Early Detection of Myeloid-Derived Suppressor Cells in the Lung Pre-Metastatic Niche by Shortwave Infrared Nanoprobes.

Metastatic breast cancer remains a significant source of mortality amongst breast cancer patients and is generally considered incurable in part due to the difficulty in detection of early micro-metastases. The pre-metastatic niche (PMN) is a tissue microenvironment that has undergone changes to support the colonization and growth of circulating tumor cells, a key component of which is the myeloid-derived suppressor cell (MDSC). Therefore, the MDSC has been identified as a potential biomarker for PMN formation, the detection of which would enable clinicians to proactively treat metastases. However, there is currently no technology capable of the in situ detection of MDSCs available in the clinic. Here, we propose the use of shortwave infrared-emitting nanoprobes for the tracking of MDSCs and identification of the PMN. Our rare-earth albumin nanocomposites (ReANCs) are engineered to bind the Gr-1 surface marker of murine MDSCs. When delivered intravenously in murine models of breast cancer with high rates of metastasis, the targeted ReANCs demonstrated an increase in localization to the lungs in comparison to control ReANCs. However, no difference was seen in the model with slower rates of metastasis. This highlights the potential utility of MDSC-targeted nanoprobes to assess PMN development and prognosticate disease progression.

Thermochemistry of 3D and 2D Rare Earth Oxychlorides (REOCls).

The thermodynamic stability of rare earth (RE) materials plays a key role in the design of separation and recycling processes for RE elements. Thermodynamic stability is fundamentally influenced by the lanthanide contraction, as observed in the systematic reduction of unit cell volumes with increasing atomic number. RE materials are found in the form of solids having primary bonds in three dimensions (3D materials) as well as ones with primary bonds in two dimensions (2D materials) whose layers are held together by weak van der Waals (vdW) forces. While studies of synthesis, structure, and physical properties of 2D RE materials are numerous, no systematic research has compared their thermodynamic stability to that of 3D materials. In the present work, RE oxychlorides (REOCls), which display a structural transition from a 3D-polyhedral network (PbFCl-type) to a vdW-bonded layered one (SmSI-type) as the RE size decreases, were all synthesized by the flux method. High-temperature oxide melt solution calorimetry was used to determine their formation enthalpies to enable Born-Haber cycles to calculate lattice energies. Our results indicate that REOCl compounds are thermodynamically stable when compared to their binary oxides and chlorides. The lattice energies of 3D REOCls increase with decreasing RE size yet are insensitive to unit cell volumes for 2D REOCls. This is caused by interatomic interactions parallel and perpendicular to layers in the SmSI-type REOCls, causing a different structure response to the lanthanide contraction than 3D RE materials.

Microbial Carbonation of Monocalcium Silicate.

Biocement formed through microbially induced calcium carbonate precipitation (MICP) is an emerging biotechnology focused on reducing the environmental impact of concrete production. In this system, CO2 species are provided via ureolysis by Sporosarcina pasteurii (S. pasteurii) to carbonate monocalcium silicate for MICP. This is one of the first studies of its kind that uses a solid-state calcium source, while prior work has used highly soluble forms. Our study focuses on microbial physiological, chemical thermodynamic, and kinetic studies of MICP. Monocalcium silicate incongruently dissolves to form soluble calcium, which must be coupled with CO2 release to form calcium carbonate. Chemical kinetic modeling shows that calcium solubility is the rate-limiting step, but the addition of organic acids significantly increases the solubility, enabling extensive carbonation to proceed up to 37 mol %. The microbial urease activity by S. pasteurii is active up to pH 11, 70 °C, and 1 mol L-1 CaCl2, producing calcite as a means of solidification. Cell-free extracts are also effective albeit less robust at extreme pH, producing calcite with different physical properties. Together, these data help determine the chemical, biological, and thermodynamic parameters critical for scaling microbial carbonation of monocalcium silicate to high-density cement and concrete.

Short-Wave Infrared Emitting Nanocomposites for Fluorescence-Guided Surgery.

Fluorescence-guided surgery (FGS) is an emerging technique for tissue visualization during surgical procedures. Structures of interest are labeled with exogenous probes whose fluorescent emissions are acquired and viewed in real-time with optical imaging systems. This study investigated rare-earth-doped albumin-encapsulated nanocomposites (REANCs) as short-wave infrared emitting contrast agents for FGS. Experiments were conducted using an animal model of 4T1 breast cancer. The signal-to-background ratio (SBR) obtained with REANCs was compared to values obtained using indocyanine green (ICG), a near-infrared dye used in clinical practice. Prior to resection, the SBR for tumors following intratumoral administration of REANCs was significantly higher than for tumors injected with ICG. Following FGS, evaluation of fluorescence intensity levels in excised tumors and at the surgical bed demonstrated higher contrast between tissues at these sites with REANC contrast than ICG. REANCs also demonstrated excellent photostability over 2 hours of continuous illumination, as well as the ability to perform FGS under ambient lighting, establishing these nanocomposites as a promising contrast agent for FGS applications.

Shortwave infrared emitting multicolored nanoprobes for biomarker-specific cancer imaging in vivo.

BACKGROUND: The ability to detect tumor-specific biomarkers in real-time using optical imaging plays a critical role in preclinical studies aimed at evaluating drug safety and treatment response. In this study, we engineered an imaging platform capable of targeting different tumor biomarkers using a multi-colored library of nanoprobes. These probes contain rare-earth elements that emit light in the short-wave infrared (SWIR) wavelength region (900-1700 nm), which exhibits reduced absorption and scattering compared to visible and NIR, and are rendered biocompatible by encapsulation in human serum albumin. The spectrally distinct emissions of the holmium (Ho), erbium (Er), and thulium (Tm) cations that constitute the cores of these nanoprobes make them attractive candidates for optical molecular imaging of multiple disease biomarkers. METHODS: SWIR-emitting rare-earth-doped albumin nanocomposites (ReANCs) were synthesized using controlled coacervation, with visible light-emitting fluorophores additionally incorporated during the crosslinking phase for validation purposes. Specifically, HoANCs, ErANCs, and TmANCs were co-labeled with rhodamine-B, FITC, and Alexa Fluor 647 dyes respectively. These Rh-HoANCs, FITC-ErANCs, and 647-TmANCs were further conjugated with the targeting ligands daidzein, AMD3100, and folic acid respectively. Binding specificities of each nanoprobe to distinct cellular subsets were established by in vitro uptake studies. Quantitative whole-body SWIR imaging of subcutaneous tumor bearing mice was used to validate the in vivo targeting ability of these nanoprobes. RESULTS: Each of the three ligand-functionalized nanoprobes showed significantly higher uptake in the targeted cell line compared to untargeted probes. Increased accumulation of tumor-specific nanoprobes was also measured relative to untargeted probes in subcutaneous tumor models of breast (4175 and MCF-7) and ovarian cancer (SKOV3). Preferential accumulation of tumor-specific nanoprobes was also observed in tumors overexpressing targeted biomarkers in mice bearing molecularly-distinct bilateral subcutaneous tumors, as evidenced by significantly higher signal intensities on SWIR imaging. CONCLUSIONS: The results from this study show that tumors can be detected in vivo using a set of targeted multispectral SWIR-emitting nanoprobes. Significantly, these nanoprobes enabled imaging of biomarkers in mice bearing bilateral tumors with distinct molecular phenotypes. The findings from this study provide a foundation for optical molecular imaging of heterogeneous tumors and for studying the response of these complex lesions to targeted therapy.

Shortwave Infrared-Emitting Theranostics for Breast Cancer Therapy Response Monitoring.

Therapeutic drug monitoring (TDM) in cancer, while imperative, has been challenging due to inter-patient variability in drug pharmacokinetics. Additionally, most pharmacokinetic monitoring is done by assessments of the drugs in plasma, which is not an accurate gauge for drug concentrations in target tumor tissue. There exists a critical need for therapy monitoring tools that can provide real-time feedback on drug efficacy at target site to enable alteration in treatment regimens early during cancer therapy. Here, we report on theranostic optical imaging probes based on shortwave infrared (SWIR)-emitting rare earth-doped nanoparticles encapsulated with human serum albumin (abbreviated as ReANCs) that have demonstrated superior surveillance capability for detecting micro-lesions at depths of 1 cm in a mouse model of breast cancer metastasis. Most notably, ReANCs previously deployed for detection of multi-organ metastases resolved bone lesions earlier than contrast-enhanced magnetic resonance imaging (MRI). We engineered tumor-targeted ReANCs carrying a therapeutic payload as a potential theranostic for evaluating drug efficacy at the tumor site. In vitro results demonstrated efficacy of ReANCs carrying doxorubicin (Dox), providing sustained release of Dox while maintaining cytotoxic effects comparable to free Dox. Significantly, in a murine model of breast cancer lung metastasis, we demonstrated the ability for therapy monitoring based on measurements of SWIR fluorescence from tumor-targeted ReANCs. These findings correlated with a reduction in lung metastatic burden as quantified via MRI-based volumetric analysis over the course of four weeks. Future studies will address the potential of this novel class of theranostics as a preclinical pharmacological screening tool.

Non-Rare-Earth Na3AlF6:Cr3+ Phosphors for Far-Red Light-Emitting Diodes.

Emerging phototherapy in a clinic and plant photomorphogenesis call for efficient red/far-red light resources to target and/or actuate the interaction of light and living organisms. Rare-earth-doped phosphors are generally promising candidates for efficient light-emitting diodes but still bear lower quantum yield for the far-red components, potential supply risks, and high-cost issues. Thus, the design and preparation of efficient non-rare-earth activated phosphors becomes extremely important and arouses great interest. Fabrication of Cr3+-doped Na3AlF6 phosphors significantly promotes the potential applications by efficiently converting blue excitation light of a commercial InGaN chip to far-red broadband emission in the 640-850 nm region. The action response of phototherapy (∼667-683 nm; ∼750-772 nm) and that of photomorphogenesis (∼700-760 nm) are well overlapped. Based on the temperature-dependent steady luminescence and time-resolved spectroscopies, energy transfer models are rationally established by means of the configurational coordinate diagram of Cr3+ ions. An optimal sample of Na3AlF6:60% Cr3+ phosphor generates a notable QY of 75 ± 5%. Additionally, an InGaN LED device encapsulated by using Na3AlF6:60% Cr3+ phosphor was fabricated. The current exploration will pave a promising way to engineer non-rare-earth activated optoelectronic devices for all kinds of photobiological applications.

Multiscale optical imaging of rare-earth-doped nanocomposites in a small animal model.

Rare-earth-doped nanocomposites have appealing optical properties for use as biomedical contrast agents, but few systems exist for imaging these materials. We describe the design and characterization of (i) a preclinical system for whole animal in vivo imaging and (ii) an integrated optical coherence tomography/confocal microscopy system for high-resolution imaging of ex vivo tissues. We demonstrate these systems by administering erbium-doped nanocomposites to a murine model of metastatic breast cancer. Short-wave infrared emissions were detected in vivo and in whole organ imaging ex vivo. Visible upconversion emissions and tissue autofluorescence were imaged in biopsy specimens, alongside optical coherence tomography imaging of tissue microstructure. We anticipate that this work will provide guidance for researchers seeking to image these nanomaterials across a wide range of biological models.

Refractive Index Tuning of Hybrid Materials for Highly Transmissive Luminescent Lanthanide Particle-Polymer Composites.

High-refractive-index ZrO2 nanoparticles were used to tailor the refractive index of a polymer matrix to match that of luminescent lanthanide-ion-doped (La0.92Yb0.075Er0.005F3) light-emitting particles, thereby reducing scattering losses to yield highly transparent emissive composites. Photopolymerization of blends of an amine-modified poly(ether acrylate) oligomer and tailored quantities of ZrO2 nanoparticles yielded optically transparent composites with tailored refractive indices between 1.49 and 1.69. By matching the refractive index of the matrix to that of La0.92Yb0.075Er0.005F3, composites with high transmittance (>85%) and low haze from the visible to infrared regions, bright 1530 nm optical emissions were achieved at solids loadings of La0.92Yb0.075Er0.005F3, ranging from 5 to 30 vol %. These optical results suggest that a hybrid matrix approach is a versatile strategy for the fabrication of functional luminescent optical composites of high transparency.

Efficient NIR Emission from Nd, Er, and Tm Complexes with Fluorinated Selenolate Ligands.

(DME)2Ln(SeC6F5)3 (Ln = Nd, Er, Tm) can be isolated in high yield by reductive cleavage of the Se-Se bond in (SeC6F5)2 with elemental Ln in DME. All three Ln compounds are isostructural, with 8 coordinate Ln bound to four O from DME, three terminally bound Se(C6F5), and a dative bond from an arene fluoride to a fluorine at the ortho position of one selenolate. Emission measurements indicate that these compounds are bright NIR sources.

Surveillance nanotechnology for multi-organ cancer metastases.

The identification and molecular profiling of early metastases remains a major challenge in cancer diagnostics and therapy. Most in vivo imaging methods fail to detect small cancerous lesions, a problem that is compounded by the distinct physical and biological barriers associated with different metastatic niches. Here, we show that intravenously injected rare-earth-doped albumin-encapsulated nanoparticles emitting short-wave infrared light (SWIR) can detect targeted metastatic lesions in vivo, allowing for the longitudinal tracking of multi-organ metastases. In a murine model of basal human breast cancer, the nanoprobes enabled whole-body SWIR detection of adrenal gland microlesions and bone lesions that were undetectable via contrast-enhanced magnetic resonance imaging (CE-MRI) as early as, respectively, three weeks and five weeks post-inoculation. Whole-body SWIR imaging of nanoprobes functionalized to differentially target distinct metastatic sites and administered to a biomimetic murine model of human breast cancer resolved multi-organ metastases that showed varied molecular profiles at the lungs, adrenal glands and bones. Real-time surveillance of lesions in multiple organs should facilitate pre-therapy and post-therapy monitoring in preclinical settings.

Bioadsorption of Rare Earth Elements through Cell Surface Display of Lanthanide Binding Tags.

With the increasing demand for rare earth elements (REEs) in many emerging clean energy technologies, there is an urgent need for the development of new approaches for efficient REE extraction and recovery. As a step toward this goal, we genetically engineered the aerobic bacterium Caulobacter crescentus for REE adsorption through high-density cell surface display of lanthanide binding tags (LBTs) on its S-layer. The LBT-displayed strains exhibited enhanced adsorption of REEs compared to cells lacking LBT, high specificity for REEs, and an adsorption preference for REEs with small atomic radii. Adsorbed Tb(3+) could be effectively recovered using citrate, consistent with thermodynamic speciation calculations that predicted strong complexation of Tb(3+) by citrate. No reduction in Tb(3+) adsorption capacity was observed following citrate elution, enabling consecutive adsorption/desorption cycles. The LBT-displayed strain was effective for extracting REEs from the acid leachate of core samples collected at a prospective rare earth mine. Our collective results demonstrate a rapid, efficient, and reversible process for REE adsorption with potential industrial application for REE enrichment and separation.

The Temperature-Dependence of Multiphonon Relaxation of Rare-Earth Ions in Solid-State Hosts.

Rare-earth ions are used in a wide range of emissive devices - ranging from lasers to displays - where high optical efficiency and narrow-linewidth are important. While their radiative properties are important, nonradiative properties are also critical since they can reduce optical efficiency and generate heat. In this paper, theories for multiphonon relaxation rate are reviewed for rare-earth excited states in solid-state dielectric hosts. A range of various approaches are used to simplify the mathematical form of the rate equations. The 2H9/2 excited state of Er3+, responsible for a technologically significant green emission, is modeled to show how the various theories manifest an order-of-magnitude variation in the thermal dependence of the multiphonon relaxation rate, as well as anomalous local minima in phonon scattering for temperatures above 0 K. This work proposes a corrective term of two quanta (Δν= + 2) of the mediating phonon energy to energy gap, so the calculated and the experimentally determined relaxation rates are equal. Radiative quantum efficiencies of both the 1G4→3H5 ~1.3 µm and 3F3→3F2 ~7 µm of Pr3+ are calculated to show the importance of both proper measurement of phonon energy and application of the multiphonon relaxation rate theory.

Line-scanning confocal microscopy for high-resolution imaging of upconverting rare-earth-based contrast agents.

Rare-earth (RE) doped nanocomposites emit visible luminescence when illuminated with continuous wave near-infrared light, making them appealing candidates for use as contrast agents in biomedical imaging. However, the emission lifetime of these materials is much longer than the pixel dwell times used in scanning intravital microscopy. To overcome this limitation, we have developed a line-scanning confocal microscope for high-resolution, optically sectioned imaging of samples labeled with RE-based nanomaterials. Instrument performance is quantified using calibrated test objects. NaYF4 : Er,Yb nanocomposites are imaged in vitro, and in ex vivo tissue specimens, with direct comparison to point-scanning confocal microscopy. We demonstrate that the extended pixel dwell time of line-scanning confocal microscopy enables subcellular-level imaging of these nanomaterials while maintaining optical sectioning. The line-scanning approach thus enables microscopic imaging of this emerging class of contrast agents for preclinical studies, with the potential to be adapted for real-time in vivo imaging in the clinic.

CXCR-4 Targeted, Short Wave Infrared (SWIR) Emitting Nanoprobes for Enhanced Deep Tissue Imaging and Micrometastatic Cancer Lesion Detection.

Realizing the promise of precision medicine in cancer therapy depends on identifying and tracking cancerous growths to maximize treatment options and improve patient outcomes. This goal of early detection remains unfulfilled by current clinical imaging techniques that fail to detect lesions due to their small size and suborgan localization. With proper probes, optical imaging techniques can overcome this by identifying the molecular phenotype of tumors at both macroscopic and microscopic scales. In this study, the first use of nanophotonic short wave infrared technology is proposed to molecularly phenotype small lesions for more sensitive detection. Here, human serum albumin encapsulated rare-earth nanoparticles (ReANCs) with ligands for targeted lesion imaging are designed. AMD3100, an antagonist to CXCR4 (a classic marker of cancer metastasis) is adsorbed onto ReANCs to form functionalized ReANCs (fReANCs). fReANCs are able to preferentially accumulate in receptor positive lesions when injected intraperitoneally in a subcutaneous tumor model. fReANCs can also target subtissue microlesions at a maximum depth of 10.5 mm in a lung metastatic model of breast cancer. Internal lesions identified with fReANCs are 2.25 times smaller than those detected with ReANCs. Thus, an integrated nanoprobe detection platform is presented, which allows target-specific identification of subtissue cancerous lesions.

Effects of Simulated Rare Earth Recycling Wastewaters on Biological Nitrification.

Increasing rare earth element (REE) supplies by recycling and expanded ore processing will result in generation of new wastewaters. In some cases, disposal to a sewage treatment plant may be favored, but plant performance must be maintained. To assess the potential effects of such wastewaters on biological treatment, model nitrifying organisms Nitrosomonas europaea and Nitrobacter winogradskyi were exposed to simulated wastewaters containing varying levels of yttrium or europium (10, 50, and 100 ppm), and the extractant tributyl phosphate (TBP, at 0.1 g/L). Y and Eu additions at 50 and 100 ppm inhibited N. europaea, even when virtually all of the REE was insoluble. Provision of TBP with Eu increased N. europaea inhibition, although TBP alone did not substantially alter activity. For N. winogradskyi cultures, Eu or Y additions at all tested levels induced significant inhibition, and nitrification shut down completely with TBP addition. REE solubility was calculated using the previously developed MSE (Mixed-Solvent Electrolyte) thermodynamic model. The model calculations reveal a strong pH dependence of solubility, typically controlled by the precipitation of REE hydroxides but also likely affected by the formation of unknown phosphate phases, which determined aqueous concentrations experienced by the microorganisms.

Rare Earth Nanoprobes for Functional Biomolecular Imaging and Theranostics.

Contrast agents designed to visualize the molecular mechanisms underlying cancer pathogenesis and progression have deepened our understanding of disease complexity and accelerated the development of enhanced drug strategies targeted to specific biochemical pathways. For the next generation probes and imaging systems to be viable, they must exhibit enhanced sensitivity and robust quantitation of morphologic and contrast features, while offering the ability to resolve the disease-specific molecular signatures that may be critical to reconstitute a more comprehensive portrait of pathobiology. This feature article provides an overview on the design and advancements of emerging biomedical optical probes in general and evaluates the promise of rare earth nanoprobes, in particular, for molecular imaging and theranostics. Combined with new breakthroughs in nanoscale probe configurations, and improved dopant compositions, and multimodal infrared optical imaging, rare-earth nanoprobes can be used to address a wide variety of biomedical challenges, including deep tissue imaging, real-time drug delivery tracking and multispectral molecular profiling.

Optoelectronic properties of graphene thin films deposited by a Langmuir-Blodgett assembly.

Large area thin films of few-layered unfunctionalized graphene platelets are developed with fine control over the thickness. The thin films are obtained by a Langmuir-Blodgett assembly at the interface of graphene solution in N-methyl-2-pyrrolidone (NMP) and water, and their optoelectronic properties and conduction mechanism are investigated in relation to lateral flake size and thin film thickness. The electrical conductivity and carrier mobility are affected by the flake size (200 nm to 1 µm) and by the packing of the nanostructure platelet network. General effective medium theory is used to explain the thickness dependent conductivity and to determine the percolation threshold film thickness which was found to be about 10 nm (at a volume fraction of ~39%) for a Langmuir-Blodgett film of an average platelet lateral size of 170 ± 40 nm. The electronic behaviour of the material shows more similarities with polycrystalline turbostratic graphite than thin films of reduced graphene oxide, carbon nanotubes, or disordered conducting polymers. While in these systems the conduction mechanism is often dominated by the presence of an energy barrier between conductive and non-conductive regions in the network, in the exfoliated graphene networks the conduction mechanism can be explained by the simple two-band model which is characteristic of polycrystalline graphite.

Surfactant effects on efficiency enhancement of infrared-to-visible upconversion emissions of NaYF4:Yb-Er.

Infrared-to-visible rare earth doped upconversion phosphors that convert multiple photons of lower energy to higher energy photons offer a wide range of technological applications. The brightness (i.e., emission intensities) and energy efficiency of phosphors are important performance characteristics that determine which applications are appropriate. Optical efficiency can be used as a measure of the upconversion emission performance of these rare earth doped phosphors. In this work, hexagonal-phase NaYF(4):Yb-Er was synthesized using the hydrothermal method in the presence of surfactants like trioctylphosphine, polyethylene glycol monooleate, and polyvinylpyrrolidone. The upconversion emission optical efficiencies of NaYF(4):Yb-Er were measured to quantify and evaluate the effects of surface coatings and accurately reflect the brightness and energy efficiency of these phosphors. Polyvinylpyrrolidone-modified NaYF(4):Yb-Er particles were found to be ~5 times more efficient and brighter than the unmodified particles. The difference in efficiency was attributed to reduced reflectance losses at the particle-air interface via refractive index mismatch reduction between the core NaYF(4):Yb-Er particles and air using polyvinylpyrrolidone as a surfactant.

Highly NIR-emissive lanthanide polyselenides.

Ln(SePh)(3) (Ln = Ce, Pr, Nd), prepared by reduction of PhSeSePh with elemental Ln and Hg catalyst, reacts with excess elemental Se to give (py)(11)Ln(7)Se(21)HgSePh, an ellipsoidal polyselenide cluster. The molecular structure contains two square arrays of eight- or nine-coordinate Ln fused at one edge to form a V shape that is also capped on the concave side by a centrally located nine-coordinate (Se(3))pyLn(Se(3)) and on the convex side by a 2-fold disordered SeHgSePh. The central Ln coordinates to selenido, triselenido, and pyridine ligands, while all other Ln coordinate to selenido, diselenido, triselenido, and pyridine ligands. Thermal treatment of the Pr compound at 650 °C gave Pr(2)Se(3) and Pr(3)Se(4). NIR emission studies of the Nd compound show four transitions from the excited-state (4)F(3/2) ion to (4)I(9/2), (4)I(11/2), (4)I(13/2), and (4)I(15/2) states. The (4)F(3/2) ion to (4)I(11/2) transition (1075 nm emission) exhibited 43% quantum efficiency. This is the highest quantum efficiency reported for a 'molecular' Nd compound and leads a group of selenide-based clusters that has shown extraordinary quantum efficiency. In terms of efficiency and concentration, these compounds compare favorably with solid-state materials.