h‐UNCP) are prepared successfully. The hollow NaYF₄:Yb,Gd,Tm possess excellent upconversion luminescence (UCL) and large longitudinal relativity (r₁ = 128.3 mm ^?1 s^?1), which can be potentially used for UCL/magnetic resonance imaging (MRI) dual mode imaging. On the basis of the optimal h‐UCNP, doxorubicin hydrochloride (DOX) and methotrexate (MTX) are used as drug models to prepare a dual drug carrier. After the encapsulation of DOX on the h‐UCNP, chitosan (CS) is further wrapped and then used to load MTX to obtain a dual drug carrier h‐UCNPs/DOX/CS/MTX. The pH responsive release of DOX and MTX is discussed. The MTX release climbs from 33% to 100% by regulating the pH from 5.8 to 7.4. The DOX release is different at different pH conditions. The synergistic effect of DOX and MTX on the cancer cells is confirmed by cell viability. The h‐UCNPs/DOX/CS/MTX are tracked by cells UCL imaging and vivo MRI imaging. The excellent performance of UCL imaging and positive MRI images demonstrates that h‐UCNPs/DOX/CS/MTX can be used for UCL/MRI dual mode imaging. All the results show the potential application of h‐UCNPs/DOX/CS/MTX in pH responsive release and UCL/MRI dual imaging.     

Dye‐Sensitized Core/Shell Upconversion Nanoparticles for Detecting Nitrites in Plant Cells

A fluorescent nanoprobe is reported for rapid detection of nitrites (NO₂^?) in plant cells. The probe is fabricated by linking neutral reds (NR) to the surface of upconversion fluorescent core/shell nanocrystalline with the bridging of polyethylene glycol (PEG) molecules. The fluorescence of upconversion nanoparticles (UCNPs) is stored by NR through fluorescence resonance energy transfer (FRET) under 980 nm excitation that can be released by further linking to NO₂^?. It is observed that the intensity rate of green to red emission of NR‐modified UCNPs changes linearly with increasing the amount of NO₂^?. So that concentration of NO₂^? can be accordingly addressed. Worth mentioning is that, comparing with bare core upconversion nanoparticles (NPs), core/shell UCNPs can greatly reduce the surface quenching of the fluorescence induced by solvents instead of NR and thus leading to the enhancement of signal‐to‐noise ratios. Moreover, excitation of core/shell UCNPs requires only a much lower power (0.06 W cm^?2) than bare cores which is beneficial to reducing the decomposition of NR to stabilize the FRET processes. Under the optimum conditions, the detection limit of nitrite in plant cells was 0.1 µg mL^?1.     

上转换纳米晶标记适配子的新型光开关

适配子是对靶分子有高特异性和亲合力的单链寡核苷酸.由于其结构特性,常用于生物检测.目前的适配子光传感器多采用染料或量子点为标记物,存在背景高,不稳定等缺点.新型的荧光材料上转换纳米晶(UCNPs)因其特殊的发光性质颇受关注.与传统的下转换材料相比,它是近红外光激发,避免产生背景荧光和杂散光.利用聚乙酰亚胺为表面配体,水...     

Upconverting nanoparticles for pre‐clinical diffuse optical imaging,microscopy and sensing: Current trends and future challenges

Upconverting nanoparticles (UCNPs) are a class of recently developed luminescent biomarkers that – in several aspects – are superior to organic dyes and quantum dots. UCNPs can emit spectrally narrow anti‐Stokes shifted light with quantum yields which greatly exceed those of two‐photon dyes for fluence rates relevant for deep tissue imaging. Compared with conventionally used Stokes‐shifting fluorophores, UCNP‐based imaging systems can acquire completely autofluorescence‐free data with superb contrast. For diffuse optical imaging, the multi‐photon process involved in the upconversion process can be used to obtain images with unprecedented resolution. These unique properties make UCNPs extremely attractive in the field of biophotonics. UCNPs have already been applied in microscopy, small‐animal imaging, multi‐modal imaging, highly sensitive bioassays, temperature sensing and photodynamic therapy. In this review, the current state‐of‐the‐art UCNPs and their applications for diffuse imaging, microscopy and sensing targeted towards solving essential biological issues are discussed.     

NaYF4:Yb3+,Er3+发光上转换纳米晶的表面修饰及其生物效应

不理想的发光上转换纳米晶(UCNPs)表面效应成为其生物标记的主要障碍。本文合成了表面带有氨基功能基团的水溶性NaYF4∶Yb3+,Er3+UCNPs,并通过共价偶联的方式将聚乙二醇(PEG)分子修饰到其表面。光谱测试表明纳米晶的发光性质基本没有变化,扫描电镜结果说明修饰的PEG分子在一定程度上减少了纳米晶的聚集。最后,细胞毒性实验证明这种修饰后的上转换纳米晶具有良好的生物相容性。     

Enhanced Near‐Infrared Shielding and Light Scattering Using Surface‐Roughened Hybrid Hollow Microparticles Synthesized with Polymer and TiO2@Al(OH)3 for Cosmetic Applications

Some materials and their micro‐/nanostructures are explored to shield near‐infrared (NIR) light. However, the structural role of polymeric matrices in terms of the sensitivity to NIR light and the scattering/absorption characteristics of particles bearing inorganic colloids lack understanding. To understand this issue further, a polymer–inorganic hybrid microparticle is synthesized, where submicrometer‐sized TiO₂ core‐thin aluminium hydroxide shell colloids (TiO₂@Al(OH)₃) are dispersed in a roughened polymer hollow particle matrix. They exhibit higher light extinction at NIR frequencies and higher light scattering efficiencies in the NIR regions compared to hybrid solid microparticles and a simple mixture of inorganic and polymer hollow microparticles. Owing to these characteristics, a cosmetic formulation containing the roughened hybrid hollow microparticles effectively suppresses the increase in the temperatures of artificial skin upon the illumination of a simulated sunlight, without displaying skin whitening which is caused by including much inorganic colloids in the formulation. The present results are helpful to those who manipulate the optical characteristics of inorganic particles whose geometries are hardly tailored. The results are also practically helpful to those who want to block NIR light by reducing the amount of inorganic particles.     

High spatial and temporal resolution using upconversion nanoparticles and femtosecond pulsed laser in single particle tracking

Recent advanced biophysical techniques allow us to monitor the cellular dynamics of biologically important molecules in real time. Bright, stable fluorophores are needed to accomplish this: photoblinking and photobleaching occurring in organic fluorophores and qdots make them an ill-suited option. In this study, we employed upconversion nanoparticles (UCNPs) since they exhibit no photobleaching or photoblinking. Another advantage of using UCNPs is that these particles absorb IR light (980 nm) and emit visible light (560 nm and 640 nm), which sig-nificantly eliminates background noise caused by autofluorescence. Moreover, excitation of UCNPs can occur using a CW-laser because they can be excited by wide-field illumination rather than requiring confocal illumination. Although a CW-laser would have been capable of exciting UCNPs, we were able to maximize the photon density and resulting number of photons emitted from UCNPs by employing a femto-second laser. Using a femto-second laser, we achieved 2.4 nm single-molecule localization accuracy with an exposure time of 2 ms. The UCNP particles and femto-second laser allowed us to stably monitor the molecular motors, kinesin and dynein, in cells.     

Raman spectroscopy at different excitation wavelengths (1064, 785 and 532 nm) as a tool for diagnosis of colon cancer

Raman spectroscopy is structure sensitive non‐destructive method that allows observing the status of biological tissues with minimal impact. This method has a great potential in the diagnosis of various types of degenerative diseases including cancer damages. Near‐infrared Fourier transform (NIR‐FT)‐Raman (λ_ex ~1064 nm), NIR‐visible (Vis)‐Raman (λ_ex ~785 nm) and Vis‐Raman (λ_ex ~532 nm) spectra of normal and colorectal carcinoma colon tissue samples were recorded in macroscopic mode at 10–20 randomly chosen independent sites. In the cases of NIR‐Vis‐ and Vis‐Raman spectra, enhanced resonance effects were observed for tissue chromophores absorbing in the visible area. Evident spectral differences were noticed for Raman spectra of normal colon tissue samples in comparison with abnormal samples. The average Raman spectra of colon tissue samples were analysed by principal component analysis (PCA) to discriminate normal and abnormal tissues. PCA of combined dataset containing Raman intensities of chosen NIR‐FT, NIR‐Vis or Vis‐Raman bands led to discrimination of normal and abnormal colon tissue samples. Therefore, combination of these three Raman methods can be helpful for recognizing cancer lesions in colon for diagnostic purposes. Copyright © 2014 John Wiley & Sons, Ltd.     

Colour tunability in a bimodal fluorescent hybrid nanostructure UCNPs@AuNPs@QDs

In the present work, lysine modified NaY_0.78Er_0.02Yb_0.2F₄ upconversion nanoparticles (UCNPs, positively charged) and lysine modified ZnSe:Mn²⁺ quantum dots (QDs, positively charged) are attached onto the surface of citrate reduced gold nanoparticles (AuNPs, negatively charged). The gold nanoparticles not only entangle the QDs and the UCNPs, through electrostatic interaction, but also tune the optical properties of UCNPs through the effect of surface plasmon resonance. The hybrid nanostructure gives green emission both through photoluminescence (under UV excitation) and through photon upconversion (under IR light excitation) process. The colour tuning is observed through variation in the size of QDs and through plasmonic effect of gold nanoparticles. In both the cases, the colour of emission gradually changes from green to red. The colour tunability and bi-modal photon conversion property of this material could be useful for its application in the field of bio-imaging and solar energy harvesting.     

Tens of thousands‐fold upconversion luminescence enhancement induced by a single gold nanorod

Upconversion nanoparticles (UCNPs) have gained increasing attention for their wide applications in bioimaging, displays and photovoltaics. However, low efficiency has been an ongoing challenge for further developments. In this work, it is proposed that the ultrasmall size of UCNPs is essential for achieving large enhancement factors and experimentally demonstrated with 4‐nm UCNPs. A strategy of plasmonic dual resonance is proposed in which two distinct localized surface plasmon resonance (LSPR) peaks of gold nanorods (GNRs) were designed to perfectly match both the excitation and emission light wavelength of UCNPs. Combining the excitation enhancement and Purcell effect, a huge enhancement factor of tens of thousands‐fold is stochastically demonstrated for single UCNPs in solution. The largest overall enhancement region is close to the end of a GNR but not in its central part. The excitation enhancement (up to three orders of magnitude) and the emission enhancement (larger than one order of magnitude) induced by the Purcell effect are experimentally demonstrated separately. This study provides insight into how to achieve a very large upconversion enhancement factor with surface plasmons and will catalyze development of UCNPs’ extensive applications.

     

Near‐infrared Raman spectroscopy for gastric precancer diagnosis

Raman spectroscopy is a molecular vibrational spectroscopic technique that is capable of optically probing the biomolecular changes associated with neoplastic transformation. The purpose of this study was to apply near‐infrared (NIR) Raman spectroscopy for differentiating dysplasia from normal gastric mucosa tissue. A total of 65 gastric mucosa tissues (44 normal and 21 dysplasia) were obtained from 35 patients who underwent endoscopy investigation or gastrectomy operation for this study. A rapid NIR Raman system was utilized for tissue Raman spectroscopic measurements at 785‐nm laser excitation. High‐quality Raman spectra in the range of 800–1800 cm⁻¹ can be acquired from gastric mucosa tissue within 5 s. Raman spectra showed significant differences between normal and dysplastic tissue, particularly in the spectral ranges of 850–1150, 1200–1500 and 1600–1750 cm⁻¹, which contained signals related to proteins, nucleic acids and lipids. The diagnostic decision algorithm based on the combination of Raman peak intensity ratios of I₈₇₅/I₁₄₅₀ and I₁₂₀₈/I₁₆₅₅ and the logistic regression analysis yielded a diagnostic sensitivity of 90.5% and specificity of 90.9% for identification of gastric dysplasia tissue. This work demonstrates that NIR Raman spectroscopy in conjunction with intensity ratio algorithms has the potential for the noninvasive diagnosis and detection of precancer in the stomach at the molecular level. Copyright © 2009 John Wiley & Sons, Ltd.     

Pulsed upconversion of Tm3+-doped sol–gel silicate glasses

Upconversion processes allow materials to emit light of shorter wavelength than the light incident upon them. Materials with high upconversion efficiency have numerous potential applications in solid-state physics, such as blue upconversion lasers. We study the time-evolution of upconversion fluorescence of Tm³⁺ in a sol–gel glass host following pulsed, red light excitation. The ¹D₂→³F₄ intensity varies quadratically with the laser intensity, indicating a two-photon upconversion mechanism. Maximum upconversion intensity occurred for 0.5% Tm³⁺ with 1% Al³⁺. We analyzed the main relaxation processes affecting the upconversion emission, namely ion clustering and atmospheric water adsorption.     

水溶性NaYF_4∶Yb/Tm纳米粒子的制备及其上转换发光性质

利用溶剂热法合成了NaYF4:20%Yb,0.5%Tm上转换发光纳米粒子(UCNPs),用扫描电子显微镜、X射线衍射分析、发光光谱测量等手段对水溶性纳米颗粒进行了形貌和发光性质表征。结果表明,UCNPs是纯立方相的NaYF4,尺寸均匀分布在30nm左右。在980nm红外光的激发下,UCNPs能够发出肉眼可见的明亮的蓝紫色光。发射光谱中最强发射峰在479nm,来源于Tm3+离子的1G4→3H6发射,并且给出了UCNPs的上转换发光机制。利用聚乙烯吡咯烷酮(PVP)作为表面活性剂所制备的上转换发光纳米颗粒具有良好的水溶性,尺寸较小,在生物荧光标记领域具有潜在的应用价值。     

Encapsulation of Photosensitizers and Upconversion Nanocrystals in Lipid Micelles for Photodynamic Therapy

Photodynamic therapy (PDT) is a promising method for cancer therapy. However, it is constrained by limited penetration depth of visible light, hydrophobicity of photosensitizers, and lack of tumor targeting. In this work, the photosensitizer zinc phthalocyanine (ZnPc) and upconversion nanocrystals (UCNs) are encapsulated into OQPGA‐PEG/RGD/TAT lipid micelles. The UCNs acting as a nanotransducer convert deep‐penetrating near‐infrared (NIR) light to visible light for activating the photosensitizer. OQPGA‐PEG/RGD/TAT lipid micelles are used as a carrier for the photosensitizer, with improved biocompatibility and cancer‐targeting ability. The results show that the photosensitizer ZnPc‐ and UCNs‐loaded OQPGA‐PEG/RGD/TAT lipid micelles are nanoparticles with an average size of 25 nm. The lipid micelle nanoparticles are stable in water with low leakage of photosensitizer. The absorption peak of the photosensitizer overlaps with the emission peak of UCNs, so the visible fluorescence emitted from the UCNs upon excitation by the NIR laser at 980 nm can activate the photosensitizer to produce singlet oxygen for PDT. The targeting RGD peptide and cell‐penetrating TAT peptide on the surface help the nanoparticles getting into cancer cells. The OQPGA‐PEG/RGD/TAT lipid micelles encapsulated with both the photosensitizer ZnPc and UCNs could be used for targeted PDT by using deep‐penetrating NIR light as the light source.     

Water‐Soluble Monolayer Molybdenum Disulfide Quantum Dots with Upconversion Fluorescence

Uniform water‐soluble monolayer MoS₂ quantum dots (MQDs) with lateral sizes of ≈2.1 nm, a clearly zigzag‐terminated edge, and a hexagonal lattice structure are achieved using ammonium molybdate, thiourea, and N‐acetyl‐l ‐cysteine (NAC) as precursors and the capping reagent in a facile one‐pot hydrothermal approach. MQDs have good dispersity and high stability in aqueous suspension and exhibit a significantly larger direct bandgap (3.96 eV) compared to monolayer MoS₂ nanosheets (1.89 eV). Pronounced blue‐shifts in the wavelengths of both the excitonic absorption and intrinsic state emission with activated strong luminescence at room temperature beyond monolayer MoS₂ nanosheets is demonstrated. Unusual upconversion photoluminescence is also observed and is caused by two successive transfers of energy from the near‐infrared (NIR) absorption generated by the NAC capping reagent to the hexagonal structure of MQDs. Additional optical properties of MQDs may provide numerous exciting technological applications. Here, MQDs are demonstrated as a highly selective fluorescent reagent for detecting tetracycline hydrochloride under UV and NIR irradiation.     

基于近红外上转换荧光共振能量传递体系的均相免疫分析

在上转换纳米晶(UCNPs)为供体的荧光共振能量传递(FRET)生物均相检测体系中,弱的供体光强度使FRET信号难于检测,同时还有来自生物基质的自发荧光干扰。这使得UCNPs不产生背景荧光和散射光的优点不能够充分地体现。针对这个问题,作者利用在800nm处有强近红外光的NaYF4:Yb3+,Tm3+UCNPs作为供体,在784nm处有表面等离子共振吸收带的金纳米粒子(GNPs)作为受体构建了新型的FRET体系。UCNPs偶联抗体(goat antihumanIgG)及GNPs偶联抗原(humanIgG),在抗原抗体免疫亲和作用下两者距离靠近;UCNPs荧光光谱和GNPs吸收光谱有效交叠,使FRET发生。当体系中加入单纯humanIgG,竞争性地争夺与goatantihumanIgG结合位点,破坏FRET构建,供体近红外光增强。根据此对应关系,确定humanIgG检测限为5μg·mL-1。这种方法可适用于更广泛的荧光分析。     

Visible Light Emission due to Resonant CO2 Laser Excitation of Dental Hard Tissue

Visible light emission of dental hard substances excited by high-power infrared pulses of a tunable TEA CO₂ laser has been investigated. A clear correlation between observed visible light emission, plasma formation as well as ablation of dental hard tissue has been demonstrated. Both, the highly nonlinear infrared to visible upconversion process and the ablation efficiency show a sharp spectral resonance close to a vibrational mode of PO₄ at 1090 cm^-1 in dental enamel and dentin. The influence of strong infrared light impulses on dental hard tissue is examined by performing upconversion studies of visible light emission of human dental enamel and dentin. Our experimental setup allows one to determine the plasma formation threshold being important in dental surgery.