Planar-structured thiadiazoloquinoxaline-based NIR-II dye for tumor phototheranostics.

Second near-infrared (NIR-II) fluorescence imaging shows huge application prospects in clinical disease diagnosis and surgical navigation, while it is still a big challenge to exploit high performance NIR-II dyes with long-wavelength absorption and high fluorescence quantum yield. Herein, based on planar π-conjugated donor-acceptor-donor systems, three NIR-II dyes (TP-DBBT, TP-TQ1, and TP-TQ2) were synthesized with bulk steric hindrance, and the influence of acceptor engineering on absorption/emission wavelengths, fluorescence efficiency and photothermal properties was systematically investigated. Compared with TP-DBBT and TP-TQ2, the TP-TQ1 based on 6,7-diphenyl-[1,2,5]thiadiazoloquinoxaline can well balance absorption/emission wavelengths, NIR-II fluorescence brightness and photothermal effects. And the TP-TQ1 nanoparticles (NPs) possess high absorption ability at a peak absorption of 877 nm, with a high relative quantum yield of 0.69% for large steric hindrance hampering the close π-π stacking interactions. Furthermore, the TP-TQ1 NPs show a desirable photothermal conversion efficiency of 48% and good compatibility. In vivo experiments demonstrate that the TP-TQ1 NPs can serve as a versatile theranostic agent for NIR-II fluorescence/photoacoustic imaging-guided tumor phototherapy. The molecular planarization strategy provides an approach for designing efficient NIR-II fluorophores with extending absorption/emission wavelength, high fluorescence brightness, and outstanding phototheranostic performance.

Sulfone/Carbonyl-Based Donor-Acceptor Fluorescent Dyes: Synthesis, Structures, Photophysical Properties and Cell Imaging.

Electron-accepting units play vital roles in constructing donor-acceptor (D-A) conjugated organic optoelectronic materials; the electronic structures and functions of the acceptors need to be carefully unveiled to controllably tailor the optoelectronic properties. We have synthesized two D-A conjugated organic fluorophores, TPA-SO and TPA-CO, with similar molecular skeletons based on sulfone- or carbonyl-containing polycyclic aromatic acceptors. Both TPA-SO and TPA-CO display obvious solvent polarity-dependent photophysical properties and large Stokes shift of over 100 nm for strong intramolecular charge transfer processes. Experimental evidence indicates that the sulfone group in TPA-SO merely serves as a strong electron-withdrawing unit. TPA-SO shows yellowish-green emission with a peak at 542 nm and an absolute photoluminescence quantum yield (PLQY) of 98 % in solution, whereas the carbonyl group in TPA-CO can act as both an electron-withdrawing unit and spin transition convertor, so TPA-CO displays red emission with a low absolute PLQY of 0.32 % in solution. Impressively, upon going from solution to aggregate state, TPA-SO nanoparticles keep a high PLQY of 9.5 % and moderate biocompatibility, thus they are good nano-agents for cellular fluorescence imaging. The results reveal that the inherent acceptor characteristic acts as a crucial effect in the photophysical properties and applications of the organic fluorophores.

Heterojunction MnO2-nanosheet-decorated Ag nanowires with enhanced oxidase-like activity for the sensitive dual-mode detection of glutathione.

The biocatalytic design of nanomaterials with enzyme-like activity is considered a reliable and promising toolkit for the generation of diagnostic agents in complex biological microenvironments. However, the preparation of nanomaterials while maintaining a high catalytic activity in tumor cells (pH 6.0-6.5) poses a prominent challenge. Herein, we constructed a biomimetic enzyme-trigged dual-mode system with colorimetry at 652 nm and photothermal biosensors to detect glutathione based on hollow MnO2-nanosheet-decorated Ag nanowires (Ag@MnO2) as an oxidase-like nanozyme. As expected, Ag@MnO2 catalyzed the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in the absence of H2O2, leading to a blue-colored oxidized TMB (oxTMB) that displayed oxidase-like activity in pH 6.0. Interestingly, the portable dual-mode colorimetry and photothermal method for GSH was developed based on the redox reaction between GSH and oxTMB. This detection method exhibited a wide linear range of 0.1-55 µM for GSH with a low detection limit of 0.08 µM. This work highlights a new insight into nanotechnology by taking advantage of biomimetic design in biological analysis.

Biodegradable Charge-Transfer Complexes for Glutathione Depletion Induced Ferroptosis and NIR-II Photoacoustic Imaging Guided Cancer Photothermal Therapy.

Suffering from the laborious synthesis and undesirable tumor microenvironment response, the exploitation of novel NIR-II absorbing organic photothermal agents is of importance to promote phototherapeutic efficacy. Herein, two kinds of charge-transfer complex nanoparticles (TMB-F4TCNQ and TMB-TCNQ) are prepared by supramolecular assembly. Because of the larger energy gap between donor and acceptor, TMB-F4TCNQ presents higher charge-transfer degree (72 %) than that of TMB-TCNQ (48 %) in nanoaggregates. Therefore, TMB-F4TCNQ exhibits stronger NIR-II absorption ability with a mass extinction coefficient of 15.4 Lg-1 cm-1 at 1300 nm and excellent photothermal effect. Impressively, the specific cysteine response can make the TMB-F4TCNQ effectively inhibit the intracellular biosynthesis of GSH, leading to redox dsyhomeostasis and ROS-mediated ferroptosis. TMB-F4TCNQ can serve as a contrast agent for NIR-II photoacoustic imaging to guide precise and efficient photothermal therapy in vivo.

Biomimetic theranostic strategy for anti-metastasis therapy of breast cancer via the macrophage membrane camouflaged superparticles.

The rational design of theranostic systems are critical for addressing challenging issues associated with cancers. Toward this objective, the multifunctional biomimetic superparticle, termed as DOX-QDs-Lip@M, which can specifically deliver drug to tumor and synergistically monitor their therapeutic effects, was fabricated. Initially, anticancer drug doxorubicin hydrochloride (DOX) and imaging agent quaternary quantum dots (QDs) were loaded into the hydrophilic core region and hydrophobic chamber of liposome by self-assembly method, respectively. The integrated nanostructure can greatly increase the fluorescence intensity of signal unit and tremendously improve the diagnostic sensitivity. Subsequently, the biomimetic DOX-QDs-Lip@M was constructed by fusing and coating the isolated macrophage membranes on the surface of liposome, which can consequently extend the circulation of the whole blood and effectively target the tumor sites. Moreover, the naturally formed biofilm can stabilize the artificial liposome structure, which can prevent the leakage of the loaded materials in the liposome. These integrated properties endow the biomimetic DOX-QDs-Lip@M with improved tumor imaging and anti-metastasis treatment in living systems.

A dual-mode resonance Rayleigh scattering and colorimetric alkaline phosphatase assay based on in situ ascorbic acid-induced signal generation from manganese dioxide nanosheets.

Multimode sensing has attracted extensive attention because they provide more than one transduction channel, thus improving accuracy and sensitivity. Due to the structural diversity, MnO2 nanosheets and nanoneedles were successively obtained via one-step redox reaction and different self-assembly methods. MnO2 nanosheets possess outstanding optical properties including extremely strong resonance Rayleigh scattering (RRS) and absorbance signal, and were selected as a dual-mode sensing material. Inspired by the selectivity of alkaline phosphatase (ALP) towards dephosphorylate ascorbic acid 2-phosphate (AAP) to generate ascorbic acid (AA), which has the ability to decompose MnO2 nanosheets along with optical signals and colour change, a dual-mode optical ALP sensing platform has been designed. Therefore, MnO2 nanosheets can serve as colorimetric probes by directly visualizing the colour variation with bare eyes. Moreover, the detection limit obtained by the RRS sensing mode can be as low as 0.17 mU L-1, which is far superior to that obtained by previously reported methods. The strategy not only has good feasibility and sensitivity, but also shows good prospects for a series of ALP-extended sensing applications.

A novel fluorescence "turn off-on" nanosensor for sensitivity detection acid phosphatase and inhibitor based on glutathione-functionalized graphene quantum dots.

In this paper, we developed a label-free and sensitive fluorescence sensor for acid phosphatase (ACP) and its inhibitor parathion-methyl (PM) detection based on glutathione-functionalized graphene quantum dots (GQDs@GSH). Upon addition of MnO2 nanosheets, the fluorescence of GQDs@GSH could be efficiently quenched via a fluorescence resonance energy transfer. ACP could easily catalyze the hydrolysis of L-Ascorbic acid-2-phosphate (AAP) to ascorbic acid (AA), which could reduce MnO2 nanosheets to Mn2+ in acidic environment, leading to dramatically increase of the fluorescence intensity of GQDs@GSH. Quantitative detection of ACP in a broad range from 0.1 to 9 mU mL-1 with a detection limit of 0.027 mU mL-1 could be achieved. The feasibility of the proposed sensor in real samples analysis was also studied and satisfactory results were obtained. Furthermore, the fluorescence assay strategy could also be used for the detection of parathion-methyl (PM) as ACP inhibitor.

Inorganic Nanozyme with Combined Self-Oxygenation/Degradable Capabilities for Sensitized Cancer Immunochemotherapy.

Recently emerged cancer immunochemotherapy has provided enormous new possibilities to replace traditional chemotherapy in fighting tumor. However, the treatment efficacy is hampered by tumor hypoxia-induced immunosuppression in tumor microenvironment (TME). Herein, we fabricated a self-oxygenation/degradable inorganic nanozyme with a core-shell structure to relieve tumor hypoxia in cancer immunochemotherapy. By integrating the biocompatible CaO2 as the oxygen-storing component, this strategy is more effective than the earlier designed nanocarriers for delivering oxygen or H2O2, and thus provides remarkable oxygenation and long-term capability in relieving hypoxia throughout the tumor tissue. Consequently, in vivo tests validate that the delivery system can successfully relieve hypoxia and reverse the immunosuppressive TME to favor antitumor immune responses, leading to enhanced chemoimmunotherapy with cytotoxic T lymphocyte-associated antigen 4 blockade. Overall, a facile, robust and effective strategy is proposed to improve tumor oxygenation by using self-decomposable and biocompatible inorganic nanozyme reactor, which will not only provide an innovative pathway to relieve intratumoral hypoxia, but also present potential applications in other oxygen-favored cancer therapies or oxygen deficiency-originated diseases.

A novel fluorimetric sensing strategy for highly sensitive detection of phytic acid and hydrogen peroxide.

In this paper, we developed a sensitive sensor for phytic acid (PA) and hydrogen peroxide (H2O2) detection based on glutathione-functionalized graphene quantum dots (GQDs@GSH). The fluorescence of GQDs@GSH was found to be effectively quenched by Fe3+ ions via photo-induced electron transfer (PET) process. Upon the addition of PA to GQDs@GSH/Fe3+ system, the fluorescence of GQDs@GSH was significantly restored due to the strong chelating and reducing ability of PA, Fe3+ ions could be reduced to Fe2+ ions by PA and formed PA/Fe2+ complex. Therefore, the "off-on" fluorescence method was constructed to detect PA by using GQDs@GSH/Fe3+ as a fluorescent probe. Furthermore, the method can be used for the detection of H2O2. H2O2 can destroy the chelate structure of PA/Fe2+, release Fe2+ ions and oxidize Fe2+ ions to produce Fe3+ ions, leading to the fluorescence quenching of GQDs@GSH again. Under optimal conditions, the fluorescence sensing platform showed good linear relationship between the relative fluorescence intensity I/I0 and the concentration of PA and H2O2 in the range of 0.05-3 µmol L-1 and 0.5-10 µmol L-1, respectively. The detection limits of PA and H2O2 were 14 nmol L-1 and 0.134 µmol L-1, respectively. Furthermore, the fluorescence assay method was also applied in real sample analysis and satisfactory results were obtained.

A novel label-free fluorescent sensor for highly sensitive detection of bleomycin based on nitrogen-doped graphene quantum dots.

In this work, we presented a novel label-free biosensor for rapid detection of bleomycinsulphate (BLM). The biosensor was based on the fluorescent "turn off-on" of nitrogen-doped graphene quantum dots (N-GQDs), which was prepared in a green way from citric acid and ammonia. The richness of carboxyl groups on the N-GQDs enabled strong adsorption of ssDNA to the surface of N-GQDs through π-π stacking interactions, resulting in the effective fluorescence quenching of N-GQDs system. The ssDNA underwent an irreversible cleavage event via the oxidative effect of BLM with Fe(II) as a cofactor, thus a turn-on fluorescence signal was observed. Thereby, the concentration of BLM can be quantitatively determined in a broad range from 0.34 nmol/L to 1300 nmol/L with a detection limit of 0.34 nmol/L. The presented method was applied to the determination of BLM in human serum samples with satisfactory results.

A novel fluorescence biosensor for sensitivity detection of tyrosinase and acid phosphatase based on nitrogen-doped graphene quantum dots.

In this paper, we developed a sensitive fluorescence biosensor for tyrosinase (TYR) and acid phosphatase (ACP) activity detection based on nitrogen-doped graphene quantum dots (N-GQDs). Tyrosine could be catalyzed by TYR to generate dopaquinone, which could efficiently quench the fluorescence of N-GQDs, and the degree of fluorescence quenching of N-GQDs was proportional to the concentration of TYR. In the presence of ACP, l-Ascorbic acid-2-phosphate (AAP) was hydrolyzed to generate ascorbic acid (AA), and dopaquinone was reduced to l-dopa, resulting in the fluorescence recovery of the quenched fluorescence by dopaquinone. Thus, a novel fluorescence biosensor for the detection of TYR and ACP activity based on N-GQDs was constructed. Under the optimized experimental conditions, the fluorescence intensity was linearly correlated with the concentration of TYR and ACP in the range of 0.43-3.85 U mL-1 and 0.04-0.7 mU mL-1 with a detection limit of 0.15 U mL-1 and 0.014 mU mL-1, respectively. The feasibility of the proposed biosensor in real samples assay was also studied and satisfactory results were obtained.

Fluorescence turn-off-on probe based on polypyrrole/graphene quantum composites for selective and sensitive detection of paracetamol and ascorbic acid.

In this work, we presented a novel biosensor for rapid detection of paracetamol and ascorbic acid. The novel biosensor was based on the fluorescent "turn off-on" of polypyrrole/graphene quantum dots (PPy/GQDs) composites. The composites exhibit strong fluorescence emission, which is dramatically enhanced as high as three times than that of pure GQDs. It is found that the fluorescence intensity of PPy/GQDs can be efficiently quenched by N-acetyl-p-benzoquinone (4-AOBQ), the oxidation product of paracetamol (PAR). And a turn-on fluorescence signal was observed when 4-AOBQ is reduced by ascorbic acid (AA). The quenched and recovered fluorescence intensity of PPy-GQDs was proportional to the concentration of PAR (0.067-233µg/L) and AA (3.33-997.5µg/L) respectively. The limit of detection is 0.022µg/L for PAR and 1.05µg/L for AA. The present method was applied to the determination of PAR and AA in human serum samples with satisfactory results.

A novel turn-on fluorescent strategy for sensing ascorbic acid using graphene quantum dots as fluorescent probe.

In this paper, a facile and rapid fluorescence turn-on assay for fluorescent detection of ascorbic acid (AA) was developed by using the orange emission graphene quantum dots (GQDs). In the presence of horse radish peroxidase (HRP) and hydrogen peroxide (H2O2), catechol can be oxidized by hydroxyl radicals and converted to o-benzoquinone, which can significantly quench the fluorescence of GQDs. However, when AA present in the system, it can consume part of H2O2 and hydroxyl radicals to inhibit the generation of o-benzoquinone, resulting in fluorescence recovery. Under the optimized experimental conditions, the fluorescence intensity was linearly correlated with the concentration of H2O2 in the range of 3.33-500µM with a detection limit of 1.2µM. The linear detection for AA was in the range from 1.11 to 300µM with a detection limit of 0.32µM. The proposed method was applied to the determination of AA in human serum samples with satisfactory results.

Sensitive fluorescence detection of ATP based on host-guest recognition between near-infrared ß-Cyclodextrin-CuInS2 QDs and aptamer.

We have developed a near-infrared (NIR) fluorescent aptamer-based sensor for sensitive detection of adenosine-5'-triphosphate (ATP) by using a ATP-binding aptamer and ß-Cyclodextrin-CuInS2 quantum dots (ß-CD-CuInS2 QDs). The fluorescence of ß-CD-CuInS2 QDs has a slight enhancement with the addition of ATP-binding aptamer due to the host-guest recognition between aptamer and ß-CD. When ATP is added, it will bind to aptamer to form G-quadruplexes. Aptamer-ATP complexes can enter into the hydrophobic cavities of ß-CD and result in great enhancement of the fluorescence intensity. Under the optimum conditions, the fluorescence intensity of ß-CD-CuInS2 QDs is proportional to the concentration of ATP, which shows a good linear response toward ATP concentration range of 6-1200µmolL-1, the detection limit for ATP is 3µmolL-1. The present assay shows a good selectivity for ATP over other biologically important proteins, and it is applied to the determination of ATP in human serum sample with satisfactory results.

Highly sensitive detection of acid phosphatase by using a graphene quantum dots-based förster resonance energy transfer.

A novel and effective fluorescence strategy was developed for sensitive and selective detection of acid phosphatase (ACP). A förster resonance energy transfer (FRET) biosensor was established by attaching nile red (NR) to graphene quantum dots (GQDs) via lecithin/ß-Cyclodextrin (lecithin/ß-CD) complex as the linker. The introduction of lecithin/ß-CD would brought GQDs-NR pair close enough through both electrostatic interaction and hydrophobic interaction, thereby making the FRET occur and thus resulting in the fluorescence quenching of GQDs (donor) and meanwhile the fluorescence enhancement of NR (acceptor). The presence of ACP in the sensing system would catalyze the hydrolysis of lecithin into two parts, resulting in the GQDs-NR pair separation. Meanwhile, considerable fluorescence recovery of GQDs and decreasing of NR was observed due to the inhibition of FRET progress. In this method, the limit of detection (LOD) is 28µUmL-1 which was considerably low for ACP detection. Using the GQDs-based fluorescence biosensor, we successfully performed in vitro imaging of human prostate cancer cells.

Sensitive detection of acid phosphatase based on graphene quantum dots nanoassembly.

In this study, we report a convenient label-free fluorescence biosensor for the detection of acid phosphatase based on the aggregation-caused quenching of graphene quantum dots (GQDs). The fluorescence of GQDs could be quenched by poly-(dimethyl diallyl ammonium chloride) (PDDA); the high efficiency of the quenching was caused by the non-covalent binding of positively charged PDDA to negatively charged GQDs through electrostatic interactions, aggregating to form a GQDs-PDDA complex. Addition of sodium hexametaphosphate (NaPO3)6 could effectively turn on the quenched fluorescence due to the stronger electrostatic interactions between positively charged PDDA and negatively charged (NaPO3)6. The introduction of acid phosphatase (ACP) would lead to the breakdown of (NaPO3)6 into small fragments and disassemble the complex of PDDA-(NaPO3)6. As a result, the recovered fluorescence could be quenched again by the addition of ACP. Quantitative evaluation of ACP activity in a broad range from 30 nU mL(-1) to 420 nU mL(-1) with a detection limit of 12 nU mL(-1) can be achieved in this way, endowing the assay with sufficiently high sensitivity for practical detection of ACP in human serum.

Graphene quantum dots as selective fluorescence sensor for the detection of ascorbic acid and acid phosphatase via Cr(vi)/Cr(iii)-modulated redox reaction.

A facile and rapid fluorescence assay based on a redox reaction for successively detecting ascorbic acid and acid phosphatase was developed via Cr(vi)-modulated graphene quantum dots (GQDs). Graphene quantum dots with yellow-green emission were first synthesized via a one-pot hydrothermal method. Based on the electrostatic adsorption of Cr3+ on GQDs and the strong chelation between Cr3+ and the -COOH and -OH groups on the surface of GQDs, the fluorescence of GQDs could be greatly quenched by Cr3+ ions. By the introduction of ascorbic acid, Cr2O7 2- could be reduced to Cr3+, which resulted in quenching of the fluorescence signal of GQDs. The degree of quenching of the fluorescence intensity of GQDs was proportional to the concentration of ascorbic acid. The dynamic detection range for ascorbic acid was from 0.5 to 250 µmol L-1 with a limit of detection (LOD) of 0.28 µmol L-1. Moreover, this phenomenon was further exploited for the sensitive and selective detection of acid phosphatase (ACP). l-Ascorbic acid-2-phosphate (AAP), which is a more stable phosphatase substrate, could be hydrolyzed by ACP to give ascorbic acid. Ascorbic acid then reduced Cr2O7 2- to Cr3+, leading to quenching of the fluorescence of GQDs. Thus, the amount of ACP could be indirectly detected in the range from 0.02 to 3 mU mL-1 with a LOD of 8.9 µU mL-1. Thus, a Cr(vi)-modulated GQDs "turn-off" fluorescence sensor for ascorbic acid and ACP was constructed. The present strategy showed high selectivity for ascorbic acid and ACP. The feasibility of the proposed sensing system in a real sample assay was also studied and satisfactory results were obtained.

Label-free aptamer biosensor for selective detection of thrombin.

We fabricated a novel fluorescence biosensor for the selective detection of thrombin by using bovine serum albumin-capped CdS quantum dots (BSA-CdS QDs). Two kinds of designed DNA (DNA1 and DNA2) could bind to CdS QDs through the electrostatic interaction between DNA and Cd(2+) on the surface of CdS QDs. The obtained DNA/BSA-CdS QDs kept stable in the solution with the fluorescence intensity obviously enhanced. Hairpin structure of DNA1contained two domains, one is the aptamer sequence of thrombin and the other is the complementary sequence of DNA2. When thrombin was added, it would bind to DNA1 and induce the hairpin structure of DNA1 changed into G-quadplex structure. Meanwhile, DNA2 would transfer from the surface of CdS QDs to DNA1 via hybridization, which resulted in the removal of DNA1 and DNA2 from the surface of CdS QDs, and led to the fluorescence intensity of CdS QDs reduced. Thus, the determination of thrombin could be achieved by monitoring the change of the fluorescence intensity of CdS QDs. The present method is simple and fast, and exhibits good selectivity for thrombin over other proteins. We have successfully detected thrombin in human serum samples with satisfactory results.

Ultrasensitive detection of amifostine and alkaline phosphatase based on the growth of CdS quantum dots.

In this study, we reported a simple and sensitive fluorescence nanosensor for rapid detection of amifostine and alkaline phosphatase (ALP). The novel nanosensor was based on the fluorescence "turn on-off" of CdS quantum dots (QDs). Firstly, Cd(2+) cation could react with S(2-) anion to generate fluorescent CdS QDs in the presence of amifostine. The fluorescence (FL) intensity of amifostine-capped CdS QDs (Amifostine-CdS QDs) was increased with the increasing amounts of amifostine, and could be used for amifostine detection. However, amifostine could be converted to 2-(3-aminopropylamino) ethanethiol (WR1065) in the presence of ALP based on the dephosphorylation of ALP. Under the optimum conditions, the affinity of WR1065 to CdS QDs was weaker than that of amifostine. Therefore the new generation of WR1065-CdS QDs would reduce the FL intensity with the increase of ALP concentration, and the fluorescence of CdS QDs was turn off. The metabolic process of amifostine in the presence of alkaline phosphatase could be also studied via the change of FL intensity of CdS QDs. The present method was cost-effective, convenient, and does not require any complicated synthetic procedures.

Fluorescence detection of adenosine-5'-triphosphate and alkaline phosphatase based on the generation of CdS quantum dots.

We have developed an analytical method to detect adenosine-5'-triphosphate (ATP) and alkaline phosphatase (ALP) based on the generation of CdS quantum dots (QDs). We demonstrated that Cd(2+) cation reacts with S(2-) anion to generate fluorescent CdS QDs in the presence of some certain amount of ATP. With increase in the ATP concentration, the fluorescence intensity of CdS QDs was also enhanced. ATP can be converted into adenosine by the dephosphorylation of ALP, so that the generation of CdS QDs would be inhibited in the presence of ALP. Therefore, this novel analysis system could be applied to assay ATP and ALP based on the growth of fluorescent CdS QDs.