Biotin-tagged fluorescent probe for in situ visualization of γ-glutamyl transpeptidase in cancerous cells and tissues.

γ-Glutamyl transpeptidase (GGT), a cell-surface enzyme, is strongly implicated in mammalian malignancy growth and migration processes including human hepatocarcinogens. However, simply and conveniently detect of GGT on the cell membrane remains highly challenging. In this study, a biotin-tagged fluorescent probe Nap-biotin-glu was developed using glutamic acid, naphthalimide, and biotin as the reaction site, fluorescent reporter, and membrane-targeting group, which required only three steps. Colocalization fluorescence imaging and immunofluorescence analysis indicated that probe Nap-biotin-glu was successfully realized in situ visualizing of GGT on the cell membrane.Owing to the significant over-expressed GGT level in tumor, the probe was successfully applied to distinguish cancer tissues from adjacent normal tissues.

Calcium-enriched carbon nanoparticles loaded with indocyanine green for near-infrared fluorescence imaging-guided synergistic calcium overload, photothermal therapy, and glutathione-depletion-enhanced photodynamic therapy.

Combining phototherapy with other treatments has significantly advanced cancer therapy. Here, we designed and fabricated calcium-enriched carbon nanoparticles (Ca-CNPs) that could effectively deplete glutathione (GSH) and release calcium ions in tumors, thereby enhancing the efficacy of photodynamic therapy (PDT) and the calcium overload effect that leads to mitochondrial dysfunction. Due to the electrostatic interaction, π-π stacking interaction, multiple hydrogen bonds, and microporous structures, indocyanine green (ICG) was loaded onto the surface of Ca-CNPs with a high loading efficiency of 44.7 wt%. The obtained Ca-CNPs@ICG can effectively improve the photostability of ICG while retaining its ability to generate singlet oxygen (1O2) and undergo photothermal conversion (Ca-CNPs@ICG vs. ICG, 45.1% vs. 39.5%). In vitro and in vivo experiments demonstrated that Ca-CNPs@ICG could be used for near-infrared fluorescence imaging-guided synergistic calcium overload, photothermal therapy, and GSH depletion-enhanced PDT. This study sheds light on the improvement of 1O2 utilization efficiency and calcium overload-induced mitochondrial membrane potential imbalance in tumor cells.

Carbon Monoxide: A Second Biomarker to Couple with Viscosity for the Construction of "Dual-Locked" Near-Infrared Fluorescent Probes for Accurately Diagnosing Non-Alcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) can progress to cirrhosis and liver cancer if left untreated. Therefore, it is of great importance to develop useful tools for the noninvasive and accurate diagnosis of NAFLD. Increased microenvironmental viscosity was considered as a biomarker of NAFLD, but the occurrence of increased viscosity in other liver diseases highly reduces the diagnosis accuracy of NAFLD by a single detection of viscosity. Hence, it is very necessary to seek a second biomarker of NAFLD. It has been innovatively proposed that the overexpressed heme oxygenase-1 enzyme in NAFLD would produce abnormally high concentrations of CO in hepatocytes and that CO could serve as a potential biomarker. In this work, we screened nine lactam Changsha dyes (HCO-1-HCO-9) with delicate structures to obtain near-infrared (NIR), metal-free, and "dual-locked" fluorescent probes for the simultaneous detection of CO and viscosity. Changsha dyes with a 2-pyridinyl hydrazone substituent could sense CO, and the 5-position substituents on the 2-pyridinyl moiety had a great electron effect on the reaction rate. The double bond in these dyes served as the sensing group for viscosity. Probe HCO-9 was utilized for precise diagnosis of NAFLD by simultaneous detection of CO and viscosity. Upon reacting with CO in a high-viscosity microenvironment, strong fluorescence at 745 nm of probe HCO-9 was turned on with NIR excitation at 700 nm. Probe HCO-9 was proven to be an effective tool for imaging CO and viscosity. Due to the advantages of NIR absorption and low toxicity, probe HCO-9 was successfully applied to image NAFLD in a mouse model.

Catalase-like pleated niobium carbide MXene loaded with polythiophene for oxygenated sonodynamic therapy in solid tumor.

Sonodynamic therapy (SDT), an emerging treatment for solid tumors, has the advantages of deep tissue penetration, non-invasiveness, low side effects, and negligible drug resistance. However, the hypoxic environment of deep solid tumors can discount the efficacy of oxygenated dependent SDT. Here, we synthesized a polythiophene-based sonosensitizer (PT2) and a two-dimensional pleated niobium carbide (Nb2C) Mxene. PT2 was loaded onto the surface of poly(vinylpyrrolidone) (PVP)-coated Nb2C MXene through electrostatic interaction to obtain Nb2C-PVP-PT2 nanosheets (NSs) with a high loading efficiency of 153.7%. Nb2C MXene exhibited catalase-like activity, which could catalyze hydrogen peroxide (H2O2) to produce O2, in turn alleviating tumor hypoxia and enhancing the efficacy of SDT. The depletion of H2O2 further results in abnormal cellular H2O2 levels and reduced tumor cell activity. Moreover, the decomposed NSs led to the release of the sonosensitizer PT2 that can efficiently generate both singlet oxygen and superoxide anions under ultrasound irradiation. These events led to the inhibition of DNA replication of tumor cells, causing tumor cell death, allowing for enhanced SDT efficacy.

Probing fluctuations in sulfur dioxide and viscosity levels during mitochondrial dysfunction using a dual-response fluorescent probe with good water solubility.

Mitochondrial dysfunction is associated with increased viscosity and reactive oxygen species (ROS) levels. As an effective antioxidant, sulfur dioxide (SO2) can actively scavenge excess ROS to regulate the redox state and protect cells from oxidative stress. However, few studies have evaluated the connection between viscosity and SO2 during mitochondrial dysfunction. Herein, a water-soluble fluorescent probe (MBI) is designed and synthesized for dual-detecting SO2 and viscosity. The probe rapidly detects SO2 within 12 s based on Michael's addition reaction. Meanwhile, increasing viscosity further inhibits the intramolecular rotation, causing the probe to show a greatly enhanced fluorescence. Probe MBI possesses mitochondria targeting capability due to its quaternary ammonium salt. More importantly, probe MBI successfully supports SO2 and viscosity imaging in living cells and can effectively monitor them during mitochondrial dysfunction and cell apoptosis.

Vascular disruption agent and phototherapeutic assembled nanoparticles for enhanced tumor inhibition.

Vascular disruption agent (combretastatin A-4 phosphate) and phototherapeutic (IEICO-4F) assembled nanoparticles (IFC NPs) were prepared for the first time. The IFC NPs have a high photo energy utilization efficiency of up to 96.1%, and could significantly inhibit tumor growth by photodynamic and photothermal therapy enhanced tumor vascular disruption.

Lysosome- and plasma membrane-accumulative and tumor-targetable polythiophene nanoparticles for enhanced sonodynamic therapy.

Sonodynamic therapy (SDT) has emerged as a promising treatment approach of solid tumors given its deep tissue penetration, non-invasiveness, few side effects, and negligible drug resistance. Herein, we report the first polythiophene derivative-based sonosensitizer (PT2) containing a quaternary ammonium salt and dodecyl chains with better ultrasound stability than that of traditional sonosensitizers, such as Rose Bengal and chlorin e6. PT2 was encapsulated by folic acid-containing polyethylene glycol. The obtained nanoparticles (PDPF NPs) exhibited excellent biocompatibility, cancer cell-targeting capacity, and accumulated mainly in the lysosomes and plasma membranes of cells. These NPs could generate singlet oxygen and superoxide anions simultaneously under ultrasound irradiation. In vitro and in vivo experimental results demonstrated that PDPF NPs could induce cancer-cell death through apoptosis and necrosis, inhibit DNA replication, and ultimately achieve tumor depletion upon US irradiation. These findings revealed that polythiophene could serve as an efficacious sonosensitizer for enhanced US treatment of deep-seated tumors.

An estradiol-functionalized red-emissive photosensitizer for enhanced and precise photodynamic therapy of breast cancers.

In this work, we developed a red-absorbing photosensitizer (NBS-ER) with specific targeting ability toward estrogen receptors (ER). NBS-ER could specifically bind the overexpressed ER in breast cancers to increase its accumulation, thereby amplifying the photodynamic therapeutic effect. With the aid of red fluorescence from NBS-ER, imaging-guided therapy could be achieved.

Correction: Copper coordination-based conjugated polymer nanoparticles for synergistic photodynamic and chemodynamic therapy.

Correction for 'Copper coordination-based conjugated polymer nanoparticles for synergistic photodynamic and chemodynamic therapy' by Qiang Cheng et al., Chem. Commun., 2023, https://doi.org/10.1039/d3cc01107k.

Copper coordination-based conjugated polymer nanoparticles for synergistic photodynamic and chemodynamic therapy.

In this work, we presented a copper coordination-based conjugated polymer nanoparticle (PPE-Cu NPs) for synergistic PDT/CDT. Upon irradiation, PPE-Cu NPs exhibited good singlet oxygen generation capability (ΦΔ = 0.33). Meanwhile, PPE-Cu NPs were able to generate ˙OH in the presence of GSH and H2O2. Cellular experiments demonstrated that PPE-Cu NPs can serve as effective agents for synergistic PDT/CDT therapy.

Three birds one stone: an enzyme-activatable theragnostic agent for fluorescence diagnosis, photodynamic and inhibitor therapies.

AX11890, an inhibitor of overexpressed enzyme, KIAA1363, in some breast cancers, was conjugated with a benzo[a]phenothiazinium photosensitizer to develop a tumor micro-environment-responsive photosensitizer NBS-L-AX. In normal cells, the special geometry of NBS-L-AX causes the fluorescence and photodynamic therapeutic (PDT) effect of NBS-L to be quenched. In cancer cells, when allowed to interact with the enzyme KIAA1363, the geometry of NBS-L-AX changes such that it becomes fluorescent and photodynamically active. Thus, the material of NBS-L-AX serves as an activated imaging and PDT treatment agent for breast cancers. In addition, NBS-L-AX also shows a selective inhibition effect against breast cancer cells.

A water-soluble thiophene-croconaine dye with a high molar extinction coefficient for NIR fluorescence imaging-guided synergistic photothermal/photodynamic therapy of cancer.

Phototherapeutic agents with near-infrared (NIR) fluorescence, strong reactive oxygen species generation and photothermal conversion capabilities are highly desirable for use in cancer therapy. Herein, a water-soluble NIR croconaine dye (TCR) with a thiophene-croconaine rigid core and two symmetric alkyl chains was designed and synthesized. TCR exhibits intense NIR absorption and fluorescence that peaked at 780 and 815 nm, respectively, with a high molar extinction coefficient of 1.19 × 105 M-1 cm-1. Moreover, TCR has a high photothermal conversion efficiency of 77% and is capable of generating hydroxyl radicals (OH˙) under 735 nm laser irradiation. Based on these outstanding properties, TCR has proven its application in NIR fluorescence imaging-guided synergistic photothermal/photodynamic therapy of cancer.

Boron Dipyrromethene-Based Phototheranostics for Near Infrared Fluorescent and Photoacoustic Imaging-Guided Synchronous Photodynamic and Photothermal Therapy of Cancer.

The regulation of photochemical properties of phototheranostics, especially the absorption, fluorescence, singlet oxygen (1O2) generation, and photothermal conversion efficiency, is a hot research topic. Here, we designed and synthesized four boron dipyrromethene (BODIPY) derivatives with high absorption coefficients and intense fluorescence in the near-infrared (NIR) region. The substituted electron-donating group significantly improved 1O2 generation and fluorescence of BODIPYs, whereas the electron-withdrawing group boosts photothermal conversion. These hydrophobic BODIPYs were further coated with DSPE-PEG-2000 to form water dispersible nanoparticles (NPs). Among these BODIPY NPs, the B-OMe-NPs with methoxyl substituted at the meso-position showed the highest 1O2 generation, a photothermal conversion efficiency of 66.5%, and an NIR fluorescence peak at 809 nm. In vitro and in vivo experiments demonstrated that B-OMe-NPs might be used for NIR fluorescent and photoacoustic imaging-guided photodynamic and photothermal therapy of cancer.

Dual-ratiometric fluorescence sensing and real-time detection of HOCl and NQO1 using a single fluorescent probe under one-wavelength excitation.

Overexposure to hypochlorous acid (HOCl) can lead to cellular oxidative stress. In response to the stress, the body activates related factor that upregulates a potent antioxidant enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1). A method that can simultaneously detect HOCl and NQO1 can help to understand their interactions during homeostasis. However, the methods are still limited due to the complexity of the biological environment. In this work, we present for the first time a dual-ratiometric fluorescent probe (NH) that can distinguish between HOCl and NQO1. Probe NH had ratiometric fluorescence responses by changing from red (λmaxem = 643 nm) to green (λmaxem = 517 nm) in the presence of HOCl and from red to mixed blue (λmaxem = 483 nm)/red in the presence of NQO1 under single-wavelength excitation. This probe had high selectivity and sensitivity towards HOCl and NQO1 in vitro. Moreover, probe NH could specifically image exogenous or endogenous HOCl and NQO1 in living cells through different emission channels. This probe provides a practical tool for studying the correlation of HOCl and NQO1 in biological systems.

Photovoltaic molecules with ultra-high light energy utilization for near-infrared laser triggered synergetic photodynamic and photothermal therapy.

Photovoltaic molecules possess strong absorption in the near-infrared (NIR) region and are suitable for NIR laser-triggered phototherapy. Herein, the star molecule IEICO of organic photovoltaic materials, which has a narrow bandgap and large A-D-A conjugated structure, was prepared into water dispersive nanoparticles (NPs) through a simple self-assembly method. The obtained IEICO NPs showed a strong NIR absorption peak at 800 nm and a high 1O2 quantum yield of 11% and photothermal conversion efficiency of 85.4% under 808 nm laser irradiation. The ultra-high light energy utilization efficacy (∼96.4%) of the IEICO NPs enables their excellent phototherapeutic effect on tumors. The present work suggested the huge application potential of organic photovoltaic materials in the biomedical field.

Tumor microenvironment-responsive S-NSs-TPZ-ICG intelligent nanoplatforms for synergistically enhanced tumor multimodal therapy.

Nanosheet carriers loaded with drugs and phototherapeutics are used for effective cancer therapy, but the process remains challenging. Here, we prepared sulfur nanosheets (S-NSs) and then loaded tirapazamine (TPZ) and indocyanine green (ICG) with a loading efficiency of 6.3% and 94%, respectively. The obtained S-NSs-TPZ-ICG exhibits near-infrared (NIR) fluorescence, high 1O2 generation and photothermal conversion capabilities, good biocompatibility, and tumor microenvironment responsiveness. In vivo and in vitro experiments reveal that S-NSs-TPZ-ICG can be selectively decomposed under acidic and H2O2 conditions to release TPZ and ICG, and significantly inhibit tumor growth under laser irradiation without obvious toxic side effects.

A-DA'D-A Structured Organic Phototheranostics for NIR-II Fluorescence/Photoacoustic Imaging-Guided Photothermal and Photodynamic Synergistic Therapy.

Multimodal imaging-guided combinational phototherapies triggered by a single near-infrared (NIR) laser are highly desirable. However, their development is still a big challenge. Herein, we have developed an "acceptor-donor-acceptor'-donor-acceptor" structured organic phototheranostics (Y16-Pr) with strong light-harvesting ability in the NIR region. After being modified with polyethylene glycol (PEG), the obtained biocompatible nanoparticles (Y16-Pr-PEG NPs) could conduct NIR-II fluorescence imaging (FLI) and photoacoustic imaging (PAI) and perform photothermal therapy (PTT) and photodynamic therapy (PDT) simultaneously. Notably, Y16-Pr-PEG NPs showed an impressive photothermal conversion efficiency (PCE) of 82.4% under 808 nm laser irradiation. The irradiated NPs could also produce hydroxyl radicals (•OH) and singlet oxygen (1O2) for type I and type II PDT, respectively. In vivo and in vitro experiments revealed that the Y16-Pr-PEG NPs significantly inhibit tumor cell growth without apparent toxic side effects under laser irradiation. Overall, the single-laser-triggered multifunctional phototheranostic Y16-Pr-PEG NPs can achieve NIR-II FLI/PAI-guided synergistic PTT/PDT against tumors.

A ratiometric fluorescent probe with large Stokes shift and emission shift for sensing hydrazine in living organisms.

As a highly toxic reagent, hydrazine (N2H4) is notorious to human beings and the environment. To simply and conveniently detect N2H4 in environmental and biological systems, a ratiometric fluorescent probe MA-N2H4 was developed with excellent sensitivity and selectivity. Probe MA-N2H4 was readily prepared based on a naphthalene as the fluorescent scaffold and an indanedione group as the responsive moiety for N2H4. This probe displayed a red-emitting fluorescence at 670 nm with a large Stokes shift (200 nm). After treatment with N2H4, a significant blue-shifted emission at 440 nm could be observerd, which led to an extremely large emission wavelength shift (230 nm). The fluorescent intensity ratio (I440/I670) of probe MA-N2H4 was rapidly and significantly increased (273-fold) within 18 min. The detection limit for N2H4 was 0.5 µM. In addition, the probe was successfully employed for tracking N2H4 in living cells and zebrafish through a ratiometric manner.

Rational Development of Dual-Ratiometric Fluorescent Probes for Distinguishing between H2S and SO2 in Living Organisms.

For better investigating the complicated relationships between H2S and SO2, simultaneously detecting and visualizing them with good selectivity is crucial. However, most sensing mechanisms for H2S and SO2 probes are based on the addition reactions with the double bonds, which have no selectivity. In this work, by introducing an active triple bond into 4-dicyanovinyl-7-diethylamino-coumarin, we construct two unique sensors for not only distinguishing between H2S and SO2 but also sensing H2S and SO2 in a dual-ratiometric manner. Moreover, the modified sensor was successfully applied in living cells and zebrafish for discriminating H2S and SO2.

A Ratiometric, Fast-Responsive, and Single-Wavelength Excited Fluorescent Probe for the Discrimination of Cys and Hcy.

The ratiometric detection of cysteine (Cys) and homocysteine (Hcy) is very challenging because of their highly similar chemical structures and properties. By introducing the phenylethynyl group into a coumarin dye as the sensing group, the ratiometric fluorescent probe CP was developed to selectively and rapidly discriminate between Cys and Hcy. With a single-wavelength excitation, the presence of Cys or Hcy induced the probe to produce distinct ratiometric fluorescence changes: from red (λmaxem = 608 nm) to blue (λmaxem = 485 nm) toward Cys and from red to mixed red/blue toward Hcy. Moreover, the probe was capable of visualizing and discriminating between intracellular Cys and Hcy in HeLa cells and zebrafish by exhibiting different ratiometric fluorescence signals.