Multifunctional Core–Shell Structured Nanocarriers for Synchronous Tumor Diagnosis and Treatment In Vivo

Multifunctional, mesoporous, silica‐coated upconversion luminescent/magnetic NaGdF₄:Yb/Er@NaGdF₄:Yb@mSiO₂? PEG (referred to as UCNPS; PEG=polyethylene glycol) nanocomposites were fabricated through a phase‐transfer‐assisted surfactant‐templating coating process, followed by hydrophilic polymer (PEG) functionalization to improve the stability and biocompatibility. The UCNP core imparts the nanomaterials with luminescence and magnetic properties for simultaneous upconversion optical and magnetic resonance (MR) imaging, whereas the mesoporous shell affords the nanomaterials the ability to load the anticancer drug doxorubicin. Proof‐of‐principle in vitro and in vivo experiments are presented to demonstrate that the resultant composite nanomaterials can serve as nanotheranostics for synchronous upconversion luminescence/MR dual modal imaging and anticancer drug delivery; this finally realizes the integration of diagnostics and the treatment of cancers.     

Multifunctional Core–Shell Upconverting Nanoparticles for Imaging and Photodynamic Therapy of Liver Cancer Cells

Lanthanide‐doped upconversion nanoparticles (UCNPs) have attracted considerable attention for their application in biomedicine. Here, silica‐coated NaGdF₄:Yb,Er/NaGdF₄ nanoparticles with a tetrasubstituted carboxy aluminum phthalocyanine (AlC₄Pc) photosensitizer covalently incorporated inside the silica shells were prepared and applied in the photodynamic therapy (PDT) and magnetic resonance imaging (MRI) of cancer cells. These UCNP@SiO₂(AlC₄Pc) nanoparticles were uniform in size, stable against photosensitizer leaching, and highly efficient in photogenerating cytotoxic singlet oxygen under near‐infrared (NIR) light. In vitro studies indicated that these nanoparticles could effectively kill cancer cells upon NIR irradiation. Moreover, the nanoparticles also demonstrated good MR contrast, both in aqueous solution and inside cells. This is the first time that NaGdF₄:Yb,Er/NaGdF₄ upconversion‐nanocrystal‐based multifunctional nanomaterials have been synthesized and applied in PDT. Our results show that these multifunctional nanoparticles are very promising for applications in versatile imaging diagnosis and as a therapy tool in biomedical engineering.     

Polynuclear SmIII Polyamidoamine‐Based Dendrimer: A Single Probe for Combined Visible and Near‐Infrared Live‐Cell Imaging

We report herein the synthesis of a luminescent polynuclear dendritic structure (Sm^III‐G3P‐2,3Nap) in which eight Sm^III ions are sensitized by thirty‐two 2,3‐naphthalimide chromophores. Upon a single excitation wavelength, the dendrimer complex exhibits two types of emission in the visible and in the near‐infrared (NIR) ranges. Sm^III‐G3P‐2,3Nap was non‐cytotoxic after 24 h of incubation and up to 2.5 μM . The ability of the Sm^III‐based probe to be taken up by cells was confirmed by confocal microscopy. Epifluorescence microscopy validated Sm^III‐G3P‐2,3Nap as a versatile probe, capable of performing interchangeably in the visible or NIR for live‐cell imaging. As both emissions are obtained from a single complex, the cytotoxicity and biodistribution are inherently the same. The possibility for discriminating the sharp Sm^III signals from autofluorescence in two spectral ranges increases the reliability of analysis and reduces the probability of artifacts and instrumental errors.     

Multifunctional Core–Shell Silica Nanoparticles for Highly Sensitive 19F Magnetic Resonance Imaging

¹⁹F magnetic resonance imaging (¹⁹F MRI) is useful for monitoring particular signals from biological samples, cells, and target tissues, because background signals are missing in animal bodies. Therefore, highly sensitive ¹⁹F MRI contrast agents are in great demand for their practical applications. However, we have faced the following challenges: 1) increasing the number of fluorine atoms decreases the solubility of the molecular probes, and 2) the restriction of the molecular mobility attenuates the ¹⁹F MRI signals. Herein, we developed novel multifunctional core–shell nanoparticles to solve these issues. They are composed of a core micelle filled with liquid perfluorocarbon and a robust silica shell. These core–shell nanoparticles have superior properties such as high sensitivity, modifiability of the surface, biocompatibility, and sufficient in vivo stability. By the adequate surface modifications, gene expression in living cells and tumor tissue in living mice were successfully detected by ¹⁹F MRI.     

Ligand‐Functionalization of BPEI‐Coated YVO4:Bi3+,Eu3+ Nanophosphors for Tumor‐Cell‐Targeted Imaging Applications

In this study, surface‐functionalized, branched polyethylenimine (BPEI)‐modified YVO₄:Bi³⁺,Eu³⁺ nanocrystals (NCs) were successfully synthesized by a simple, rapid, solvent‐free hydrothermal method. The BPEI‐coated YVO₄:Bi³⁺,Eu³⁺ NCs with high crystallinity show broad‐band excitation in the λ=250 to 400 nm near‐ultraviolet (NUV) region and exhibit a sharp‐line emission band centered at λ=619 nm under excitation at λ=350 nm. The surface amino groups contributed by the capping agent, BPEI, not only improve the dispersibility and water/buffer stability of the BPEI‐coated YVO₄:Bi³⁺,Eu³⁺ NCs, but also provide a capability for specifically targeted biomolecule conjugation. Folic acid (FA) and epidermal growth factor (EGF) were further attached to the BPEI‐coated YVO₄:Bi³⁺,Eu³⁺ NCs and exhibited effective positioning of fluorescent NCs toward the targeted folate receptor overexpressed in HeLa cells or EGFR overexpressed in A431 cells with low cytotoxicity. These results demonstrate that the ligand‐functionalized, BPEI‐coated YVO₄:Bi³⁺, Eu³⁺ NCs show great potential as a new‐generation biological luminescent bioprobe for bioimaging applications. Moreover, the unique luminescence properties of BPEI‐coated YVO₄:Bi³⁺,Eu³⁺ NCs show potential to combine with a UVA photosensitizing drug to produce both detective and therapeutic effects for human skin cancer therapy.     

Filtration Shell Mediated Power Density Independent Orthogonal Excitations–Emissions Upconversion Luminescence

Lanthanide doped core–multishell structured NaGdF₄:Yb,Er@NaYF₄:Yb@NaGdF₄:Yb,Nd@NaYF₄@NaGdF₄:Yb,Tm@NaYF₄ nanoparticles with power‐density independent orthogonal excitations‐emissions upconversion luminescence (UCL) were fabricated for the first time. The optical properties of these core–multishell structured nanoparticles were related to the absorption filtration effect of the NaGdF₄:Yb,Tm layer. By tuning the thickness of the filtration layer, the nanoparticles can exhibit unique two independent groups of UCL: Tm³⁺ prominent UV/blue (UV=ultraviolet) UCL under the excitation at 980 nm and Er³⁺ prominent green/red UCL under the excitation at 796 nm. The filtration‐shell mediated orthogonal excitations‐emissions UCL are power‐density independent. As a proof of concept, the core–multishell nanoparticles are used in multi‐dimensional security design and imaging‐guided combined photodynamic therapy and chemotherapy.     

Multifunctional Uniform Core–Shell Fe3O4@mSiO2 Mesoporous Nanoparticles for Bimodal Imaging and Photothermal Therapy

Multimodal imaging and simultaneous therapy is highly desirable because it can provide complementary information from each imaging modality for accurate diagnosis and, at the same time, afford an imaging‐guided focused tumor therapy. In this study, indocyanine green (ICG), a near‐infrared (NIR) imaging agent and perfect NIR light absorber for laser‐mediated photothermal therapy, was successfully incorporated into superparamagnetic Fe₃O₄@mSiO₂ core–shell nanoparticles to combine the merit of NIR/magnetic resonance (MR) bimodal imaging properties with NIR photothermal therapy. The resultant nanoparticles were homogenously coated with poly(allylamine hydrochloride) (PAH) to make the surface of the composite nanoparticles positively charged, which would enhance cellular uptake driven by electrostatic interactions between the positive surface of the nanoparticles and the negative surface of the cancer cell. A high biocompatibility of the achieved nanoparticles was demonstrated by using a cell cytotoxicity assay. Moreover, confocal laser scanning microscopy (CLSM) observations indicated excellent NIR fluorescent imaging properties of the ICG‐loaded nanoparticles. The relatively high r₂ value (171.6 mM ^?1 s^?1) of the nanoparticles implies its excellent capability as a contrast agent for MRI. More importantly, the ICG‐loaded nanoparticles showed perfect NIR photothermal therapy properties, thus indicating their potential for simultaneous cancer diagnosis as highly effective NIR/MR bimodal imaging probes and for NIR photothermal therapy of cancerous cells.     

Selected‐Control Fabrication of Multifunctional Fluorescent–Magnetic Core–Shell and Yolk–Shell Hybrid Nanostructures

The selected‐control preparation of uniform core–shell and yolk–shell architectures, which combine the multiple functions of a superparamagnetic iron oxide (SPIO) core and europium‐doped yttrium oxide (Y₂O₃:Eu) shell in a single material with tunable fluorescence and magnetic properties, has been successfully achieved by controlling the heat‐treatment conditions. Furthermore, the shell thickness and interior cavity of SPIO@Y₂O₃:Eu core–shell and yolk–shell nanostructures can be precisely tuned. Importantly, as‐prepared SPIO@Y₂O₃:Eu yolk–shell nanocapsules (NCs) modified with amino groups as cancer‐cell fluorescence imaging agents are also demonstrated. To the best of our knowledge, this is the first report on the selected‐control fabrication of uniform SPIO@Y₂O₃:Eu core–shell nanoparticles and yolk–shell NCs. The combined magnetic manipulation and optical monitoring of magnetic–fluorescent SPIO@Y₂O₃:Eu yolk–shell NCs will open up many exciting opportunities in dual imaging for targeted delivery and thermal therapy.     

Targeted Tumor Computed Tomography Imaging Using Low‐Generation Dendrimer‐Stabilized Gold Nanoparticles

We report a facile approach to fabricating low‐generation poly(amidoamine) (PAMAM) dendrimer‐stabilized gold nanoparticles (Au DSNPs) functionalized with folic acid (FA) for in vitro and in vivo targeted computed tomography (CT) imaging of cancer cells. In this study, amine‐terminated generation 2 PAMAM dendrimers were employed as stabilizers to form Au DSNPs without additional reducing agents. The formed Au DSNPs with an Au core size of 5.5 nm were covalently modified with the targeting ligand FA, followed by acetylation of the remaining dendrimer terminal amines to endow the particles with targeting specificity and improved biocompatibility. Our characterization data show that the formed FA‐modified Au DSNPs are stable at different pH values (5—8) and temperatures (4–50 °C), as well as in different aqueous media. MTT assay data along with cell morphology observations reveal that the FA‐modified Au DSNPs are noncytotoxic in the particle concentration range of 0–3000 nM . X‐ray attenuation coefficient measurements show that the CT value of FA‐modified Au DSNPs is much higher than that of Omnipaque (a clinically used CT contrast agent) at the same concentration of the radiodense elements (Au or iodine). Importantly, the FA‐modified Au DSNPs are able to specifically target a model cancer cell line (KB cells, a human epithelial carcinoma cell line) over‐expressing FA receptors and they enable targeted CT imaging of the cancer cells in vitro and the xenografted tumor model in vivo after intravenous administration of the particles. With the simple synthesis approach, easy modification, good cytocompatibility, and high X‐ray attenuation coefficient, the FA‐modified low‐generation Au DSNPs could be used as promising contrast agents for targeted CT imaging of different tumors over‐expressing FA receptors.     

Precisely Tailoring Upconversion Dynamics via Energy Migration in Core–Shell Nanostructures

Upconversion emission dynamics have long been believed to be determined by the activator and its interaction with neighboring sensitizers. Herein this assumption is, however, shown to be invalid for nanostructures. We demonstrate that excitation energy migration greatly affects upconversion emission dynamics. “Dopant ions’ spatial separation” nanostructures are designed as model systems and the intimate link between the random nature of energy migration and upconversion emission time behavior is unraveled by theoretical modelling and confirmed spectroscopically. Based on this new fundamental insight, we have successfully realized fine control of upconversion emission time behavior (either rise or decay process) by tuning the energy migration paths in various specifically designed nanostructures. This result is significant for applications of this type of materials in super resolution spectroscopy, high‐density data storage, anti‐counterfeiting, and biological imaging.     

Water‐Soluble Triarylboron Compound for ATP Imaging In Vivo Using Analyte‐Induced Finite Aggregation

Adenosine 5′‐triphosphate (ATP) is a multifunctional molecule that participates in many important biological processes. Currently, fluorescence indicators for ATP with high performance are in demand. Reported herein is a novel water‐soluble triarylboron compound which displays an apparent ATP‐dependent fluorescence enhancement when dispersed in water. It can selectively recognize ATP from other bioactive substances in vitro and in vivo. The ATP‐induced finite aggregation endows the indicator with appreciable photostability and superior tolerance to environmental electrolytes. This indicator has been successfully applied to the ATP imaging in NIH/3T3 fibroblast cells. The difference in the ATP levels within the membrane and cytosol is clearly visible.     

A Lanthanide‐Complex‐Based Ratiometric Luminescent Probe Specific for Peroxynitrite

A lanthanide‐complex‐based ratiometric luminescence probe specific for peroxynitrite (ONOO^?), 4′‐(2,4‐dimethoxyphenyl)‐2,2′:6′,2′′‐terpyridine‐6,6′′‐diyl]bis(methylenenitrilo)tetrakis(acetate)‐Eu³⁺/Tb³⁺ ([Eu³⁺/Tb³⁺(DTTA)]), has been designed and synthesized. Both [Eu³⁺(DTTA)] and [Tb³⁺(DTTA)] are highly water soluble with large stability constants at ≈10²⁰, and strongly luminescent with luminescence quantum yields of 10.0 and 9.9 %, respectively, and long luminescence lifetimes of 1.38 and 0.26 ms, respectively. It was found that the luminescence of [Tb³⁺(DTTA)] could be quenched by ONOO^? rapidly and specifically in aqueous buffers, while that of [Eu³⁺(DTTA)] did not respond to the addition of ONOO^?. Thus, by simply mixing [Eu³⁺(DTTA)] and [Tb³⁺(DTTA)] in an aqueous buffer, a ratiometric luminescence probe specific for time‐gated luminescence detection of ONOO^? was obtained. The performance of [Tb³⁺(DTTA)] and [Eu³⁺/Tb³⁺(DTTA)] as the probes for luminescence imaging detection of ONOO^? in living cells was investigated. The results demonstrated the efficacy and advantages of the new ratiometric luminescence probe for highly sensitive luminescence bioimaging application.     

Atom‐Precise Polyoxometalate–Ag2S Core–Shell Nanoparticles

Atomically precise polyoxometalate–Ag₂S core–shell nanoparticles were generated in a top‐down approach under solvothermal conditions and structurally confirmed by X‐ray single‐crystal diffraction as an interesting core–shell structure comprising an in situ generated Mo₆O₂₂^8? polyoxometalate core and a mango‐like Ag₅₈S₃₈ shell. This result demonstrates the possibility to integrate polyoxometalate and Ag₂S nanoparticles into a core–shell heteronanostructure with precisely controlled atomical compositions of both core and shell.     

Non‐Aqueous Sol–Gel Synthesis of Ultra Small Persistent Luminescence Nanoparticles for Near‐Infrared In Vivo Imaging

Ultra‐small ZnGa₂O₄:Cr³⁺ nanoparticles (6 nm) that exhibit near‐infrared (NIR) persistent luminescence properties are synthesized by using a non‐aqueous sol–gel method assisted by microwave irradiation. The nanoparticles are pegylated, leading to highly stable dispersions under physiological conditions. Preliminary in vivo studies show the high potential for these ultra‐small ZnGa₂O₄:Cr³⁺ nanoparticles to be used as in vivo optical nanotools as they emit without the need for in situ excitation and, thus, avoid the autofluorescence of tissues.     

Gold Nanorod/Fe3O4 Nanoparticle “Nano‐Pearl‐Necklaces” for Simultaneous Targeting,Dual‐Mode Imaging,and Photothermal Ablation of Cancer Cells

Gold and pearls : Multifunctional nanoparticles, each composed of a single, amine‐modified gold nanorod, decorated with multiple “pearls” of Fe₃O₄ nanoparticles capped with carboxy groups, are prepared. Their effectiveness in simultaneous targeting, dual‐mode imaging, and photothermal ablation of breast cancer cells is demonstrated.