Tailored Phototherapy Agent by Infection Site In Situ Activated Against Methicillin-Resistant S. aureus.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising treatment approach for multidrug resistant infections. PDT/PTT combination therapy can more efficiently eliminate pathogens without drug resistance. The key to improve the efficacy of photochemotherapy is the utilization efficiency of non-radiation energy of phototherapy agents. Herein, a facile phototherapy molecule (SCy-Le) with the enhancement of non-radiative energy transfer is designed by an acid stimulation under a single laser. Introduction of the protonated receptor into SCy-Le results in a distorted intramolecular charge in the infected acidic microenvironment, pH ≈ 5.5, which in turn, enhances light capture, reduces the singlet-triplet transition energies (ΔES1-T1), promotes electron system crossing, enhances capacity of reactive oxygen species generation, and causes a significant increase in temperature by improving vibrational relaxation. SCy-Le shows more than 99% bacterial killing rate against both methicillin-resistant Staphylococcus aureus and its biofilms in vitro and causes bacteria-induced wound healing in mice. This work will provide a new perspective for the design of phototherapy agents, and the emerging photochemotherapy will be a promising approach to combat the problem of antibiotic resistance.

Precise Design of TiO2@CoOx Heterostructure via Atomic Layer Deposition for Synergistic Sono-Chemodynamic Oncotherapy.

Sonodynamic therapy (SDT), a tumor treatment modality with high tissue penetration and low side effects, is able to selectively kill tumor cells by producing cytotoxic reactive oxygen species (ROS) with ultrasound-triggered sonosensitizers. N-type inorganic semiconductor TiO2 has low ROS quantum yields under ultrasound irradiation and inadequate anti-tumor activity. Herein, by using atomic layer deposition (ALD) to create a heterojunction between porous TiO2 and CoOx, the sonodynamic therapy efficiency of TiO2 can be improved. Compared to conventional techniques, the high controllability of ALD allows for the delicate loading of CoOx nanoparticles into TiO2 pores, resulting in the precise tuning of the interfaces and energy band structures and ultimately optimal SDT properties. In addition, CoOx exhibits a cascade of H2O2→O2→·O2 - in response to the tumor microenvironment, which not only mitigates hypoxia during the SDT process, but also contributes to the effect of chemodynamic therapy (CDT). Correspondingly, the synergistic CDT/SDT treatment is successful in inhibiting tumor growth. Thus, ALD provides new avenues for catalytic tumor therapy and other pharmaceutical applications.

Hemicyanine-based sensor for mitochondrial viscosity imaging in BV2 cells.

Mitochondrial viscosity is a critical factor affecting numerous physiological processes, including phagocytosis. Abnormal viscosity in mitochondria is related to some pathological activities and diseases. Evaluating and detecting the changes in mitochondrial viscosity in vivo is crucial. Thus, a mitochondria-targeted red-emitting fluorescent probe (VP) was prepared, and can be used to detect viscosity with high selectivity and sensitivity. The synthesis of probe VP was as simple as two steps and the cost was low. In addition, the fluorescence intensity (log I615) exhibited an excellent relationship with viscosity (log η) in the range of 0.5 - 2.5 (R2 = 0.9985) in water/glycerol mixture. It is noteworthy that the probe VP displayed the highest signal-to-noise ratio (about 50-fold) for viscosity in water and glycerol system. The probe VP can visualize the mitochondrial viscosity change in living cells. More importantly, phagocytic test for BV2 cells further demonstrated that phagocytosis decreased with increased viscosity. Furthermore, VP was successfully used for monitoring the mitophagy process induced by starvation, and mitochondrial viscosity exhibited enhancement during mitophagy. The probe was a potential tool for studying viscosity and phagocytosis.

Tumor Cell Targeting and Responsive Nanoplatform for Multimodal-Imaging Guided Chemodynamic/Photodynamic/Photothermal Therapy toward Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with ineffective treatment and poor prognosis. It is in great demand to develop a novel theranostic strategy for accurate diagnosis and targeted treatment of TNBC. In the present study, one nanoplatform (HA-ICG-Fe-PDA), endowed with multimodal imaging-guided chemodynamic/photodynamic/photothermal (CDT/PDT/PTT) synergistic therapy capacity toward TNBC, was innovatively constructed. The nanoplatform was prepared by covalently conjugating ICG-decorated hyaluronic acid (HA) on Fe3+-chelated polydopamine (PDA). HA facilitated the targeting and accumulating of the nanoplatform in tumor tissue and cells of TNBC, thus producing enhanced magnetic resonance signal. Upon entering into TNBC cells, the intracellular hyaluronidase-catalyzed cleavage of HA-ICG-Fe-PDA activated the prequenched near-infrared (NIR) fluorescence signal, allowing for the activatable NIR fluorescence imaging. On the other hand, Fe3+ in the nanoplatform could be reduced to reactive Fe2+ in tumor microenvironment, guaranteeing efficient Fenton reaction-mediated CDT. The combination of ICG with Fe-PDA enhanced the NIR absorption of the nanoplatform so that considerable PTT/PDT and photothermal imaging were achieved under 808 nm laser irradiation. In vitro and in vivo experiments have verified that the proposed nanoplatform integrates the potential of TNBC-targeting, precise NIR fluorescence/magnetic resonance/photothermal trimodal imaging, efficient treatment via synergistic CDT/PDT/PTT, as well as excellent biocompatibility. Therefore, this multifunctional nanoplatform provides a simple and versatile strategy for imaging-guided theranostics of TNBC.

A carboxylesterase-activatable near-infrared phototheranostic probe for tumor fluorescence imaging and photodynamic therapy.

Phototheranostic probes have been proven to be a promising option for cancer diagnosis and treatment. However, near-infrared phototheranostic probes with specific tumor microenvironment responsiveness are still in demand. In this paper, a carboxylesterase (CES)-responsive near-infrared phototheranostic probe was developed by incorporating 6-acetamidohexanoic acid into a hemicyanine dye through an ester bond. The probe exhibits highly sensitive and selective fluorescence enhancement towards CES because CES-catalyzed cleavage of the ester bond leads to the release of the fluorophore. By virtue of its near-infrared analytical wavelengths and high sensitivity, the probe has been employed for endogenous CES activatable fluorescence imaging of tumor cells. Moreover, under 660 nm laser irradiation, the probe can generate toxic reactive oxygen species and efficiently kill tumor cells, with low cytotoxicity in dark. As far as we know, the probe was the first CES-responsive phototheranostic probe with both near-infrared analytical wavelengths and photosensitive capacity, which may be useful in the real-time and in situ imaging of CES as well as imaging-guided photodynamic therapy of tumors. Therefore, the proposed probe may have wide application prospect in cancer theranostics.

Targeted chemo-photodynamic therapy toward esophageal cancer by GSH-sensitive theranostic nanoplatform.

As the sixth leading cause of cancer death, esophageal cancer is threatening the life of people worldwide. Traditional treatments, such as surgery, chemotherapy, radiotherapy, are facing always augmented challenges including invasion, multidrug resistance (MDR), off-target toxicity. Chemo & Photodynamic synergistic therapy represents one promising strategy for improved treatment efficiency. But it is still hindered by the lack of tumor targeting, deleterious side effects, and unfavorable microenvironment for photodynamic therapy (PDT). To overcome those obstacles, one theranostic nano-assambly drug, GCDs-Ce6/Pt-EGF, was designed and fabricated. Green fluorescence carbon dots (GCDs) with the excellent optical properties, modifiability and low toxicity were prepared as drug carrier. Epidermal growth factor (EGF) was conjugated to the nano-assembly to realize tumor specific targeting. Chlorin e6 (Ce6) in the presence of laser irradiation achieved PDT by generating proapoptosis reactive oxygen species (ROS). Moreover, Ce6 incorporated into GCDs endowed the nano-assambly imaging ability and facilitate image-guided therapy. Pt(IV), cisplatin prodrug, in the nano-assambly depleted the glutathione (GSH) of tumor microenvironment when it was reduced to cytotoxicity Pt(II). Compared with single treatment, GCDs-Ce6/Pt-EGF exhibited enhanced tumor cell killing capacity and better biosafety in vitro and in vivo, especially for EGFR bearing tumor. It paved ways for developing novel theranostic agent to be potentially applied in clinic.

Construction of mitochondria targeted and FRET based ratiometric sensing nanoplatform for sulfur dioxide accurate detection in vitro and in vivo.

Sulfur dioxide (SO2) is a key molecule in organisms that is involved in the regulation of different physiological procedures. Aberrant SO2 causes a variety of diseases, such as cancer and neurodegeneration. Thus, sensitive and selective detection of SO2 is of great importance. Based on the Förster resonance energy transfer (FRET) between green fluorescence carbon dots (GCDs) donor and amide-linked near-infrared fluorescence emissive organic small molecular dye (CDDBT) acceptor, one ratiometric fluorescent nano platform, Mito-GCDs-CDDBT for mitochondria SO2 sensing was constructed. In this FRET sensing system, CDDBT served as the receptor for SO2, and the presence of SO2 enhanced GCDs green fluorescence signal and quenched CDDBT near-infrared fluorescence signal due to the disruption of FRET. Mito-GCDs-CDDBT could sensitively detect SO2 with a detection limit of as low as 0.701 µM. Meanwhile, Mito-GCDs-CDDBT achieved fluorescence imaging to measure the response of cellular exogenous and endogenous SO2 with remarkable mitochondrial targeting. Moreover, Mito-GCDs-CDDBT also realized SO2 sensing in vivo including zebrafish and mice. The as-prepared versatile nanoplatform displayed several advantages, such as mitochondria targeting, FRET-based sensitive detection, and sensing capabilities in biological milieu. Potentially, it could be applied in the diagnostics of SO2 involved diseases.

Folic acid functionalized aggregation-induced emission nanoparticles for tumor cell targeted imaging and photodynamic therapy.

Recently, molecules with aggregation-induced luminescence (AIE) characteristics have received more and more attention due to the fluorescence of traditional dyes being easily quenched in the aggregated state. AIE molecules have significant advantages, such as excellent light stability, bright fluorescence, high contrast, and large Stokes shift. These characteristics have aroused wide interest of researchers and opened up new applications in many fields, especially in the field of biological applications. However, AIE molecules or their aggregates have certain limitations in multifunctional biological research due to their low specific targeting ability, poor biocompatibility, and poor stability in physiological body fluids. In order to overcome these problems, a novel nanoparticle, FFM1, was fabricated and characterized. FFM1 displayed good water solubility, biocompatibility, and AIE emission properties. It could target HeLa cells specifically by recognizing their folate receptor. Reactive oxygen triggered by light irradiation induced tumor cell apoptosis. Summarily, FFM1 displayed excellent capacity in target imaging and photodynamic killing of HeLa cells. It has shown potential application value in targeted diagnosis and photodynamic therapy of tumors, and has important guiding significance for the treatment of malignant tumors. It paves a way for the development of a novel strategy for tumor theranostics.

A nitroreductase-responsive near-infrared phototheranostic probe for in vivo imaging of tiny tumor and photodynamic therapy.

The hypoxia-activated and nitroreductase-responsive phototheranostic probe has been developed by incorporating a nitro group into a hemicyanine fluorophore. The probe displays extremely sensitive and selective near-infrared fluorescence enhancement to nitroreductase with the detection limit of 2.10 ng/mL. The detection mechanism relies on the nitroreductase-catalyzed reduction of the nitro group to an amino group, along with the generation of the fluorophore. The availability of the probe in fluorescence imaging and photodynamic therapy was demonstrated at cellular level and in vivo. The probe can image endogenous nitroreductase and the hypoxia status of living cells. The probe also exhibits significant phototoxicity to hypoxia tumor cells under the 660 nm laser irradiation. More importantly, the probe has been successfully utilized in imaging tiny tumor (about 6 mm3) and tumor photodynamic therapy in vivo. The proposed probe integrates accurate near-infrared fluorescence imaging and photodynamic therapy into the same molecule, which probably become a promising agent in the early diagnosis and therapy of tumors.

Facile antibacterial materials with turbine-like structure for P. aeruginosa infected scald wound healing.

Pseudomonas aeruginosa (P. aeruginosa) is a popular hospital pathogen and the major cause of morbidity and mortality in patients with cystic fibrosis (CF) and impaired immune system. Herein, we designed and synthesized a series of organic molecules MTEBT-n (n = 1, 2, 3) to specifically and effectively kill P. aeruginosa. Hydrophobic triphenylamine was selected as the skeleton, and hydrophilic primary ammonium salts that can easily penetrate the cell walls of Gram-negative bacteria and accumulate in the bacteria were used to adjust the hydrophilic-hydrophobic ratio of the molecules, resulting in different antibacterial activity. As the hydrophilic-hydrophobic ratio increased in the structures from MTEBT-1 to MTEBT-3, the antibacterial activity of the three molecules were gradually enhanced with killing effects of 25%, 75% and 95% against P. aeruginosa, respectively. The antibacterial mechanisms of MTEBT-n were demonstrated to destroy the bacterial membrane, which could effectively prevent the development of drug resistance. In addition, MTEBT-3 with the highest antibacterial activity could inhibit P. aeruginosa biofilm very well, and heal the P. aeruginosa infected scald wounds. This work provides a potential organic antimicrobial material for clinical antimicrobial therapy of P. aeruginosa infection, and offers a molecular engineering strategy for designing new antimicrobials.

Ultrafast fluorescent probe with near-infrared analytical wavelength for fluoride ion detection in real samples.

The first ultrafast fluorescence probe with response time in seconds (10 s) for fluoride ions (F-) has been proposed by conjugating dimethylthiophosphoryl group as a recognition unit with the near-infrared fluorophore of hemicyanine. The response mechanism is the F--induced cleavage of the dimethylthiophosphoryl group, along with the liberation of the fluorophore, which results in a distinctly enhanced fluorescence intensity at 730 nm (λex = 680 nm). The fluorescence enhancement of the probe is directly proportional to the F- concentration in the range of 10-300 µM with the detection limit of 4.28 µM. The probe has been successfully used to determine F- concentration in real water and toothpaste samples as well as image F- in living cells. The simplicity and quick response of this probe endow it with the ability of detecting F- rapidly in real samples.

Targeted Delivery of Doxorubicin Using Transferrin-Conjugated Carbon Dots for Cancer Therapy.

A transferrin receptor (TfR)-targeted nanodrug [green fluorescence emission carbon dot (GCD)-polyethylene glycol (PEG)-transferrin (Tf)@doxorubicin (Dox)] for cancer therapy was developed by functionalizing GCDs with PEG, Tf, and Dox. GCDs were synthesized by the one-step hydrothermal method, followed by conjugating PEG and Tf by covalent bonds and loading Dox by electrostatic interactions. The nanodrug exhibits high stability under neutral conditions and effectively releases Dox at pH of 5.5. GCD-PEG-Tf@Dox can be selectively internalized by TfR-overexpressed tumor cells (MCF-7 and K150) via receptor-mediated endocytosis and further release Dox to the nuclei. As a result, GCD-PEG-Tf@Dox exhibits significant lethality to tumor cells (MCF-7 and K150) but greatly reduced toxicity to normal cells [Chinese hamster ovary cell line (CHO)] compared with free Dox. In vivo studies have confirmed that GCD-PEG-Tf@Dox can effectively inhibit tumor proliferation with negligible side effects.

Efficient preparation of nitrogen-doped fluorescent carbon dots for highly sensitive detection of metronidazole and live cell imaging.

Herein, nitrogen-doped carbon dots (N-CDs) emitting blue fluorescence were prepared using L-tartaric acid and triethylenetetramine through a simple and quick microwave-assisted method. The synthesized N-CDs displayed excitation-dependent fluorescence behavior, and their maximum excitation and emission wavelengths were 350 and 425 nm, respectively. The obtained N-CDs, which featured excellent fluorescence properties with a high fluorescence quantum yield of 31%, were applied to detect metronidazole (MNZ), which can effectively quench the fluorescence intensity of N-CDs due to the inner filter effect. This phenomenon was used as basis to develop a label-free fluorescent method for rapid MNZ determination, with the limit of detection of 0.22 µM and corresponding linear range of 0.5-22 µM. Hence, we had established a fluorescence method for MNZ detection and applied it to detect MNZ in real samples with satisfactory results. Finally, N-CDs with superior biocompatibility were applied for cell imaging and MNZ detection by the changes in fluorescence intensity.

A novel fluorescent off-on probe for the sensitive and selective detection of fluoride ions.

A highly sensitive and selective fluorescent probe for fluoride ions has been developed by incorporating the dimethylphosphinothionyl group as a recognition moiety into the fluorophore of coumarin. The detection mechanism is based on the fluoride ion-triggered cleavage of the dimethylphosphinothionyl group, followed by the release of coumarin, which leads to a large fluorescence enhancement at 455 nm (λ ex = 385 nm). Under the optimized conditions, the fluorescence enhancement of the probe is directly proportional to the concentration of fluoride ions in the range of 0-30 µM with a detection limit of 0.29 µM, which is much lower than the maximum content of fluoride ions guided by WHO. Notably, satisfying results have been obtained by utilizing the probe to determine fluoride ions in real-water samples and commercially available toothpaste samples. The proposed probe is rather simple and may be useful in the detection of fluoride ions in more real samples.

Effects of the equimolarly mixed cationic-nonionic surfactants of didodecyldimethylammonium bromide and polyoxyethylene sorbitan monooleate 80 on serum proteins-spectroscopic study.

Liposomes are a common delivery vehicle for drugs or biologicals, but some common surfactants used as liposome components may cause denaturation and malfunction of serum proteins and cell surface proteins. In this study, we examined the effects of liposome lipid didodecyldimethylammonium bromide (DDAB), nonionic polyoxyethylene sorbitan monooleate 80 (Tween 80), and the equimolar mixture on the properties of serum proteins. Bovine serum albumin was selected as the main model protein, and the effects of the DDAB, Tween 80, and a 1:1 mixture on its spectroscopic behavior were investigated. The effects of surfactants on the five major serum proteins: human serum albumin, apolipoprotein A1, transferrin, fibrinogen and immunoglobulin G were also examined. Finally, the results were verified on human serum. The results indicated that weak interactions exist between human serum proteins and the equimolar mixture of DDAB-Tween 80, significantly different from the strong interactions of DDAB and Tween 80 with proteins. The salient features of cationic-nonionic surfactants enable their use in liposome composition, with improved drug delivery efficiency.

Facile and green synthesis of fluorescent carbon dots with tunable emission for sensors and cells imaging.

Most carbon dots (CDs) conventional fabrication approaches produce single colored fluorescent materials, different methods are required to synthesize distinct carbon dots for specific optical applications. Herein, using one-pot hydrothermal treatment of Syringa obtata Lindl, a facile, low-cost and green assay is achieved in the controllable synthesis of blue and green fluorescent carbon dots. The fluorescent emission of CDs can be well-tuned by adding sodium hydroxide in the precursor solution. Blue fluorescent CDs are applied to Fe3+ sensing with a low detection limit of 0.11 µM of linear range from 0.5 to 80 µM, and then further extended to analysis river water samples. Green fluorescent CDs can be applied to pH detection, which show a remarkable linear enhancement in the green fluorescence emission region when the pH is increased from 1.98 to 8.95. Eventually, the detection of Fe3+ and pH are applied for the living cells fluorescent images in MCF-7 cells are achieved successfully, indicating as-synthesized CDs potential toward diverse application as promising candidate.

Gap junctional intercellular communication and endoplasmic reticulum stress regulate chronic cadmium exposure induced apoptosis in HK-2 cells.

Cadmium (Cd), a toxic heavy metal, is known to induce renal toxicity by primarily targeting at renal proximal tubule. Endoplasmic reticulum (ER) stress and gap junctional intercellular communication (GJIC) regulate many pathophysiological processes. Yet, how ER stress and GJIC regulate Cd-induced nephrotoxicity remain elusive. In this study, we treated human proximal tubule (HK-2) cells with 1 µM CdCl2 every other day for 12 days and found that Cd significantly increased cell apoptosis at 10 and 12 days. This cytotoxicity correlated with activation of ER stress and apoptotic signaling evidenced by upregulation of inositol-requiring enzyme 1 (IRE1α), splice X-box binding protein-1 (XBP-1s), and apoptosis signal-regulating kinase 1 (ASK1) proteins. Interestingly, the AKT signaling was activated at 2- and 4-day and then inhibited at 10- and 12-day of Cd treatment; by contrast, Cd decreased GJIC levels at 2- and 4-day followed by a significant increase at 10- and 12-day treatment. Activation of AKT by SC79 or inhibition of GJIC by 18α-glycyrrhetinic acid (18α-GA) completely abolished Cd-induced AKT inhibition and IRE1α-ASK1 activation. Importantly, pretreatment with ER stress inhibitor or 18α-GA significantly mitigated Cd-induced apoptosis. These results suggest that GJIC collaborates with AKT signaling and ER stress in regulating prolonged Cd-treatment-induced apoptosis in HK-2 cells.

A novel polymer probe for Zn(II) detection with ratiometric fluorescence signal.

A conjugated polymer probe comprised of fluorene, quinolone and benzothiazole units was designed and synthesized by the Suzuki coupling reaction. Through the studies of photophysical and thermal properties, the polymer displays blue-emitting feature and good thermal stability. A ratiometric fluorescence signal of the probe for Zn(II) was observed in ethanol with a new emission peak at 555 nm. The probe possesses a high selectivity and sensitivity for Zn(II) during familiar metal ions in ethanol. The detection limit of the probe for Zn (II) is up to 10-8 mol/L. The electron distributions of the polymer before and after bonding with Zn (II) were investigated by the Gaussian 09 software, which agreed with the experimental results. Noticeably, based on the color property of the probe with Zn(II), a series of color test paper were developed for visual detecting Zn(II) ions. This work helps to provide a platform or pattern for the development of polymer fluorescence probe in the chemosensor field.

Connexin 43 mediates changes in protein phosphorylation in HK-2 cells during chronic cadmium exposure.

Connexin 43 (Cx43) is believed to play a role in the mechanisms of toxicity of many chemical species, include cadmium (Cd). In this study, human renal proximal tubule (HK-2) cells were exposed to Cd (1µM, 10 days). Of the 584 protein residues detected using a Phospho Explorer antibody microarray (PEX100), more than half changed their levels of phosphorylation after chronic Cd exposure. Cx43 siRNA attenuated Cd-induced apoptosis and inhibited proliferation, while also attenuating changes in the levels of phosphorylation of many protein residues. According to DAVID Bioinformatics Resources analysis and KEGG PATHWAY database, AKT signal pathway may be the important one. Focusing on the AKT pathway confirmed that Cx43 mediated increased levels of p-PTENSer380/Ser382/Thr383 and decreased levels of p-AKTThr308, p-AKTTyr326, p-ASK1Ser83, and p-p27Thr187, thereby possibly contributing to the Cd-induced apoptosis and inhibited proliferation. These results suggested that AKT pathway was the dominant pathway involved in Cx43-mediated chronic Cd toxicity.

Role of connexin 43 in cadmium-induced proliferation of human prostate epithelial cells.

Connexins (Cxs), the subunits of gap junction channels, are involved in many physiological processes. Aberrant control of Cxs and gap junction intercellular communication may contribute to many diseases, including the promotion of cancer. Cd exposure is associated with increased risk of human prostate cancer and benign prostatic hyperplasia. The roles of Cxs in the effects of Cd on the prostate have, however, not been reported previously. In this study, the human prostate epithelial cell line RWPE-1 was exposed to Cd. A low dose of Cd stimulated cell proliferation along with a lower degree of gap junction intercellular communication and an elevated level of the protein Cx43. Cd exposure increased the levels of intracellular Ca2+ and phosphorylated Cx43 at the Ser368 site. Knockdown of Cx43 using siRNA blocked Cd-induced proliferation and interfered with the Cd-induced changes in the protein levels of cyclin D1, cyclin B1, p27Kip1 (p27) and p21Waf1/Cip1 (p21). The increase in Cx43 expression induced by Cd was presumably mediated by the androgen receptor, because it was abolished upon treatment with the androgen receptor antagonist, flutamide. Thus, a low dose of Cd promotes cell proliferation in RWPE-1, possibly mediated by Cx43 expression through an effect on cell cycle-associated proteins. Cx43 might be a target for prostatic diseases associated with Cd exposure. Copyright © 2017 John Wiley & Sons, Ltd.