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.

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.

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.

A Zero Cross-Talk Ratiometric Two-Photon Probe for Imaging of Acid pH in Living Cells and Tissues and Early Detection of Tumor in Mouse Model.

Acid-base disorders disrupt proper cellular functions, which are associated with diverse diseases. Development of highly sensitive pH probes being capable of detecting and monitoring the minor changes of pH environment in living systems is of considerable interest to diagnose disease as well as investigate biochemical processes in vivo. We report herein two novel high-resolution ratiometric two-photon (TP) fluorescent probes, namely, PSIOH and PSIBOH derived from carbazole-oxazolidine π-conjugated system for effective sensing and monitoring acid pH in a biological system. Remarkably, PSIOH exhibited the largest emission shift of ∼169 nm from 435 to 604 nm upon pH changing from basic to acidic with an ideal p Ka value of 6.6 within a linear pH variation range of 6.2-7.0, which is highly desirable for high-resolution tracking and imaging the minor fluctuation of pH in live cells and tissues. PSIOH also exhibits high pH sensitivity, excellent photostability, and reversibility as well as low cytotoxicity. More importantly, this probe was successfully applied to (i) sense and visualize the pH alteration in HeLa cells caused by various types of exogenous stimulation and (ii) detect and differentiate cancer and tumors in liver tissues and a mouse model, realizing its practical in vitro and in vivo applications.

Dual-Modal NIR-Fluorophore Conjugated Magnetic Nanoparticle for Imaging Amyloid-ß Species In Vivo.

Senile plaques, the extracellular deposit of amyloid-ß (Aß) peptides, are one of the neuropathological hallmarks found in Alzheimer's disease (AD) brain. The current method of brain imaging of amyloid plaques based on positron emission tomography (PET) is expensive and invasive with low spatial resolution. Thus, the development of sensitive and nonradiative amyloid-ß (Aß)-specific contrast agents is highly important and beneficial to achieve early AD detection, monitor the disease progression, and evaluate the effectiveness of potential AD drugs. Here a neuroprotective dual-modal nanoprobe developed by integrating highly Aß-specific and turn-on fluorescence cyanine sensors with superparamagnetic iron oxide nanoparticles as an effective near-infrared imaging (NIRI)/magnetic resonance imaging (MRI) contrast agent for imaging of Aß species in vivo is reported. This Aß-specific probe is found not only nontoxic and noninvasive, but also highly blood brain barrier permeable. It also shows a potent neuroprotective effect against Aß-induced toxicities. This nanoprobe is successfully applied for in vivo fluorescence imaging with high sensitivity and selectivity to Aß species, and MRI with high spatial resolution in an APP/PS1 transgenic mice model. Its potential as a powerful in vivo dual-modal imaging tool for early detection and diagnosis of AD in humans is affirmed.

Highly Selective Two-Photon Fluorescent Probe for Ratiometric Sensing and Imaging Cysteine in Mitochondria.

A novel ratiometric mitochondrial cysteine (Cys)-selective two-photon fluorescence probe has been developed on the basis of a merocyanine as the fluorophore and an acrylate moiety as the biothiol reaction site. The biocompatible and photostable acrylate-functionalized merocyanine probe shows not only a mitochondria-targeting property but also highly selective detection and monitoring of Cys over other biothiols such as homocysteine (Hcy) and glutathione (GSH) and hydrogen sulfide (H2S) in live cells. In addition, this probe exhibits ratiometric fluorescence emission characteristics (F518/F452), which are linearly proportional to Cys concentrations in the range of 0.5-40 µM. More importantly, the probe and its released fluorophore, merocyanine, exhibit strong two-photon excited fluorescence (TPEF) with two-photon action cross-section (Φσmax) of 65.2 GM at 740 nm and 72.6 GM at 760 nm in aqueous medium, respectively, which is highly desirable for high contrast and brightness ratiometric two-photon fluorescence imaging of the living samples. The probe has been successfully applied to ratiometrically image and detect mitochondrial Cys in live cells and intact tissues down to a depth of 150 µm by two-photon fluorescence microscopy. Thus, this ratiometric two-photon fluorescent probe is practically useful for an investigation of Cys in living biological systems.

Mitochondrial Delivery of Therapeutic Agents by Amphiphilic DNA Nanocarriers.

The first example of mitochondrial delivery of the anticancer drug doxorubicin (Dox) is presented by lipid-functionalized DNA nanocages (LNCs). Dox localized in mitochondria induces significant cytotoxicity and cellular apoptosis in MCF-7 compared with Dox localized in lysosomes. These results suggest that LNC has the potential to be an outstanding tool in the treatment of specific organelle-related diseases such as cancers.

Highly Efficient Multiphoton-Pumped Frequency-Upconversion Stimulated Blue Emission with Ultralow Threshold from Highly Extended Ladder-Type Oligo(p-phenylene)s.

A series of highly extended π-conjugated ladder-type oligo(p-phenylene)s containing up to 10 phenyl rings with (L)-Ph(n)-NPh (n=7-10) or without diphenylamino endcaps (L)-Ph(n) (n=7 and 8) were synthesized and investigated for their multiphoton absorption properties for frequency upconverted blue ASE/lasing. Extremely large two-photon absorption (2PA) cross-sections and highly efficient 2PA ASE/lasing with ultralow threshold were achieved. (L)-Ph(10)-NPh exhibits the highest intrinsic 2PA cross-section of 3643 GM for a blue emissive organic fluorophore reported so far. The record-high 2PA pumped ASE/lasing efficiency of 2.06 % was obtained by un-endcapped oligomer, (L)-Ph(8) rather than that with larger σ2 , suggesting that a molecule with larger σ2 is not guaranteed to exhibit higher η2 . All of these oligomers exhibit exceptionally ultralow 2PA pumped ASE/lasing thresholds, among which the lowest 2PA pumped threshold of circa 0.26 µJ was achieved by (L)-Ph(10)-NPh.

Ratiometric emission fluorescent pH probe for imaging of living cells in extreme acidity.

A novel ratiometric emission fluorescent probe, 1,1-dimethyl-2-[2-(quinolin-4-yl)vinyl]-1H-benzo[e]indole (QVBI), is facilely synthesized via ethylene bridging of benzoindole and quinoline. The probe exhibits ratiometric fluorescence emission (F(522nm)/F(630nm)) characteristics with pKa 3.27 and linear response to extreme-acidity range of 3.8-2.0. Also, its high fluorescence quantum yield (Φ = 0.89) and large Stokes shift (110 nm) are favorable. Moreover, QVBI possesses highly selective response to H(+) over metal ions and some bioactive molecules, good photostability, and excellent reversibility. The probe has excellent cell membrane permeability and is further applied successfully to monitor pH fluctuations in live cells and imaging extreme acidity in Escherichia coli cells without influence of autofluorescence and native cellular species in biological systems.

Molecular engineering of a theranostic molecule that detects Aß plaques, inhibits Iowa and Dutch mutation Aß self-aggregation and promotes lysosomal biogenesis for Alzheimer's disease.

Extracellular clustering of amyloid-ß (Aß) and an impaired autophagy lysosomal pathway (ALP) are the hallmark features in the early stages of incurable Alzheimer's disease (AD). There is a pressing need to find or develop new small molecules for diagnostics and therapeutics for the early stages of AD. Herein, we report a small molecule, namely F-SLCOOH, which can bind and detect Aß1-42, Iowa mutation Aß, Dutch mutation Aß fibrils and oligomers exhibiting enhanced emission with high affinity. Importantly, F-SLCOOH can readily pass through the blood-brain barrier and shows highly selective binding toward the extracellular Aß aggregates in real-time in live animal imaging of a 5XFAD mice model. In addition, a high concentration of F-SLCOOH in both brain and plasma of wildtype mice after intraperitoneal administration was found. The ex vivo confocal imaging of hippocampal brain slices indicated excellent colocalization of F-SLCOOH with Aß positive NU1, 4G8, 6E10 A11 antibodies and THS staining dye, affirming its excellent Aß specificity and targetability. The molecular docking studies have provided insight into the unique and specific binding of F-SLCOOH with various Aß species. Importantly, F-SLCOOH exhibits remarkable anti-fibrillation properties against toxic Aß aggregate formation of Aß1-42, Iowa mutation Aß, and Dutch mutation Aß. F-SLCOOH treatment also exerts high neuroprotective functions and promotes autophagy lysosomal biogenesis in neuronal AD cell models. In summary, the present results suggest that F-SLCOOH is a highly promising theranostic agent for diagnosis and therapeutics of AD.

Fluorescence-enhanced chemosensor for metal cation detection based on pyridine and carbazole.

A series of donor-acceptor systems incorporating a carbazole moiety as the donating unit and pyridine moiety as the accepting unit have been designed and synthesized. The spectroscopic and electrochemical behaviors of the carbazole derivatives demonstrate that the carbazole unit interacts with the electron-accepting group through the π-conjugated spacer, thus leading to the intramolecular charge transfer (ICT). The pyridine-substituted carbazole derivatives show significant sensing and coordinating properties toward a wide range of metal cations. Compound S2 exhibits fluorescence enhancement upon association with transition metal cations, and compound V3 shows high selectivity for Cu(2+) among this series of materials. DFT calculations indicate the different association abilities of the dyes and the enhancement of ICT upon addition of the metal cations.

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.

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.

Exceptionally strong multiphoton-excited blue photoluminescence and lasing from ladder-type oligo(p-phenylene)s.

We report the synthesis and investigation of multiphoton absorption properties of a novel series of diphenylamino-end-capped ladder-type oligo(p-phenylene)s which exhibit greatly enhanced and efficient multiphoton (from two- to five-photon) upconverted blue photoluminescence with which the record-high intrinsic three-photon absorption cross-section of 4.56 × 10(-76) cm(6) s(2) in the femtosecond regime has been obtained. Exceptionally efficient two- to five-photon-excited lasing in the blue region has also been demonstrated in which the highest two-photon-excited lasing efficiency of 0.34% has been achieved.

Reinforced self-assembly of donor-acceptor π-conjugated molecules to DNA templates by dipole-dipole interactions together with complementary hydrogen bonding interactions for biomimetics.

One of the most important criteria for the successful DNA-templated polymerization to generate fully synthetic biomimetic polymers is to design the complementary structural monomers, which assemble to the templates strongly and precisely before carrying polymerization. In this study, water-soluble, laterally thymine-substituted donor-acceptor π-conjugated molecules were designed and synthesized to self-assemble with complementary oligoadenines templates, dA(20) and dA(40), into stable and tubular assemblies through noncovalent interactions including π-π stacking, dipole-dipole interactions, and the complementary adenine-thymine (A-T) hydrogen-bonding. UV-vis, fluorescence, circular dichroism (CD), atomic force microscopy (AFM), and transmission electron microscopy (TEM) techniques were used to investigate the formation of highly robust nanofibrous structures. Our results have demonstrated for the first time that the dipole-dipole interactions are stronger and useful to reinforce the assembly of donor-acceptor π-conjugated molecules to DNA templates and the formation of the stable and robust supramolecular nanofibrous complexes together with the complementary hydrogen bonding interactions. This provides an initial step toward DNA-templated polymerization to create fully synthetic DNA-mimetic polymers for biotechnological applications. This study also presents an opportunity to precisely position donor-acceptor type molecules in a controlled manner and tailor-make advanced materials for various biotechnological applications.

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.

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.

Highly efficient multiphoton-absorbing quadrupolar oligomers for frequency upconversion.

Two series of quadrupolar diphenylamino-endcapped oligofluorenes, PhN-OF(n)-NPh (n=2-5) and PhN-OF(n)-TAZ-OF(n)-NPh (n=1-4), which have an electron-withdrawing 1,2,4-triazole (TAZ) moiety as central core, with D-π-A-π-D structural motif (D=donor, A=acceptor), have been synthesized by palladium-catalyzed Suzuki cross-coupling of 9,9-dibutyl-7-(diphenylamino)-2-fluorenylboronic acid and the corresponding (1,2,4-triazole-based) aryl halide as key step. On pumping with infrared femtosecond lasers, these oligomers showed very strong multiphoton-excited blue photoluminescence. These D-π-D and D-π-A-π-D quadrupolar oligofluorenes exhibit superior three-photon absorption properties compared to the respective D-π-A counterparts with a highest three-photon absorption cross-section (σ(3)) of up to 2.72×10(-77) cm(6) s(2) . Despite the comparable linear and multiphoton absorption properties of the two types of quadrupolar oligomers PhN-OF(n)-NPh and PhN-OF(n)-TAZ-OF(n)-NPh, only the former exhibit remarkably intense and highly efficient multiphoton-excited frequency-upconverted deep blue lasing, which gives rise to record high lasing efficiency of 0.097% and very narrow of full width at half-maximum of the lasing spectra. Our findings suggest that quadrupolar-type molecules/oligomers are superior for multiphoton excited frequency upconverted lasing to their dipolar counterparts and also provide important guidelines to design highly efficient three-photon absorption molecules for photoluminescence and lasing applications.

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.