Highly Efficient Singlet Oxygen Generation by BODIPY-Ruthenium(II) Complexes for Promoting Neurite Outgrowth and Suppressing Tau Protein Aggregation.

Singlet oxygen (1O2) has been recently identified as a key molecule against toxic Aß aggregation, which is associated with the currently incurable Alzheimer's disease (AD). However, limited research has studied its efficiency against tau protein aggregation, the other major hallmark of AD. Herein, we designed and synthesized boron-dipyrromethene (BODIPY)-ruthenium conjugates and isolated three isomers. Under visible-light irradiation, the ε isomer can be photoactivated and efficiently generate singlet oxygen. Particularly, the complex demonstrated successful results in attenuating tauopathy─an appreciable decrease to 43 ± 2% at 100 nM. The photosensitizer was further found to remarkably promote neurite outgrowth and significantly increased the length and number of neurites in nerve cells. As a result of effective photoinduced singlet oxygen generation and proactive neurite outgrowth, the hybrid design has great potential for therapeutics for Alzheimer's disease.

Porous Supramolecular Assembly of Pentiptycene-Containing Gold(I) Complexes: Persistent Excited-State Aurophilicity and Inclusion-Induced Emission Enhancement.

We report herein a porous supramolecular framework formed by a linear mononuclear Au(I) complex (1) via the tongue-and-groove-like joinery between the pentiptycene U-cavities (grooves) and the rod-shaped π-conjugated backbone and alkyl chains (tongues) with the assistance of C-H···π and aurophilic interactions. The framework contains distorted tetrahedral Au4 units, which undergo stepwise and persistent photoinduced Au(I)-Au(I) bond shortening (excited-state aurophilicity), leading to multicolored luminescence photochromism. The one-dimensional pore channels could accommodate different solvates and guests, and the guest inclusion-induced luminescence enhancement (up to 300%) and/or vapochromism are characterized. A correlation between the aurophilic bonding and the luminescence activity is uncovered by TDDFT calculations. Isostructural derivatives 2 and 3 corroborate both the robustness of the porous supramolecular assembly and the mechanisms of the stimulation-induced luminescence properties of 1. This work demonstrates the cooperation of aurophilicity and structural porosity and adaptability in achieving novel supramolecular photochemical properties.

Alkyl Chain Length- and Polymorph-Dependent Photomechanochromic Fluorescence of Anthracene Photodimerization in Molecular Crystals: Role of the Lattice Stiffness.

Anthracene-pentiptycene hybrid systems 1-Cn, where n refers to the number of carbon atoms in the linear alkyl chain, crystallize in three different polymorphs, denoted Y (yellow), G (green), and B (blue) forms in terms of the fluorescence color. While all Y-form crystals show the same yellow-to-blue fluorescence color response to the photomechanical stress generated by the anthracene [4+4] photodimerization reaction, the four G forms exhibit distinct photomechanofluorochromism (PMFC): from green to blue for G-1-C4, to orange for G-1-C7, to red for G-1-C8, and to red then blue for G-1-C9, and the B forms show no photochromic activity. The intriguing RGB three-color PMFC and abnormal topochemical reactivity of G-1-C9 are attributed to inherent softness of the crystal lattice.

Metal Carbonyls for the Biointerference-Free Ratiometric Surface-Enhanced Raman Spectroscopy-Based Assay for Cell-Free Circulating DNA of Epstein-Barr Virus in Blood.

By taking advantage of the spectral properties of metal carbonyls, we have designed a surface-enhanced Raman spectroscopy (SERS) ratiometric assay for measuring cell-free circulating DNA (cfDNA) from Epstein-Barr virus in blood for nasopharyngeal carcinoma (NPC). This assay consists of a rhenium carbonyl (Re-CO) to serve as a DNA probe, an osmium carbonyl (Os-CO) embedded within the SERS-active substrate as an internal reference, and a streptavidin layer on the surface of the substrate. Hybridization of cfDNA with biotinylated-capture sequence leads to immobilization of cfDNA on the substrate. The binding of Re-CO via daunorubicin (DNR) to cfDNA is accompanied by an appearance of a strong symmetry stretching vibrations peak at 2113 cm-1, which has spectral overlap with Os-CO (2025 cm-1). This results in an increase in the I2113/ I2025 ratio and quantitatively correlates with cfDNA. This SERS assay can be readily used to detect cfDNA in blood samples from patients due to the intensity ratio of I2113/ I2025 lying in a silent region (1780-2200 cm-1) in the SERS spectrum of the biomolecules.

Facile Construction of Metallo-supramolecular Poly(3-hexylthiophene)-block-Poly(ethylene oxide) Diblock Copolymers via Complementary Coordination and Their Self-Assembled Nanostructures.

Complementary coordination of two predesigned 2,2':6',2″-terpyridine-based ligands to a ZnII ion led to the exclusive formation of a heteroleptic bis(terpyridine) complex under ambient conditions. This highly self-selective process was facilitated by 9-anthracenyl substituents at the 6,6″-positions of a terpyridine, which not only decelerated the formation rate of its homoleptic complex, but also provided π-stacking stabilization in the heteroleptic complex. Facile construction of metallo-supramolecular poly(3-hexylthiophene) (P3HT)-block-poly(ethylene oxide) (PEO) diblock copolymers was realized using the complementary ligand pair. The morphological studies of the amphiphilic block copolymers in solution were conducted by atomic force microscopy and transmission electron microscopy, indicating that the self-assembled core-shell morphology such as spherical and fibrillar nanostructures could be controlled by adjusting the rod-coil block ratios. The heteroleptic complexes residing at the junction between two polymer blocks could be readily dissociated by EDTA to afford the unshelled P3HT nanofiber networks, and restored by treatment of bifunctional ZnII-terpyridine-capped PEO to redisperse the aggregates. The presented supramolecular methodology highlights the merits of complementary metal-ligand coordination, and offers a new approach to engineering nanostructures assembled from rod-coil block copolymers.

Vibrational spectroscopy of metal carbonyls for bio-imaging and -sensing.

Transition metal carbonyls exhibit strong CO absorptions in the 2200-1800 cm(-1) region, which is free of interference from other functional groups. This feature has led to their applications in bio-imaging and -sensing, in particular through mid-IR, Raman and more recently, surface-enhanced Raman spectroscopy (SERS). Their use in mid-IR quantitative sensing based on vibrational intensities, and chemical sensing based on frequency shifts and vibrational lifetimes, is reviewed. Their development for Raman sensing following the breakthrough in SERS highlights the potential of coupling metal carbonyls to plasmonic nanostructures as novel optical materials for SERS-based bio-imaging and -sensing.

A rapid and label-free SERS detection method for biomarkers in clinical biofluids.

A metal carbonyl-functionalized nanostructured substrate can be used in a rapid and simple assay for the detection of A1AT, a potential biomarker for bladder cancer, in clinical urine samples. The assay involves monitoring changes in the carbonyl stretching vibrations of the metal carbonyl via surface-enhanced Raman spectroscopy (SERS). These vibrations lie in the absorption spectral window of 1800-2200 cm(-1), which is free of any spectral interference from biomolecules.

Recent progress in voltage-sensitive dye imaging for neuroscience.

Voltage-sensitive dye imaging (VSDi) enables visualization of information processing in different areas of the brain with reasonable spatial and temporal resolution. VSDi employs different chemical compounds to transduce neural activity directly into the changes in intrinsic optical signal. Physically, voltage-sensitive dyes (VSDs) are chemical probes that reside in the neural membrane and change their fluorescence or absorbance in response to membrane potential changes. Based on these features, VSDs can be divided into two groups-absorbance and fluorescence. The spatial and temporal resolution of the VSDi is limited mainly by the technical characteristics of the optical imaging setup (e.g., computer and light-sensitive device-charge-coupled device (CCD) camera or photodiode array). In this article, we briefly review the development of the VSD, technique of VSDi and applications in functional brain imaging.

A transition metal carbonyl probe for use in a highly specific and sensitive SERS-based assay for glucose.

A triosmium carbonyl cluster-boronic acid conjugate is used as a secondary carbohydrate probe in a SERS-based assay. The assay does not require conjugation of the metal carbonyl probe to a SERS-active species, and it utilizes the CO stretching vibrations of the metal carbonyl, which lies in a silent region of the SERS spectrum (1800-2200 cm(-1)), for quantification. High selectivity for glucose over fructose and galactose is obtained, and a human urine sample doped with glucose is detected accurately.

Laser tweezer Raman spectroscopy combined with deep neural networks for identification of liver cancer cells.

Rapid identification of cancer cells is crucial for clinical treatment guidance. Laser tweezer Raman spectroscopy (LTRS) that provides biochemical characteristics of cells can be used to identify cell phenotypes through classification models in a non-invasive and label-free manner. However, traditional classification methods require extensive reference databases and clinical experience, which is challenging when sampling at inaccessible locations. Here, we describe a classification method combing LTRS with deep neural network (DNN) for differential and discriminative analysis of multiple liver cancer (LC) cells. By using LTRS, we obtained high-quality single-cell Raman spectra of normal hepatocytes (HL-7702) and liver cancer cell lines (SMMC-7721, Hep3B, HepG2, SK-Hep1 and Huh7). The tentative assignment of Raman peaks indicated that arginine content was elevated and phenylalanine, glutathione and glutamate content was decreased in liver cancer cells. Subsequently, we randomly selected 300 spectra from each cell line for DNN model analysis, achieving a mean accuracy of 99.2%, a mean sensitivity of 99.2% and a mean specificity of 99.8% for the identification and classification of multiple LC cells and hepatocyte cells. These results demonstrate the combination of LTRS and DNN is a promising method for rapid and accurate cancer cell identification at single cell level.

Metal carbonyl-gold nanoparticle conjugates for live-cell SERS imaging.

Conjugates of organometallic osmium carbonyl clusters and gold nanoparticles show a strong carbonyl signal in surface-enhanced Raman spectroscopy. The ease of bio-functionalization and the high stability and good dispersibility in aqueous solution make these conjugates excellent candidates for biomedical applications, as demonstrated by live-cell imaging with the carbonyl signals of OM-NP(PEG)-L conjugates.

Diagnostic plasmonic sensors: opportunities and challenges.

The medical fraternity is currently burgeoned and stressed with a huge rush of patients who have inflammatory conditions, metabolite diseases, and cardiovascular diseases. In these circumstances, advanced sensing technologies could have a huge impact on the quality of life of patients. Given plasmonic resonance effects significantly improve the ability to rapidly and accurately detect biological markers, plasmonic technology is harnessed to develop a fast and accurate diagnosis that can provide timely intervention with the diseases and can also aid the recovery process by complementing the therapy stage. In this short review, we provide an overlook of how the field of plasmonic sensing has revolutionized the field of medical diagnostics. This article reviews the fundamentals and development of plasmonics. In addition, we highlight the sensitivity of various SPR and LSPR sensors. The chemistry for functionalizing plasmonic sensors is also discussed. This review also outlines some general suggestions for future directions that we feel might be useful to advance our understanding of the universe or speed up the development of plasmonic sensors in the future.

Plasmonic Biosensing with Nano-Engineered Van der Waals Interfaces.

Observing a Goos-Hänchen (GH) shift of the incident light beam provides a simple and convenient method of detecting fast phase variations without the need for cumbersome direct phase measurements. Here, we show that few-monolayers-thick van der Waals structures (WS2 , MoSe2 and graphene) nano-engineered onto a plasmonic surface can enhance the phase variation sensitivity to analyte presence, leading to more than 3 orders of magnitude increase in the Goos-Hänchen shift (ca. 886 mm/RIU for a WS2 /graphene/Au multilayer). The detection limit is evaluated to be as low as 0.1 aM (6.7 pg/mL) for bovine serum albumin protein with molecular weight of 67 kDa and 1 fM (24.4 ng/mL) for biotin (244 Da) molecules.

Optical biosensor based on SERS with signal calibration function for quantitative detection of carcinoembryonic antigen.

Monitoring the levels of cancer biomarkers is essential for cancer diagnosis and evaluation. In this study, a novel sandwich type sensing platform based on surface-enhanced Raman scattering (SERS) technology was developed for the detection of carcinoembryonic antigen (CEA), with a limit of detection (LOD) of 0.258 ng/mL. In order to achieve sensitive detection of CEA in complex samples, gold nanoparticle monolayer modified with CEA antibodies and with aptamer-functionalized probes was fabricated to target CEA. Two gold layers were integrated into the SERS platform, which greatly enhanced the signal of the probe by generating tremendous "hot spots". Meanwhile, the intensity ratio of Raman probes and the second-order peak of the silicon wafer was used to achieve dynamic calibration of the Raman probe signal. Excitingly, this sensing platform was capable of distinguishing cancer patients from healthy individuals via CEA concentrations in blood samples with the accuracy of 100%. This sandwich structure SERS sensing platform presented promising potential to be an alternative tool for clinical biomarker detection in the field of cancer diagnosis.

Highly Efficient Blood Protein Analysis Using Membrane Purification Technique and Super-Hydrophobic SERS Platform for Precise Screening and Staging of Nasopharyngeal Carcinoma.

Early screening and precise staging are crucial for reducing mortality in patients with nasopharyngeal carcinoma (NPC). This study aimed to assess the performance of blood protein surface-enhanced Raman scattering (SERS) spectroscopy, combined with deep learning, for the precise detection of NPC. A highly efficient protein SERS analysis, based on a membrane purification technique and super-hydrophobic platform, was developed and applied to blood samples from 1164 subjects, including 225 healthy volunteers, 120 stage I, 249 stage II, 291 stage III, and 279 stage IV NPC patients. The proteins were rapidly purified from only 10 µL of blood plasma using the membrane purification technique. Then, the super-hydrophobic platform was prepared to pre-concentrate tiny amounts of proteins by forming a uniform deposition to provide repeatable SERS spectra. A total of 1164 high-quality protein SERS spectra were rapidly collected using a self-developed macro-Raman system. A convolutional neural network-based deep-learning algorithm was used to classify the spectra. An accuracy of 100% was achieved for distinguishing between the healthy and NPC groups, and accuracies of 96%, 96%, 100%, and 100% were found for the differential classification among the four NPC stages. This study demonstrated the great promise of SERS- and deep-learning-based blood protein testing for rapid, non-invasive, and precise screening and staging of NPC.

Demethylation of an artificial hydrogenase agent for prolonged CO release and enhanced anti-tau aggregation activity.

Carbon monoxide (CO) plays an important role in signaling in cells, making its use as a therapeutic tool highly intriguing. Reduced burst emissions are important to avoid the cytotoxicity and tissue damage caused by CO. Here, we developed a stable diiron carbonyl [FeFe] hydrogenase agent that enables prolonged CO release activity (half-life of over 9 h) in cells. The integrated analysis allowed the identification of the key intermediate sites and CO accumulations with subcellular resolution. We observed that the [FeFe]A complex was enriched in neurons with S-methyl bond rupture. Furthermore, the [FeFe]A complex efficiently reduced the aggregation of tau proteins (49.3% reduction) and showed superior biocompatibility in nerve cells (∼ 95% survival).

Probing Molecular-Scale Oxidative Generation of Quinone Methides and Their Transformation Using Tip-Enhanced Raman Spectroscopy.

Quinone methides (QMs) are very important intermediates in chemistry. These species are most often generated in situ with metal oxidants and transition metal complexes. Here, tip-enhanced Raman spectroscopy (TERS) has been implemented to investigate the in situ oxidative generation of a QM species from alkylphenols facilitated by a transition metal complex. Using TERS, the metal oxidant-mediated transformation of a phenol species has been observed. The subsequent oxidative addition reaction of QM has also been identified based on distinct vibrational features, which have been assigned based on density functional theory (DFT). This study may establish TERS as a chemical detection tool for various QM-mediated reactions.

Tandem Quantification of Multiple Carbohydrates in Saliva Using Surface-Enhanced Raman Spectroscopy.

The detection of carbohydrates in human body fluids is critical for disease diagnosis and healthy monitoring. Despite recent advances in glucose sensing, multiplex detection of different carbohydrates within a single assay that is capable of efficiently providing richer health information remains challenging. Herein, we report a versatile surface-enhanced Raman spectroscopy-based platform for the quantitative detection of monosaccharides (glucose, fructose, and galactose) in one test using a displace-and-trap mechanism. Moreover, due to the use of multiple optical interference-free (1800-2200 cm-1) signal-independent Raman probes, the detection range of this platform (0.125-7 mg/dL) perfectly covers physiological concentrations, enabling the quantitative detection of glucose and galactose in clinical human saliva samples. This work provides a noninvasive and high-efficiency potential tool for the screening of clinical diabetes and other carbohydrate-related diseases.

Geometrically encoded SERS nanobarcodes for the logical detection of nasopharyngeal carcinoma-related progression biomarkers.

The limited availability of nasopharyngeal carcinoma-related progression biomarker array kits that offer physicians comprehensive information is disadvantageous for monitoring cancer progression. To develop a biomarker array kit, systematic identification and differentiation of a large number of distinct molecular surface-enhanced Raman scattering (SERS) reporters with high spectral temporal resolution is a major challenge. To address this unmet need, we use the chemistry of metal carbonyls to construct a series of unique SERS reporters with the potential to provide logical and highly multiplex information during testing. In this study, we report that geometric control over metal carbonyls on nanotags can produce 14 distinct barcodes that can be decoded unambiguously using commercial Raman spectroscopy. These metal carbonyl nanobarcodes are tested on human blood samples and show strong sensitivity (0.07 ng/mL limit of detection, average CV of 6.1% and >92% degree of recovery) and multiplexing capabilities for MMPs.

Photoinduced Enhanced Raman Probe for Use in Highly Specific and Sensitive Imaging for Tyrosine Dimerization in Inflammatory Cells.

A background-free photoinduced enhanced Raman (PIER) probe for highly sensitive detection of tyrosine dimerization process due to oxidative reaction in inflammatory cells is presented. The PIER probe could monitor oxidative reaction in real time by producing time-resolved spectral with discrete changes in Raman intensity. To the best of our knowledge, this is the first report on C≡C probes with PIER and vastly improved Raman activity. These results will contribute to the cutting edge of development of stable and highly sensitive chemical imaging technology.