Multifunctional theranostic carbazole-based cyanine for real-time imaging of amyloid-ß and therapeutic treatment of multiple pathologies in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by the synaptic and neuronal loss, which results in cognitive impairment in particular learning and memory. Currently, AD is incurable and no single confirmative test can clinically be used to diagnose AD. In light of the complex and multifactorial nature of AD etiology, the development of multifunctional/multi-target drugs that act on multiple pathological pathways and mechanisms shows great therapeutic potential for intervention of this devastating disease. We report herein a multifunctional theranostic cyanine, SLCOOH, which serves not only as a highly sensitive fluorescent probe for real-time imaging of amyloid-ß (Aß) contents in different age groups of transgenic (Tg) AD mice but also as an effective therapeutic agent for early AD intervention via multiple pathological targets in the AD mouse model. Remarkably, treatment with SLCOOH gives rise to multiple therapeutic benefits, including the amelioration of cognitive decline, a reduction in Aß levels, a decrease in hyperphosphorylated tau proteins and tau depositions, and the alleviation of synaptic loss and dysfunctions in young triple Tg AD mice. Our results have demonstrated that in addition to superior Aß imaging capability, SLCOOH exhibits versatile and effective multiple modes of drug action, signifying outstanding therapeutic potential to treat early onset AD. Our work also paves the way for the development of effective Aß-targeted theranostic agents for AD.

Real-Time Detection and Visualization of Amyloid-ß Aggregates Induced by Hydrogen Peroxide in Cell and Mouse Models of Alzheimer's Disease.

Oxidative stress, caused by an imbalance between the production and the accumulation of reactive oxygen species (ROS), is a prominent cause of the neurotoxicity induced by aggregated amyloid-ß (Aß) in Alzheimer's disease (AD). Tools that can directly detect and monitor the presence and amount of Aß-induced ROS are still lacking. We report herein the first Aß-targeted ratiometric H2O2-responsive fluorescent probe for real-time detection and monitoring of the Aß-induced H2O2 level in cell and AD mouse models. The H2O2-responsive probe is constructed based on a methylamino-substituted quinolinium-based cyanine as the fluorescence moiety and a phenylboronate ester as the sensing reaction site. This sensing probe exhibits a large emission wavelength shift of ∼87 nm upon reacting with H2O2, a high binding selectivity for Aß, and a faster response toward H2O2 in the presence of Aß, concomitant with an enhanced fluorescence intensity, hence greatly boosting the sensitivity of in-situ H2O2 detection. This biocompatible and nontoxic probe is capable of ratiometrically detecting and imaging endogenous H2O2 induced by Aß in a neuronal cell model. Remarkably, this Aß-targeted H2O2-responsive probe is also able to detect, monitor, and differentiate different Aß-induced H2O2 levels in real time in different age groups of transgenic AD mice in which the cerebral H2O2 level increases age dependently concomitant with the plaque contents. Therefore, this smart probe can act as a powerful tool to diagnose high-risk subjects and diseased brains of AD and to further study the role of ROS in AD pathology.

Plasma amyloid-beta levels correlated with impaired hepatic functions: An adjuvant biomarker for the diagnosis of biliary atresia.

Background: Biliary atresia (BA) is an infantile fibro-obstructive cholestatic disease with poor prognosis. An early diagnosis and timely Kasai portoenterostomy (KPE) improve clinical outcomes. Aggregation of amyloid-beta (Aß) around hepatic bile ducts has been discovered as a factor for BA pathogenesis, yet whether plasma Aß levels correlate with hepatic dysfunctions and could be a biomarker for BA remains unknown. Method: Plasma samples of 11 BA and 24 controls were collected for liver function test, Aß40 and Aß42 measurement by enzyme-linked immunosorbent assay (ELISA). Pearson's chi-squared test or Mann-Whitney U test was performed to assess differences between groups. Correlation between Aß42/Aß40 and liver function parameters was performed using Pearson analysis. The area under the receiver-operative characteristic (ROC) curve (area under curve; AUC) was measured to evaluate the diagnostic power of Aß42/Aß40 for BA. Diagnostic enhancement was further evaluated by binary regression ROC analysis of Aß42/Aß40 combined with other hepatic function parameters. Results: Plasma Aß42/Aß40 was elevated in BA patients. Aß42 displayed a weak positive correlation with γ-glutamyl transpeptidase (GGT) (Pearson's correlation = 0.349), while there was no correlation for Aß40 with hepatic functions. Aß42/Aß40 was moderately correlated with GGT, total bile acid (TBA), direct bilirubin (DBIL) (Pearson's correlation = 0.533, 0.475, 0.480), and weakly correlated with total bilirubin (TBIL) (Pearson's correlation = 0.337). Aß42/Aß40 showed an acceptable predictive power for cholestasis [AUC = 0.746 (95% CI: 0.552-0.941), p < 0.05]. Diagnostic powers of Aß42/Aß40 together with hepatic function parameters for cholestasis were markedly improved compared to any indicator alone. Neither Aß42/Aß40 nor hepatic function parameters displayed sufficient power in discriminating BA from choledochal cysts (CC); however, combinations of Aß42/Aß40 + GGT along with any other hepatic function parameters could differentiate BA from CC-cholestasis (AUC = 1.000, p < 0.05) with a cut-off value as 0.02371, -0.28387, -0.34583, 0.06224, 0.01040, 0.06808, and 0.05898, respectively. Conclusion: Aß42/Aß40 is a good indicator for cholestasis, but alone is insufficient for a distinction of BA from non-BA. However, Aß42/Aß40 combined with GGT and one other hepatic function parameter displayed a high predictive power as a screening test for jaundiced neonates who are more likely to be BA, enabling them to early intraoperative cholangiography for BA confirmation and KPE to improve surgical outcomes. However, a multi-centers validation is needed before introduction into daily clinical practice.

Theranostic F-SLOH mitigates Alzheimer's disease pathology involving TFEB and ameliorates cognitive functions in Alzheimer's disease models.

Accumulation of amyloid-ß (Aß) oligomers and phosphorylated Tau aggregates are crucial pathological events or factors that cause progressive neuronal loss, and cognitive impairments in Alzheimer's disease (AD). Current medications for AD have failed to halt, much less reverse this neurodegenerative disorder; therefore, there is an urgent need for the development of effective and safe drugs for AD therapy. In the present study, the in vivo therapeutic efficacy of an Aß-oligomer-targeted fluorescent probe, F-SLOH, was extensively investigated in 5XFAD and 3XTg-AD mouse models. We have shown that F-SLOH exhibits an efficient inhibitory activity against Aß aggregation in vivo, and acts as an effective theranostic agent for the treatment of multiple neuropathological changes in AD mouse models. F-SLOH has been found to significantly reduce not only the levels of Aß oligomers, Tau aggregates and plaques but also the levels of amyloid precursor protein (APP) and its metabolites via autophagy lysosomal degradation pathway (ALP) in the brains of 5XFAD and 3XTg-AD mice. It also reduces astrocyte activation and microgliosis ultimately alleviating neuro-inflammation. Furthermore, F-SLOH mitigates hyperphosphorylated Tau aggregates, synaptic deficits and ameliorates synaptic memory function, and cognitive impairment in AD mouse models. The mechanistic studies have shown that F-SLOH promotes the clearance of C-terminal fragment 15 (CTF15) of APP and Paired helical filaments of Tau (PHF1) in stable cell models via the activation of transcription factor EB (TFEB). Moreover, F-SLOH promotes ALP and lysosomal biogenesis for the clearance of soluble, insoluble Aß, and phospho Tau. Our results unambiguously reveal effective etiological capabilities of theranostic F-SLOH to target and intervene multiple neuropathological changes in AD mouse models. Therefore, F-SLOH demonstrates tremendous therapeutic potential for treating AD in its early stage.

γ-Glutamyl transpeptidase-activated indole-quinolinium based cyanine as a fluorescence turn-on nucleolus-targeting probe for cancer cell detection and inhibition.

A nucleolus as a prominent sub-nuclear, membraneless organelle plays a crucial role in ribosome biogenesis, which is in the major metabolic demand in a proliferating cell, especially in aggressive malignancies. We develop a γ-glutamyltranspeptidase (GGT)-activatable indole-quinolinium (QI) based cyanine consisting of a novel tripeptide fragment (Pro-Gly-Glu), namely QI-PG-Glu as a turn-on red fluorescent probe for the rapid detection of GGT-overexpressed A549 cancer cells in vivo. QI-PG-Glu can be triggered by GGT to rapidly release an activated fluorophore, namely HQI, in two steps including the cleavage of the γ-glutamyl group recognized by GGT and the rapid self-driven cyclization of the Pro-Gly linker. HQI exhibits dramatically red fluorescence upon binding to rRNA for imaging of nucleolus in live A549 cells. HQI also intervenes in rRNA biogenesis by declining the RNA Polymerase I transcription, thus resulting in cell apoptosis via a p53 dependent signaling pathway. Our findings may provide an alternative avenue to develop multifunctional cancer cell-specific nucleolus-targeting fluorescent probes with potential anti-cancer effects.

Multimodal Theranostic Cyanine-Conjugated Gadolinium(III) Complex for In Vivo Imaging of Amyloid-ß in an Alzheimer's Disease Mouse Model.

Despite the wide use of magnetic resonance imaging (MRI) as a clinical diagnostic tool, there are still no clinically approved MRI contrast agents that can be applied for cerebral Alzheimer's disease (AD) biomarker imaging. We report here the design and development of the first amyloid-ß (Aß)-targeted, blood-brain barrier (BBB) penetrable theranostic Gd(DOTA)-cyanine dyad, which was synthesized by the conjugation of Gd(DOTA) complex and carbazole-based cyanine dye by the copper(I)-catalyzed azide-alkyne cycloaddition click reaction for imaging of Aß in vivo and ex vivo in AD mouse models. This dyad, as a multimodal probe, possesses desirable multifunctional properties, including good biocompatibility, low cytotoxicity, high Aß selectivity, strong fluorescence enhancement upon binding with Aß species, good paramagnetic properties, high stability, good BBB penetrability, and fast elimination from the mouse. The longitudinal relaxivity (r1) of the dyad was found to be 4.42 mM-1 s-1 at 3 T, suggesting it to be promising as a T1-weighted MRI contrast agent. The probe has been successfully demonstrated to be able to be applied for one- and two-photon excited fluorescence and magnetic resonance (MR) imaging of Aß in transgenic mouse models of AD. In addition, it can inhibit Aß aggregation, protect against toxicity induced by Aß, and suppress Aß-induced reactive oxygen species (ROS) production. Our results demonstrate the highly promising theranostic capability of the dyad for diagnosis and therapy of AD and extraordinary potential for MRI of Aß in humans.

Amyloid-ß oligomer targeted theranostic probes for in vivo NIR imaging and inhibition of self-aggregation and amyloid-ß induced ROS generation.

To enable the early detection and intervention of Alzheimer's disease (AD), it is highly desirable to develop novel theranostic agents for simultaneous detection of toxic and pathogenic amyloid-ß (Aß) oligomers in vivo and attenuation of Aß-induced toxicity. Herein, we report a new series of oligomeric Aß targeted near infrared (NIR) emissive dibutylnaphthylamine-based cyanine probes for in vivo and ex vivo imaging of Aß in AD mouse model. These new fluorophores exhibited strong solvatochromism and a large bathochromic shift of the emission spectrum upon binding with Aß species, giving rise to advantageous NIR emission. Besides, they showed an intriguingly stronger fluorescence enhancement upon interacting with Aß oligomers and monomers, and binding affinity toward Aß oligomers and monomers than Aß fibrils, suggesting they were selective to Aß oligomers and monomers. In addition to low toxicity, one of the fluorophores, DBAN-SLM, showed remarkably effective inhibitory effect on Aß aggregation, significant neuroprotection effect against the Aß-induced toxicities, and suppression on Aß-induced reactive oxygen species (ROS) generation. Because of excellent blood-brain barrier (BBB) permeability, good biocompatibility and stability, high specificity towards Aß oligomers as well as strong turn-on fluorescence upon Aß binding, DBAN-SLM was successfully applied for in vivo and ex vivo imaging of Aß in AD mouse model, signifying its great promise as a useful theranostic agent for the early diagnosis and therapy of AD. Our results also demonstrated for the first time that the dibutyl-2-naphthylamine moiety is a useful and effective structural building block to promote the targeting capability of oligomeric Aß.

A benzothiazolium-based fluorescent probe with ideal pKa for mitochondrial pH imaging and cancer cell differentiation.

A mitochondrial pH sensing fluorescent probe namely 2-(2-(6-hydroxynaphthalen-2-yl)vinyl)-3-(6-(triphenyl-phosphonio)hexyl)benzothiazol-3-ium bromide (HTBT2) was designed and facilely synthesized via the Knoevenagel condensation reaction. HTBT2 displayed a linear fluorescence enhancement at 612 nm in response to pH changes between 8.70 and 7.20. The pKa value was determined to be 8.04 ± 0.02, which might be ideal for mitochondrial pH (pHmito∼8.0) detection. HTBT2 also exhibited a remarkable large Stokes shift of 176 nm, which could diminish the interference of excitation light. The results of live cell imaging studies suggested that HTBT2 showed excellent targeting ability for mitochondria. Importantly, it was successfully applied to visualize mitochondrial pH changes in live cells and differentiate the pHmito difference between cancer cell lines and normal cell lines. Our results consistently supported that HTBT2 held practical promise for the investigation of physiological processes related to pHmito changes and clinical potential for cancer cell differentiation.

Deep Red Blinking Fluorophore for Nanoscopic Imaging and Inhibition of ß-Amyloid Peptide Fibrillation.

Deposition and aggregation of ß-amyloid (Aß) peptides are demonstrated to be closely related to the pathogenesis of Alzheimer's disease (AD). Development of functional molecules capable of visualizing Aß1-40 aggregates with nanoscale resolution and even modulating Aß assembly has attracted great attention recently. In this work, we use monocyanine fluorophore as the lead structure to develop a set of deep red carbazole-based cyanine molecules, which can specifically bind with Aß1-40 fibril via electrostatic and van der Waals interactions. Spectroscopic and microscopic characterizations demonstrate that one of these fluorophores, (E)-1-(2-(2-methoxyethoxy)ethyl)-4-(2-(9-methyl-9H-carbazol-3-yl)vinyl) quinolinium iodide (me-slg) can bind to Aß1-40 aggregates with strong fluorescence enhancement. The photophysical properties of me-slg at the single-molecule level, including low "on/off" duty cycle, high photon output, and sufficient switching cycles, enable real-time nanoscopic imaging of Aß1-40 aggregates. Morphology-dependent toxic effect of Aß1-40 aggregates toward PC12 cells is unveiled from in situ nanoscopic fluorescence imaging. In addition, me-slg displays a strong inhibitory effect on Aß1-40 fibrillation in a low inhibitor-protein ratio (e.g., I:P = 0.2). A noticeably reduced cytotoxic effect of Aß1-40 after the addition of me-slg is also confirmed. These results afford promising applications in the design of a nanoscopic imaging probe for amyloid fibril as well as the development of inhibitors to modulate the fibrillation process.

Hypoxia imaging in living cells, tissues and zebrafish with a nitroreductase-specific fluorescent probe.

Hypoxia in solid tumors is directly linked to the elevated levels of endogenous nitroreductase (NTR). We present a novel fluorescent probe, namely NTNO, for nitroreductase-specific detection based on the NTR-catalyzed reduction of the nitro unit to an amine functionality, and demonstrated its application for hypoxia imaging. NTNO was designed by incorporating a nitro unit as the NTR response site into a benzothiazole derivative. Upon reacting with NTR in the presence of reduced nicotinamide adenine dinucleotide (NADH), the fluorescence of the probe was strongly and sensitively turned on, with a good linearity in the NTR concentration range of 0.5-8.0 µg mL-1 and a detection limit of 48 ng mL-1. Most notably, NTNO has been successfully used for imaging hypoxia levels in living cells, tumor tissues and zebrafish, making it of great potential to monitor NTR in biological systems.

Cognitive improvement and synaptic deficit attenuation by a multifunctional carbazole-based cyanine in AD mice model through regulation of Ca2+/CaMKII/CREB signaling pathway.

Accumulation of ß-amyloid (Aß) peptide and hyperphosphorylated tau in the brain is one of the pathological characteristics of Alzheimer's disease (AD) and attractive therapeutic targets in its treatment. In the present study, the cognitive ability of 4-month-old 3 × Tg-AD mice significantly improved after 40 days treatment with intraperitoneal injection of 2.25 mg/kg of SLOH, which is a multifunctional carbazole-based cyanine fluorophore. It reduced Aß deposition, tau levels and its hyperphosphorylation by modulating AKT and promoting protein phosphatase 2A activity in the brain as well as in the primary neurons of 3 × Tg-AD mice. Moreover, SLOH attenuated synaptic deficit both in vitro and in vivo by regulating the Ca2+/CaMKII/CREB signaling pathway. These findings strongly suggest that SLOH owns a high therapeutic potential to treat early onset AD.

The ratiometric fluorescent probe with high quantum yield for quantitative imaging of intracellular pH.

Intracellular pH, especially cytoplasmic pH (~7.2) plays a crucial role in cell functions and metabolism. A ratiometric fluorescent probe namely, 6-(2-(benzothiazol-2-yl)vinyl)naphthalen-2-ol (BTNO) was facilely synthesized by the condensation of 6-hydroxy-2-naphthaldehyde and 2-methylbenzothiazole. BTNO exhibited a remarkable ratiometric emission (F456/F526) enhancement in response to a pH change with a linear range of pH = 9.50-7.00 and a pKa value of 7.91 ±â€¯0.03, which is desirable for measuring and monitoring the cytoplasmic pH fluctuations. In addition, because of the high fluorescence quantum yield of BTNO (Φ = 0.88 in DMSO and 0.61 in water relative to quinine sulfate solution in 0.1 M H2SO4), the interferences of the probe on the physiological functions could be greatly reduced. This could also provide enhanced measurement sensitivity. The successful demonstration of BTNO in detecting and monitoring the intracellular pH changes in live HeLa cells via a ratiometric approach confirmed that BTNO held a practical potential in biomedical research.

Amyloid-ß Aggregation Inhibitory and Neuroprotective Effects of Xanthohumol and its Derivatives for Alzheimer's Diseases.

BACKGROUND: Xanthohumol has been reported to have cytoprotection through activation of Nrf2-ARE signaling pathway and; it has capability of scavenging free radicals, suggesting its potential for the prevention of neurodegeneration. However, the bio-incompatibility and blood-brain barrier impermeability of xanthohumol hindered its in vivo efficacy potential for treating Alzheimer's disease (AD). OBJECTIVE: We designed and prepared a series of xanthohumol derivatives to enhance the desirable physical, biological and pharmacological properties in particular the blood-brain barrier permeability for intervention of AD. METHODS: We designed and synthesized a novel series of 9 xanthohumol derivatives. Their inhibitory effect on amyloid-ß (1-42), Aß1-42, oligomerization and fibrillation as well as neuroprotection against amyloid-ß induced toxicities, were explored. RESULTS: Among the 9 xanthohumol derivatives, some of them exhibited a moderate to high inhibitory effect on Aß1-42 oligomerization and fibrillation. They were biocompatible and neuroprotective to the SH-SY5Y cells by reducing the ROS generation and calcium uploading that were induced by the amyloid- ß. Importantly, two of the derivatives were found to be blood-brain barrier permeable showing promising potential for AD treatment. CONCLUSION: Two derivatives have been identified to be biocompatible, non-toxic, neuroprotective against Aß-induced toxicities and blood-brain barrier permeable highlighting their promising potential as AD drug candidates for future clinical use.

Tuning the pKa of two-photon bis-chromophoric probes for ratiometric fluorescence imaging of acidic pH in lysosomes.

Lysosomes are organelles containing many hydrolytic enzymes responsible for degrading macromolecules. Abnormal lysosomal pH changes are known to associate with dysfunction of cells linking to various diseases such as cancer and neurodegenerative disorders. Thus, it is of paramount importance to monitor lysosomal pH changes in order to investigate the pathological conditions. We report herein two novel, highly sensitive and fast responsive bis-chromophoric ratiometric two-photon fluorescent probes with different emission wavelengths, namely VP and VL for acidic pH sensing in live cells. Importantly, by adopting bis-chromophoric approach, the VP and VL probes bearing pyridyl and quinolyl as acid sensing sites exhibit pKa values of 4.62 and 5.26, respectively, which are ideal for quantitative analysis of lysosomal pH changes in live cells. These two biocompatible probes are not only highly lysosomal targeting, sensitive towards pH change with distinct emission color shifting but also highly two-photon active in cells with excellent photostability and reversibility. These probes were successfully applied to ratiometrically track and image pH fluctuation in lysosomes of HeLa cells by one- and two-photon excited fluorescence microscopy. For the first time, we have demonstrated here that the bis-chromophoric strategy is a useful tool to effectively modify and tune the pKa of a fluorescent probe.

Novel long-wavelength emissive lysosome-targeting ratiometric fluorescent probes for imaging in live cells.

Lysosomes are acidic organelles containing many hydrolytic enzymes responsible for degrading macromolecules. Aberrant lysosomal pH changes are known to associate with lysosomal dysfunctions linking to various diseases including cancer and neurodegenerative disorders. Thus, it is of paramount importance to monitor lysosomal pH changes in order to investigate the pathological conditions. We report herein two novel, highly sensitive and fast responsive carbazole-based ratiometric fluorescent probes with different emission wavelengths, namely MCDBI and MCDI for lysosomal pH detection and imaging. Importantly, the MCDBI and MCDI probes bearing indole and benzoindoles as acid-sensing sites exhibit pKa values of 4.26 and 4.51, respectively, which are ideal for the quantitative analysis of lysosomal pH changes in living cells. These probes exhibited a strong pH-dependent behavior and responded linearly and rapidly to minor pH fluctuations. Moreover, the two biocompatible probes are highly lysosomal targeting, sensitive towards H+ over metal ions and some bioactive molecules, and exhibit excellent photostability and good reversibility. These probes have excellent cell membrane permeability and are further applied successfully to monitor lysosomal pH fluctuations in the lysosomes of HepG2 cells.

Highly sensitive quantification of Alzheimer's disease biomarkers by aptamer-assisted amplification.

Alzheimer's disease (AD), a chronic neurodegenerative disease associated with the loss of neurons in the brain, is the most pervasive type of dementia; 47 million people are affected, and the number is expected to increase to more than 131 million by 2050, according to Alzheimer's Disease International. Both early diagnosis and continuous monitoring are crucial for early intervention, symptomatic treatment, monitoring of the efficacy of intervention and improved patient function. Beta-amyloid peptide, tau, and phosphorylated tau are useful for screening and diagnosis; meanwhile, simultaneous assessment of multiple biomarkers is of paramount importance for accurate disease diagnosis. Methods: Herein, we report a direct, inexpensive and ultrasensitive aptamer-based multiplex assay for the quantification of trace amounts of AD biomarkers in both human serum and cerebrospinal fluid (CSF) samples. In this newly developed assay, molecular recognition of an antibody-aptamer pair provides high specificity in target detection, and the use of a DNA amplification strategy affords high sensitivity, allowing quantification of AD biomarkers in both biological fluids in 1.5 h with only a diminutive amount of the sample consumed. A tailor-made turn-on fluorophore, namely, SPOH, was employed to label the antibody-aptamer hybrids and provide a strong fluorescence signal, which was then detected with a total internal reflection fluorescence microscopy electron-multiplying charge-coupled device (TIRFM-EMCCD) imaging system. The simultaneous detection of biomarkers was achieved by a direct shape-coded method in which the nanoplatforms can be distinguished from one another by their morphologies. Results: This assay demonstrated a lower detection limit (in the femtomolar range) for AD biomarkers than the previously reported antibody-antibody method. Conclusion: The developed assay holds tremendous clinical potential for early diagnosis of AD and monitoring of its progression.

Differentiation of Intracellular Hyaluronidase Isoform by Degradable Nanoassembly Coupled with RNA-Binding Fluorescence Amplification.

Hyaluronidase has two cruical isoforms, hyaluronidase-1 (Hyal-1) and hyaluronidase-2 (Hyal-2), which are essential for cellular hyaluronic acid (HA) catabolism to generate different-sized oligosaccharide fragments for performing different physiological functions. In particular, Hyal-1 is the major tumor-derived hyaluronidase. Thus, specific detection of one hyaluronidase isoform, especially Hyal-1, in live cells is of scientific significance but remains challenging. Herein, by use of differentiated tolerance capability of an amphiphilic HA-based nanoassembly to Hyal-1 and Hyal-2, we rationally design a Hyal-1 specific nanosensor, consisting of cholesterylamine-modified HA nanoassembly (CHA) and RNA-binding fluorophores (RBF). The RBF molecules were entrapped in CHA to switch off their fluorescence via aggregation caused quenching. However, CHA can be disassembled by Hyal-1 to release RBF, resulting in fluorescence activation. Moreover, the fluorescence of the released RBF is further enhanced by cytoplasm RNA. Owing to this cascade signal amplification, this nanosensor RBF@CHA displays a significant change of signal-to-background-noise ratio (120-fold) toward 16 µg/mL Hyal-1 in cellular lysates. In contrast, it is resistant to Hyal-2. By virtue of its selective and sensitive characteristics under a complicated matrix, RBF@CHA had been successfully applied for specifically visualizing Hyal-1 over Hyal-2 inside live cells for the first time, detecting a low level of intracellular Hyal-1 and distinguishing normal and cancer cells with different expressions of Hyal-1. This approach would be useful to better understand biological functions and related diseases of intracellular Hyal-1.

Versatile fluorescent probes for near-infrared imaging of amyloid-ß species in Alzheimer's disease mouse model.

The self-aggregation of amyloid-ß peptides into soluble oligomers and then into insoluble fibril-associated amyloid plaques is a key event in the progression of Alzheimer's disease (AD). The imaging of Aß aggregates in the brain is a powerful and practical approach for the diagnosis and progression monitoring of AD and the evaluation of the effectiveness of novel therapies for this devastating disease. Near-infrared (NIR) imaging is a sensitive and noninvasive method to detect and visualize Aß aggregates in vivo because of its good penetration depth and low autofluorescence of biological substances. In this article, we comprehensively reviewed the recent progresses made in the development of molecular NIR fluorescent probes for Aß detection and imaging in vivo with a particular emphasis on the design strategies, optical characteristics, Aß-binding abilities and potential applications in AD mouse models.

Benzodithiophene-Dithienylbenzothiadiazole Copolymers for Efficient Polymer Solar Cells: Side-Chain Effect on Photovoltaic Performance.

A new series of low band gap D-A alternating polymers based on 4,5-bis((2-ethylhexyl)oxy)benzo[2,1- b:3,4- b']dithiophene (BDT) and 5-fluoro-4,7-bis(4-alkylthien-2-yl)benzo[ c][1,2,5]thiadiazole bearing different size of lateral alkyl substituents, namely, PfBB- n, n = 8, 10, 12, 14, and 16, was designed and synthesized for high-performance bulk heterojunction (BHJ) polymer solar cells (PSCs). PfBB- n-bearing linear alkyl side chains exhibited strong and controllable aggregation in both solution and solid states, which gives rise to a significant bathochromic shift of the absorption cut-off down to ∼780 nm in thin film. In addition, the strong and wide absorption (350-800 nm) of PfBB- n polymers can compensate for the relatively weak absorption of PC71BM, particularly in the 300-400 range nm to enhance light harvesting of such an active blend. BHJ solar cells based on PfBB- n:PC71BM blends as an active layer showed power conversion efficiency (PCE) in the range 7.8-9.7%. Because of the strong stacking interchain interactions, PfBB-12-based PSC exhibited aggregation-induced spectral broadening, superior structural order, higher exciton dissociation, higher and more balanced charge carrier mobilities, as well as reduced recombination losses. As a result, PfBB-12-based device afforded the best PCE of 9.7%, with the highest short-circuit current density ( Jsc) of 16.6 mA cm-2 and open-circuit voltage ( Voc) of 0.92 V among devices fabricated. These results demonstrate that the alkyl side chain of the polymer significantly affects the absorption, morphology, and electronic properties of the active blend of PfBB- n/PC71BM, which would provide an alternative useful tool to fine-tune the device performance. Our results also highlight that the electron-rich benzo[2,1- b:3,4- b']dithiophene building block, BDT, is highly useful for the construction of low band gap D-A polymer for highly efficient PSCs.