Development of Human Serum Albumin Fluorescent Probes in Detection, Imaging, and Disease Therapy.

Human serum albumin (HSA) acts as a repository and transporter of substances in the blood. An abnormal concentration may indicate the occurrence of liver- and kidney-related diseases, which has attracted people to investigate the precise quantification of HSA in body fluids. Fluorescent probes can combine with HSA covalently or noncovalently to quantify HSA in urine and plasma. Moreover, probes combined with HSA can improve its photophysical properties; probe-HSA has been applied in real-time monitoring and photothermal and photodynamic therapy in vivo. This Review will introduce fluorescent probes for quantitative HSA according to the three reaction mechanisms of spatial structure, enzymatic reaction, and self-assembly and systematically introduce the application of probes combined with HSA in disease imaging and phototherapy. It will help develop multifunctional applications for HSA probes and provide assistance in the early diagnosis and treatment of diseases.

A new fluorescent probe for the visualization of progerin.

Hutchinson-Gilford progeria syndrome (HGPS) or progeria is a rare genetic disease that causes premature aging, leading to a drastic reduction in the life expectancy of patients. Progeria is mainly caused by the intracellular accumulation of a defective protein called progerin, generated from a mutation in the LMNA gene. Currently, there is only one approved drug for the treatment of progeria, which has limited efficacy. It is believed that progerin levels are the most important biomarker related to the severity of the disease. However, there is a lack of effective tools to directly visualize progerin in the native cellular models, since the commercially available antibodies are not well suited for the direct visualization of progerin in cells from the mouse model of the disease. In this context, an alternative option for the visualization of a protein relies on the use of fluorescent chemical probes, molecules with affinity and specificity towards a protein. In this work we report the synthesis and characterization of a new fluorescent probe (UCM-23079) that allows for the direct visualization of progerin in cells from the most widely used progeroid mouse model. Thus, UCM-23079 is a new tool compound that could help prioritize potential preclinical therapies towards the final goal of finding a definitive cure for progeria.

Activatable fluorescent probes for imaging and diagnosis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is primarily manifested as synovitis and polyarticular opacity and typically leads to serious joint damage and irreversible disability, thus adversely affecting locomotion ability and life quality. Consequently, good prognosis heavily relies on the early diagnosis and effective therapeutic monitoring of RA. Activatable fluorescent probes play vital roles in the detection and imaging of biomarkers for disease diagnosis and in vivo imaging. Herein, we review the fluorescent probes developed for the detection and imaging of RA biomarkers, namely reactive oxygen/nitrogen species (hypochlorous acid, peroxynitrite, hydroxyl radical, nitroxyl), pH, and cysteine, and address the related challenges and prospects to inspire the design of novel fluorescent probes and the improvement of their performance in RA studies.

Recent progress on near-infrared fluorescence heptamethine cyanine dye-based molecules and nanoparticles for tumor imaging and treatment.

Recenly, near-infrared fluorescence heptamethine cyanine dyes have shown satisfactory values in bioengineering, biology, and pharmacy especially in cancer diagnosis and treatment, owing to their excellent fluorescence property and biocompatibility. In order to achieve broad application prospects, diverse structures, and chemical properties of heptamethine cyanine dyes have been designed to develop novel functional molecules and nanoparticles over the past decade. For fluorescence and photoacoustic tumor imaging properties, heptamethine cyanine dyes are equipped with good photothermal performance and reactive oxygen species production properties under near-infrared light irradiation, thus holding great promise in photodynamic and/or photothermal cancer therapies. This review offers a comprehensive scope of the structures, comparisons, and applications of heptamethine cyanine dyes-based molecules as well as nanoparticles in tumor treatment and imaging in current years. Therefore, this review may drive the development and innovation of heptamethine cyanine dyes, significantly offering opportunities for improving tumor imaging and treatment in a precise noninvasive manner. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Sufentanil inhibits Pin1 to attenuate renal tubular epithelial cell ischemia-reperfusion injury by activating the PI3K/AKT/FOXO1 pathway.

BACKGROUND: Renal ischemia-reperfusion injury (RIRI) has become a great concern in clinical practice with high morbidity and mortality rates. Sufentanil has protective effects on IRI-induced organ injury. Herein, the effects of sufentanil on RIRI were investigated. METHODS: RIRI cell model was established by hypoxia/reperfusion (H/R) stimulation. The mRNA and protein expressions were assessed using qRT-PCR and western blot. TMCK-1 cell viability and apoptosis were assessed using MTT assay and flow cytometry, respectively. The mitochondrial membrane potential and ROS level were detected by JC-1 mitochondrial membrane potential fluorescent probe and DCFH-DA fluorescent probe, respectively. LDH, SOD, CAT, GSH and MDA levels were determined by the kits. The interaction between FOXO1 and Pin1 promoter was analyzed using dual luciferase reporter gene and ChIP assays. RESULTS: Our results revealed that sufentanil treatment attenuated H/R-induced cell apoptosis, mitochondrial membrane potential (MMP) dysfunction, oxidative stress, inflammation and activated PI3K/AKT/FOXO1 associated proteins, while these effects were reversed by PI3K inhibitor, suggesting that sufentanil attenuated RIRI via activating the PI3K/AKT/FOXO1 signaling pathway. We subsequently found that FOXO1 transcriptionally activated Pin1 in TCMK-1 cells. Pin1 inhibition ameliorated H/R-induced TCMK-1 cell apoptosis, oxidative stress and inflammation. In addition, as expected, the biological effects of sufentanil on H/R-treated TMCK-1 cells were abrogated by Pin1 overexpression. CONCLUSION: Sufentanil reduced Pin1 expression through activation of the PI3K/AKT/FOXO1 signaling to suppress cell apoptosis, oxidative stress and inflammation in renal tubular epithelial cells during RIRI development.

Early diagnosis of heterotopic ossification with a NIR fluorescent probe by targeting type II collagen.

Heterotopic ossification (HO) is a devastating sequela in which the pathologic extracellular matrix of the cartilage and bone forms abnormally in soft tissues following traumatic injuries or orthopaedic surgeries. Early treatment is essential for inhibiting the progression of HO but is currently limited by the absence of sensitive and specific early diagnosis. Herein, this study exploits the enrichment of type II collagen (Col2a1) in the HO cartilage formation stage towards developing a near-infrared (NIR) probe for early HO diagnosis, namely WL-808 by conjugating a Col2a1-binding peptide (WYRGRL) and a cyanine dye (IR-808). WL-808 exhibits high specificity for targeting the cartilage in vitro and in vivo with no apparent cytotoxicity. The NIR signal of WL-808 can be detected in the HO cartilage lesions as early as 1 week after injury when micro-CT cannot show any ectopic bone formation. Moreover, the probe is rarely distributed in the normal knee articular cartilage in vivo via the intravenous administration method. Taken together, WL-808 demonstrates great potential in early HO diagnosis under NIR imaging, facilitating early HO prophylaxis and treatment in the clinic.

An ultra-small bispecific protein augments tumor penetration and treatment for pancreatic cancer.

PURPOSE: The once highly anticipated antibody-based pathway-targeted therapies have not achieved promising outcomes for deadly pancreatic ductal adenocarcinoma (PDAC), mainly due to drugs' low intrinsic anticancer activity and poor penetration across the dense physiological barrier. This study aims to develop an ultra-small-sized, EGFR/VEGF bispecific therapeutic protein to largely penetrate deep tumor tissue and effectively inhibit PDAC tumor growth in vivo. METHODS: The bispecific protein, Bi-fp50, was constructed by a typical synthetic biology method and labeled with fluorescent dyes for in vitro and in vivo imaging. Physicochemical properties, protein dual-binding affinity, and specificity of the Bi-fp50 were evaluated in several PDAC cell lines. In vitro quantitatively and qualitatively anticancer activity of Bi-fp50 was assessed by live/dead staining, MTT assay, and flow cytometry. In vivo pharmacokinetic and biodistribution were evaluated using blood biopsy samples and near-infrared fluorescence imaging. In vivo real-time tracking of Bi-fp50 in the local tumor was conducted by fibered confocal fluorescence microscopy. The subcutaneous PDAC tumor model was used to assess the in vivo antitumor effect of Bi-fp50. RESULTS: Bi-fp50 with an ultra-small size of 50 kDa (5 ~ 6 nm) showed an excellent binding ability to VEGF and EGFR simultaneously and had enhanced, accumulated binding capability for Bxpc3 PDAC cells compared with anti-VEGF scFv and anti-EGFR scFv alone. Additionally, bi-fp50 significantly inhibited the proliferation and growth of Bxpc3 and Aspc1 PDAC cells even under a relatively low concentration (0.3 µM). It showed synergistically enhanced therapeutic effects relative to two individual scFv and Bi-fp50x control in vitro. The half-life of blood clearance of Bi-fp50 was 4.33 ± 0.23 h. After intravenous injection, Bi-fp50 gradually penetrated the deep tumor, widely distributed throughout the whole tissue, and primarily enriched in the tumor with nearly twice the accumulation than scFv2 in the orthotopic PDAC tumor model. Furthermore, the Bi-fp50 protein could induce broad apoptosis in the whole tumor and significantly inhibited tumor growth 3 weeks after injection in vivo without other noticeable side effects. CONCLUSION: The proof-of-concept study demonstrated that the ultra-small-sized, bispecific protein Bi-fp50 could be a potential tumor suppressor and an efficient, safe theranostic tool for treating PDAC tumors.

A Novel PSMA-Targeted Probe for NIRF-Guided Surgery and Photodynamic Therapy: Synthesis and Preclinical Validation.

A total of 20% to 50% of prostate cancer (PCa) patients leave the surgery room with positive tumour margins. The intraoperative combination of fluorescence guided surgery (FGS) and photodynamic therapy (PDT) may be very helpful for improving tumour margin delineation and cancer therapy. PSMA is a transmembrane protein overexpressed in 90−100% of PCa cells. The goal of this work is the development of a PSMA-targeted Near InfraRed Fluorescent probe to offer the surgeon a valuable intraoperative tool for allowing a complete tumour removal, implemented with the possibility of using PDT to kill the eventual not resected cancer cells. PSMA-617 binding motif was conjugated to IRDye700DX-NHS and the conjugation did not affect the photophysical characteristics of the fluorophore. The affinity of IRDye700DX-PSMA-617 towards PCa cells followed the order of their PSMA expression, i.e., PC3-PIP > LNCaP > PC3, PC3-FLU. NIRF imaging showed a significant PC3-PIP tumour uptake after the injection of 1 or 5 nmol with a maximum tumour-to-muscle ratio (ca. 60) observed for both doses 24 h post-injection. Importantly, urine, healthy prostate, and the bladder were not fluorescent at 24 h post-injection. Flow cytometry and confocal images highlighted a co-localization of PSMA+ cells with IRDye700DX-PSMA uptake. Very interestingly, ex vivo analysis on a tumour specimen highlighted a significant PSMA expression by tumour-associated macrophages, likely attributable to extracellular vesicles secreted by the PSMA(+) tumour cells. FGS proved that IRDye700DX-PSMA was able to easily delineate tumour margins. PDT experiments showed a concentration-dependent decrease in cell viability (from 75% at 10 nM to 12% at 500 nM), whereas controls did not show any cytotoxicity. PC3-PIP tumour-bearing mice subjected to photodynamic therapy showed a delayed tumour growth. In conclusion, a novel PSMA-targeted NIRF dye with dual imaging-PDT capabilities was synthesized and displayed superior specificity compared to other small PSMA targeted molecules.

Cardiolipin-Targeted NIR-II Fluorophore Causes "Avalanche Effects" for Re-Engaging Cancer Apoptosis and Inhibiting Metastasis.

Restoring innate apoptosis and simultaneously inhibiting metastasis by a molecular drug is an effective cancer therapeutic approach. Herein, a large rigid and V-shaped NIR-II dye, DUT850, is rationally designed for potential cardiolipin (CL)-targeted chemo-phototheranostic application. DUT850 displays moderate NIR-II fluorescence, excellent photodynamic therapy (PDT) and photothermal therapy (PTT) performance, and ultra-high photostability. More importantly, the unique rigid V-shaped backbone, positive charge, and lipophilicity of DUT850 afford its specific recognition and efficient binding to CL; such an interaction of DUT850-CL induced a spectrum of physiological disruptions, including translocation of cytochrome c, Ca2+ overload, reactive oxygen species burst, and ATP depletion, which not only activated cancer cell apoptosis but also inhibited tumor metastasis both in vitro and in vivo. Furthermore, the tight binding of DUT850-CL improves the phototoxicity of DUT850 toward cancer cells (IC50 as low as 90 nM) under safe 808 nm laser irradiation (330 mW cm-2). Upon encapsulation into bovine serum albumin (BSA), DUT850@BSA exerted a synergetic chemo-PDT-PTT effect on the 4T1 tumor mouse model, eventually leading to solid tumor annihilation and metastasis inhibition, which could be followed in real time with the NIR-II fluorescence of DUT850. This work contributed a promising approach for simultaneously re-engaging cancer cell apoptotic networks and activating the anti-metastasis pathway by targeting a pivotal upstream effector, which will bring a medical boon for inhibition of tumor proliferation and metastasis.

Viscosity-sensitive NIR probe for in vivo imaging of early-stage hepatic fibrosis.

Herein, a viscosity-sensitive and hepatic-targeted NIR fluorescent probe has been developed for early diagnosis of hepatic fibrosis. Importantly, we observed increased liver viscosity upon CCl4-induced hepatotoxicity and decreased liver viscosity after metformin treatment, which confirmed its high clinical application prospects.

Photon Upconversion in Small Molecules.

Upconversion (UC) is a process that describes the emission of shorter-wavelength light compared to that of the excitation source. Thus, UC is also referred to as anti-Stokes emission because the excitation wavelength is longer than the emission wavelength. UC materials are used in many fields, from electronics to medicine. The objective of using UC in medical research is to synthesize upconversion nanoparticles (UCNPs) composed of a lanthanide core with a coating of adsorbed dye that will generate fluorescence after excitation with near-infrared light to illuminate deep tissue. Emission occurs in the visible and UV range, and excitation mainly in the near-infrared spectrum. UC is observed for lanthanide ions due to the arrangement of their energy levels resulting from f-f electronic transitions. Organic compounds and transition metal ions are also able to form the UC process. Biocompatible UCNPs are designed to absorb infrared light and emit visible light in the UC process. Fluorescent dyes are adsorbed to UCNPs and employed in PDT to achieve deeper tissue effects upon irradiation with infrared light. Fluorescent UCNPs afford selectivity as they may be activated only by illumination of an area of diseased tissue, such as a tumor, with infrared light and are by themselves atoxic in the absence of infrared light. UCNP constructs can be monitored as to their location in the body and uptake by cancer cells, aiding in evaluation of exact doses required to treat the targeted cancer. In this paper, we review current research in UC studies and UCNP development.

Diagnosis of Alzheimer's Disease and In Situ Biological Imaging via an Activatable Near-Infrared Fluorescence Probe.

Alzheimer's disease (AD) is a common neurodegenerative disease that makes the brain nervous system degenerate rapidly and is accompanied by some special cognitive and behavioral dysfunction. Recently, butyrylcholinesterase (BChE) was reported as an important enzyme, whose activity can provide predictive value for timely discovery and diagnosis of AD. Therefore, it is indispensable to design a detection tool for selective and rapid response toward BChE. In this study, we developed a novel near-infrared fluorescent probe (Chy-1) for the detection of BChE activity. An excellent sensitivity, good biocompatibility, and lower limit of detection (LOD) of 0.12 ng/mL made the probe extremely specific for BChE, which was successfully used in biological imaging. What is more, Chy-1 can not only clearly distinguish tumor from normal cells but also forms a clear boundary between the normal and cancer tissues due to the obvious difference in fluorescence intensity produced via in situ spraying. Most important of all, Chy-1 was also successfully applied to track the BChE activity in AD mouse models. Based on this research, the novel probe may be a powerful tool for clinical diagnosis and therapy of tumor and neurodegenerative diseases.

Recent progress on the development of fluorescent probes targeting the translocator protein 18 kDa (TSPO).

The translocator protein 18 kDa (TSPO) was first identified in 1997, and has now become one of the appealing subcellular targets in medicinal chemistry and its related fields. TSPO involves in a variety of diseases, covering neurodegenerative diseases, psychiatric disorders, cancers, and so on. To date, various high-affinity TSPO ligands labelled with single-photon emission computed tomography (SPECT)/positron emission tomography (PET) radionuclides have been reported, with some third-generation radioligands advanced to clinical trials. On the other hand, only a few number of TSPO ligands have been labelled with fluorophores for disease diagnosis. It is noteworthy that the majority of the TSPO fluorescent probes synthesised to date are based on visible fluorophores, suggesting that their applications are limited to in vitro studies, such as in vitro imaging of cancer cells, post-mortem analysis, and tissue biopsies examinations. In this context, the potential application of TSPO ligands can be broadened for in vivo investigations of human diseases by labelling with near-infrared (NIR)-fluorophores or substituting visible fluorophores with NIR-fluorophores on the currently developed fluorescent probes. In this review article, recent progress on fluorescent probes targeting the TSPO are summarised, with an emphasis on development trend in recent years and application prospects in the future.

A potent estrogen receptor and microtubule specific purine-benzothiazole-based fluorescent molecular probe induces apoptotic death of breast cancer cells.

Breast cancer is the most common malignancy in women and is a heterogeneous disease at molecular level. Early detection and specificity are the key prerequisite for the treatment of this deadly cancer. To address these issues attention on the breast cancer specific receptor protein(s) is the most realistic option. Herein estrogen (E) and progesterone (Pg) receptors(R) were considered to design fluorescent molecular probes with possible therapeutic option. We adopted QSAR technique to design a library of benzothiazole-purine hybrid molecules. Molecular docking offers us three screened molecules as most potential. Among these molecules one abbreviated as "CPIB" showed blue fluorescence and detected ER positive cancer cells at 1 nM concentration. At elevated concentration, CPIB induces apoptotic deaths of same cancer cells through targeting intracellular microtubules without affecting normal cells or ER negative cells. CPIB is one of its kind with two-in-one potential of "Detection and Destroy" ability targeting ER positive breast cancer cells.

Discovery of Imaging and Therapeutic Integration Bifunctional Molecules Based on Bio-Orthogonal Reaction and Releasable Disulfide Bond.

The application of conventional fluorescent probes in living cells has been limited by excess fluorescence interference, reduced selectivity, and poor permeability. Herein, we describe a convenient solution for overcoming the above limitations based on bio-orthogonal reactions and releasable linkers that provide bifunctional molecules for imaging and therapeutic integration. To reduce the interference of excess fluorescent moieties, a bio-orthogonal reaction was applied to activate the fluorescence of the active parent drugs without fluorophores. Moreover, disulfide bonds were incorporated as releasable linkers. After imaging the target protein, the newly yielded fluorophore could be released from the active drugs based on the highly reducing conditions of the tumor. Thus, these bifunctional molecules are comparable in therapeutic activity to the parent drug. These novel imaging and therapeutic integration molecules could be used to realize imaging-aided diagnosis and perform efficient real-time monitoring of cancer cells. Our findings are expected to enable efficient and specific imaging and real-time in vivo prognostic monitoring in the clinic.

Fractional CO2 laser ablation leads to enhanced permeation of a fluorescent dye in healthy and mycotic nails-An imaging investigation of laser-tissue effects and their impact on ungual drug delivery.

PURPOSE: Conventional oral antifungal therapies for onychomycosis (OM) often do not achieve complete cure and may be associated with adverse effects, medical interactions, and compliance issues restricting their use in a large group of patients. Topical treatment can bypass the systemic side effects but is limited by the physical barrier of the nail plate. Ablative fractional laser (AFL) treatment can be used to improve the penetration of topical drugs into the nail. This study visualized the effects of laser ablation of nail tissue and assessed their impact on the biodistribution of a fluorescent dye in healthy and fungal nail tissue. METHODS: For the qualitative assessment of CO2 AFL effects on healthy nail tissue, scanning electron microscopy (SEM), coherent anti-Stokes Raman scattering microscopy (CARS-M), and widefield fluorescence microscopy (WFM) were used. To quantitate the effect of laser-pretreatment on the delivery of a fluorescent dye, ATTO-647N, into healthy and fungal nail tissue, ablation depth, nail plate thickness, and ATTO-647N fluorescence intensity in three nail plate layers were measured using WFM. A total of 30 nail clippings (healthy n = 18, fungal n = 12) were collected. An aqueous ATTO-647N solution was directly applied to the dorsal surface of 24 nail samples (healthy n = 12, fungal n = 12) and incubated for 4 hours, of which half (healthy n = 6, fungal n = 6) had been pretreated with AFL (30 mJ/mb, 15% density, 300 Hz, pulse duration <1 ms). RESULTS: Imaging revealed a three-layered nail structure, an AFL-induced porous ablation crater, and changes in autofluorescence. While intact fungal samples showed a 106% higher ATTO-647N signal intensity than healthy controls, microporation led to a significantly increased fluorophore permeation in all samples (p < 0.0001). AFL processing of nail tissue enhanced topical delivery of ATTO-647N in all layers, (average increase: healthy +108%, fungal +33%), most pronounced in the top nail layer (healthy +122%, fungal +68%). While proportionally deeper ablation craters correlated moderately with higher fluorescence intensities in healthy nail tissue, fungal samples showed no significant relationship. CONCLUSION: Fractional CO2 laser microporation is a simple way of enhancing the passive delivery of topically applied ATTO-647N. Although the impaired nail plate barrier in OM leads to greater diffusion of the aqueous solution, AFL can increase the permeability of both structurally deficient and intact nails.

Pharmacological suppression of the kallikrein kinin system with KVD900: An orally available plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE. METHODS: Pharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)-stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial. RESULTS: KVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a Ki of 3.02 nM. The association constant (Kon ) of KVD900 for PKa is >10 × 106  M-1  s-1 . Oral administration of KVD900 in a first-in-human clinical trial achieved rapid and near complete inhibition of DXS-stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS-stimulated PKa activity in plasma by ≥95% from 45 min to at least 4 h post-dose and provided rapid protection of HK from cleavage. CONCLUSION: KVD900 is a fast-acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On-demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks.

Hydrogel-Coated Gate Field-Effect Transistor for Real-Time and Label-Free Monitoring of ß-Amyloid Aggregation and Its Inhibition.

In this paper, we propose a hydrogel-coated gate field-effect transistor (FET) for the real-time and label-free monitoring of ß-amyloid (Aß) aggregation and its inhibition. The hydrogel used in this study is composed of poly tetramethoxysilane (TMOS), in which Aß monomers are entrapped and then aggregate, and coated on the gate insulator; that is, Aß aggregation is induced in the vicinity of the sensing surface. With the Aß hydrogel-coated gate FET, the steplike decrease in the surface potential of the Aß hydrogel-coated gate electrode is electrically monitored in real time, according to the stepwise aggregation of Aß monomers to form into fibrils through oligomers and so forth in stages. This is because the capacitance of the Aß-hydrogel membrane decreases depending on the stage of aggregation; that is, the hydrophobicity of the Aß-hydrogel membrane increases stepwise depending on the amount of Aß aggregates. The formation of Aß fibrils is also confirmed in the measurement solution using a fluorescent dye, thioflavin T, which selectively binds to the Aß fibrils. Moreover, the addition of daunomycin, an inhibitor of Aß aggregation, to the measurement solution suppresses the stepwise electrical response of the Aß hydrogel-coated gate FET. Thus, a platform based on the Aß hydrogel-coated gate FET is suitable for a simple screening system for inhibitors of Aß aggregation, which may lead the identification of potential therapeutic agents for Alzheimer's disease.

Evaluation of Nitric Oxide Fluctuation Via a Fast, Responsive Fluorescent Probe in Idiopathic Pulmonary Fibrosis Cells and Mice Models.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial pneumonia with unknown pathogenesis. Early diagnosis and therapeutic intervention are essential for improving the prognosis of patients with IPF. The level of nitric oxide upregulates in the alveoli of IPF patients, which is correlated with the severity of the disease. Herein, we report a fluorescent probe DCM-nitric oxide (NO) to detect IPF by monitoring the concentration changes of NO. This probe displays a fast response time and a good linear response to NO in vitro. Fluorescence imaging experiments with probe DCM-NO revealed that the level of intracellular NO increases in the pulmonary fibrosis cells and IPF mice models. Probe DCM-NO displayed a strong red fluorescence in IPF mice models. However, a declining fluorescence was evidenced in the OFEV-treated IPF mice, implying that DCM-NO is capable of evaluating the therapeutic effects on IPF. Thus, probe DCM-NO can quickly predict the progression of pulmonary fibrosis at an early stage and thus help improve the effective treatment.

A Second Near-Infrared Ru(II) Polypyridyl Complex for Synergistic Chemo-Photothermal Therapy.

The clinical success of cisplatin ushered in a new era of the application of metallodrugs. When it comes to practice, however, drug resistance, tumor recurrence, and drug systemic toxicity make it implausible to completely heal the patients. Herein, we successfully transform an electron acceptor [1, 2, 5]thiadiazolo[3,4-g]quinoxaline into a novel second near-infrared (NIR-II) fluorophore H7. After PEGylation and chelation, HL-PEG2k exhibits a wavelength bathochromic shift, enhanced photothermal conversion efficiency (41.77%), and an antineoplastic effect against glioma. Its potential for in vivo tumor tracking and image-guided chemo-photothermal therapy is explored. High levels of uptake and high-resolution NIR-II imaging results are thereafter obtained. The hyperthermia effect could disrupt the lysosomal membranes, which in turn aggravate the mitochondria dysfunction, arrest the cell cycle in the G2 phase, and finally lead to cancer cell apoptosis. HL-PEG2k displays a superior biocompatibility and thus can be a potential theranostic platform to combat the growth and recurrence of tumors.