Functionalized Green Carbon dots for Specific Detection of Copper in Human Serum Samples and Living Cells.

Intracellular copper ion (Cu2+) is irreplaceable and essential in regulation of physiological and biological processes, while excessive copper from bioaccumulation may cause potential hazards to human health. Hence, effective and sensitive recognition is urgently significant to prevent over-intake of copper. In this work, a novel highly sensitive and green carbon quantum dots (Green-CQDs) were synthesized by a low-cost and facile one-step microwave auxiliary method, which utilized gallic acid, carbamide and PEG400 as carbon source, nitrogen source and surface passivation agent, respectively. The decreased fluorescence illustrated excellent linear relationship with the increasing of Cu2+ concentration in a wide range. Substantial surface amino and hydroxyl group introduced by PEG400 significantly improved selectivity and sensitivity of Green-CQDs. The surface amino chelation mechanism and fluorescence internal filtration effect were demonstrated by the restored fluorescence after addition of EDTA. Crucially, the nanosensor illustrated good cell permeability, high biocompatibility and recovery rate, significantly practical application in fluorescent imaging and biosensing of intracellular Cu2+ in HepG-2 cells, which revealed a potential and promising biological applications in early diagnosis and treatment of copper ion related disease.

Oxidized Dextran/Chitosan Hydrogel Engineered with Tetrasulfide-Bridged Silica Nanoparticles for Postsurgical Treatment.

Tumor recurrence and wound microbial infection after tumor excision are serious threats to patients. Thus, the strategy to supply a sufficient and sustained release of cancer drugs and simultaneously engineer antibacterial properties and satisfactory mechanical strength is highly desired for tumor postsurgical treatment. Herein, A novel double-sensitive composite hydrogel embedded with tetrasulfide-bridged mesoporous silica (4S-MSNs) is developed. The incorporation of 4S-MSNs into oxidized dextran/chitosan hydrogel network, not only enhances the mechanical properties of hydrogels, but also can increase the specificity of drug with dual pH/redox sensitivity, thereby allowing more efficient and safer therapy. Besides, 4S-MSNs hydrogel preserves the favorable physicochemical properties of polysaccharide hydrogel, such as high hydrophilicity, satisfactory antibacterial activity, and excellent biocompatibility. Thus, the prepared 4S-MSNs hydrogel can be served as an efficient strategy for postsurgical bacterial infection and inhibition of tumor recurrence.

Construction of optical dual-mode sensing platform based on green emissive carbon quantum dots for effective detection of ClO- and cellular imaging.

Hypochlorite (ClO-) is an important redox regulator in reactive oxygen species, which play a considerable role in oxidative stress and related diseases. Hence, accurate and sensitive monitoring of ClO- concentration was urgently needed in the fields of life sciences, food and environment. Bright green fluorescent carbon quantum dots (G-CQDs) were synthesized utilizing one-step hydrothermal method with citric acid and acriflavine precursors. Through TEM, FTIR, XPS and zeta potential characterization procedures, G-CQDs illustrated uniformly dispersed and significant number of -NH2 and -OH on the surface. Meanwhile, the fluorescence and colorimetric analysis exhibited wide linear range and low detection limit response to ClO-. The fluorescence changes of G-CQDs were identified via smartphone to realize mobile sensing of ClO-. Subsequently, G-CQDs was applied for visualization and quantitative detection of ClO- in drinking water samples with satisfactory recovery rate. More importantly, G-CQDs demonstrated good water solubility, optical stability and excellent biocompatibility, which offered a promising analysis approach in cell imaging and exogenous ClO- detection in living cells. G-CQDs illustrated bright prospect and great potential in practical application of ClO- associated disease prevention and early clinical diagnosis.

Inducing tumor ferroptosis via a pH-responsive NIR-II photothermal agent initiating lysosomal dysfunction.

Ferroptosis is a unique programmed cell death process that was discovered a few years ago and plays an important role in tumor biology and treatment. However, it still remains a challenge to modulate tumor ferroptosis by spatiotemporally controlled cell-intrinsic Fenton chemistry. Herein, a pH activated photothermal sensitizer IR-PE has been designed and synthesized on the basis of cyanine bearing a diamine moiety, which is capable of triggering the lysosomal dysfunction-mediated Fenton pathway under the irradiation of near-infrared light to evoke ferroptosis, thereby improving antitumor efficacy and mitigating systemic side effects.

Photo-crosslinked enhanced double-network hydrogels based on modified gelatin and oxidized sodium alginate for diabetic wound healing.

The diabetic wound is hard to repair due to bacterial infection, lasting inflammation, and so on. Therefore, it is vital to fabricate a multi-functional hydrogel dressing for the diabetic wound. In this study, a kind of dual-network hydrogel loaded with gentamicin sulfate (GS) based on sodium alginate oxide (OSA) and glycidyl methacrylate gelatin (GelGMA) was designed through the Schiff base bonding and photo-crosslinking to promote the diabetic wound healing. The hydrogels exhibited stable mechanical properties, high water absorbency, and good biocompatibility and biodegradability. Antibacterial results showed that gentamicin sulfate (GS) had a remarkable antibacterial effect on Staphylococcus aureus and Escherichia coli. In a diabetic full-thickness skin wound model, the GelGMA-OSA@GS hydrogel dressing dramatically decreases inflammation and accelerated re-epithelialization and granulation tissue formation, promising applications in promoting diabetic wound healing.

A mitochondria-targeting self-assembled carrier-free lonidamine nanodrug for redox-activated drug release to enhance cancer chemotherapy.

Mitochondria play a vital role in maintaining cellular homeostasis. In recent years, studies have found that mitochondria have an important role in the occurrence and development of tumors, and targeting mitochondria has become a new strategy for tumor treatment. Lonidamine (LND), as a hexokinase inhibitor, can block the energy supply and destroy mitochondria. However, poor water solubility and low mitochondrial selectivity limit its clinical application. To overcome these obstacles, we report redox-activated self-assembled carrier-free nanoparticles (Cy-TK-LND NPs) based on a small molecule prodrug, in which photosensitizer IR780 (Cy) which targets mitochondria is conjugated to LND via a sensitive thioketal (TK) linker. Intracellular oxidative stress induced by laser radiation leads to the responsive cleavage of Cy-TK-LND NPs, facilitating the release of free LND into mitochondria. Subsequently, LND damages mitochondria, triggering the apoptosis pathway. The results show the effective killing effect of Cy-TK-LND NPs on cancer cells in vitro and in vivo. The IC50 value of irradiated Cy-TK-LND NPs is 5-fold lower than that of free LND. Moreover, tumor tissue section staining results demonstrate that irradiated Cy-TK-LND NPs induce necrosis and apoptosis of tumor cells, upregulate cytochrome C and pro-apoptotic Bax, and downregulate anti-apoptotic Bcl-2. Generally, Cy-TK-LND NPs exhibit efficient mitochondria-targeted delivery to improve the medicinal availability of LND. Accordingly, such a carrier-free prodrug-based nanomedicine holds promise as an effective cancer chemotherapy strategy.

Novel Green Fluorescent Probe Stem From Carbon Quantum Dots for Specific Recognition of Tyrosinase in Serum and Living Cells.

Tyrosinase (TYR), an important biomarker for melanoma, offered significant information early detection of melanoma and may decrease the likelihood of mortality. Therefore, this article constructed a highly sensitive and selective green fluorescent functionalized carbon quantum dots (TYR-CQDs) for tyrosinase (TYR) activity detection by one-step hydrothermal protocol utilizing catechol, citric acid and urea as precursors. The prepared TYR-CQDs illustrated excellent linear relationship and broad linear range with a low detection limit, which exhibited high accuracy and recovery in quantitative determination of TYR in human serum samples. Furthermore, the TYR-CQDs had successfully realized intracellular TYR detection owing to excellent biocompatibility, high anti-interference ability and good cellular imaging capability, suggesting the potential biomedical applications in early diagnosis of melanoma and other tyrosinase-related diseases.

Paleoenvironment Evolutionary Characteristics of Niutitang Shale in Western Hubei, Middle Yangtze, China.

The black shale developed in the first section of the Niutitang formation (ϵ1 n 1) is one of the most important shale gas reservoirs in western Hubei, and its geological characteristics have been sufficiently studied by many predecessors. However, there are still three aspects that need further research: the origin of silicon, the discrimination of the euxinic sulfuretted and the anoxic ferruginous conditions, and the main controlling factors of organic matter enrichment. Based on geochemical data from well ZD1 located in the city of Yichang in western Hubei, first, the geochemical characteristics of ϵ1 n 1 are analyzed, then the provenance, depositional site, and paleoenvironment evolution are discussed, and finally, the main controlling factor of organic matter enrichment is revealed. The results show that ϵ1 n 1 can be divided into two units, organic-rich shales (ORS) and organic-lean shales (OLS), which have average total organic carbon contents of 4.21 and 0.84%, respectively. Additionally, the ORS is characterized by high contents of SiO2, U, V, Ni, Zn, and Cu and left-inclining types of rare earth element distribution curves. ϵ1 n 1 is located in a passive continental margin with a material source mainly from mixed felsic and mafic rocks. Compared with the OLS, the content of biological quartz is much greater, and the terrigenous input is less in the ORS. The paleoclimate is cold and humid with low salinity in the ORS, whereas it is hot and dry with high salinity in the OLS. ϵ1 n 1 is deposited in a semistagnant basin, and the ORS shows a relatively lower stagnant degree with euxinic to anoxic conditions and moderate to high paleoproductivity, while the OLS shows a high stagnant degree with suboxic to oxic conditions and lower paleoproductivity. The redox conditions are the main controlling factors affecting organic matter enrichment. The environmental evolution model with three stages shows that there is a good causal relationship between redox conditions, paleoproductivity, and sea level fluctuation. The black carbonaceous siliceous in the lower part of the ORS with a thickness of approximately 40 m is the most favorable layer, which will provide a theoretical basis for further shale gas exploration of ϵ1 n 1 in the western Hubei.

Adenine-stabilized carbon dots for highly sensitive and selective sensing of copper(II) ions and cell imaging.

Adenine-stabilized carbon dots (A-CDs) are shown to be a viable fluorescent probe for highly sensitive detection and imaging of Cu2+. The probe has a linear fluorometric response in the 1-700 nM concentration range and a 0.3 nM detection limit. The probe, with excitation/emission maxima at 380/435 nm, is highly selective for Cu2+ over other metal ions, anions, amino acids, and biomolecules. The fluorescence quenching mechanism of the A-CDs by Cu2+ is investigated using transmission electron microscopy images coupled with elemental mapping, X-ray photoelectron spectroscopy, X-ray-excited Auger electron spectroscopy, fluorescence lifetime, UV-visible spectroscopy, and cyclic voltammetry. The experimental results show that the fluorescence quenching is caused by the combination of Cu2+-coordination-induced aggregation of the A-CDs, the reduction of Cu2+ by the A-CDs, and the nonradiative photoinduced electron transfer process from the A-CDs to Cu2+ or metallic Cu. The high sensitivity and high selectivity of the sensor are ascribed to the chemical interactions between the A-CDs and Cu2+, the photophysical process between the A-CDs and Cu2+, and the high fluorescence quantum yield of the A-CDs (44.6%). The A-CDs have excellent water solubility, good stability to variation of pH values, high photostability, fast response time, and low cytotoxicity. They are successfully employed for intracellular imaging of Cu2+ in HepG2 cells and Cu2+ detection in the tap water samples.

Fluorescent recognition and selective detection of nitrite ions with carbon quantum dots.

The nitrite ion (NO2-) is a vital inorganic species that occurs both in natural ecological systems and human bodies. The high concentration of NO2- can be harmful for animal and human health. It is important to develop a simple, sensitive, reliable, and economic methodology to precisely monitor NO2- in various environmental and biological fields. Thus, a novel nitrite biosensor based on carbon quantum dots (PA-CDs) has been constructed and prepared via a high-efficiency, one-pot hydrothermal route using primary arylamines (PA) such as m-phenylenediamine. The device exhibits bright green fluorescence and a high quantum yield of 20.1% in water. In addition, the PA-CDs also possess two broad linear ranges: 0.05-1.0 µM and 1.0-50 µM with a low detection limit of 7.1 nM. The classical diazo reaction is firstly integrated into the PA-CD system by primary arylamines, which endows the system with high sensitivity and specific selectivity towards nitrite. Importantly, the nanosensor can detect NO2- in environmental water and serum samples with high fluorescence recoveries, demonstrating its feasibility in practical applications. This work broadens a new method to fabricate novel nanosensors and provides a prospective application for fluorescent carbon quantum dots (CDs). Graphical abstract.

A Probe for Fluorescence Detection of the Acetylcholinesterase Activity Based on Molecularly Imprinted Polymers Coated Carbon Dots.

This paper presents a new probe for fluorescence detection of the acetylcholinesterase (AChE) activity based on molecularly imprinted polymer (MIP) coated carbon dots (C-dots) composite. The C-dots were hydrothermally synthesized with grafted silica surface and sealed with molecularly imprinted polymers in silica pores (MIP@C-dots) in situ. Removed the original template molecules, the MIP@C-dots composite exhibits quite high selectivity for acetylthiocholine (ACh). With AChE, its substrate ACh will be hydrolyzed into thiocholine and the fluorescence signals exhibit a dramatic decrease at 465 nm, Under optimal conditions, the fluorescent probe shows sensitive responses to AChE in the range of 0.01-0.6 mU/mL. The detection limits of AChE are as low as 3 µU/mL. These experiments results validate the novel fluorescent probe based on MIP@C-dots composite, paving a new way to evaluation of AChE activity and Screening inhibitors.

Phosphinate-based mitochondria-targeted fluorescent probe for imaging and detection of endogenous superoxide in live cells and in vivo.

Monitoring superoxide anion radical (O2•-) in live cells and in vivo is of great significance since O2•- is the precursor of other reactive oxygen species and has been closely associated with various physiological and pathological processes. Herein, we developed a novel mitochondria-targeted fluorescent probe PF-MitoSOX Green in which the phosphinate moiety is utilized to recognize O2•- with high sensitivity and selectivity. Confocal imaging results illustrated that PF-MitoSOX Green can not only detect intracellular O2•-, but also can conveniently visualize its production in cells and Caenorhabditis elegans. The present study illustrates that PF-MitoSOX Green provides a novel approach for imaging and detecting O2•- in live cells and in vivo.

Fabrication of Konjac glucomannan-based composite hydrogel crosslinked by calcium hydroxide for promising lacrimal plugging purpose.

Swelling, mechanical strength, flexibility, and toughness are important parameters in hydrogel preparation for application in the human body. Herein, composite hydrogels were prepared using a mix of Konjac glucomannan (KGM), sodium alginate (SA), and polyvinyl alcohol (PVA) cross-linked by calcium hydroxide. The PVA/KGM/SA composite hydrogel showed a suitable swelling ratio and rate, as well as elasticity and flexibility. In addition, the elongation at break was 660.3%, with a breaking strength of 87.25 kPa and a compression modulus of 1.660 MPa. Rheological studies showed that the composite hydrogel was composed of a multiply cross-linked network involving chemical and physical interactions, thereby affecting the elasticity and flexibility of the gel. Interestingly, the composite gel network was reformed when the temperature decreased. In rabbit models of dry eye, the hydrogel effectively maintained the normal tear meniscus height and increased the low tear meniscus area. The results therefore showed that the PVA/KGM/SA gels not only provide a simple, effective, and safe method for the preparation of hydrogels, but also have potential applications in the treatment of dry eye syndrome.

A mitochondria-targeted nitric oxide donor triggered by superoxide radical to alleviate myocardial ischemia/reperfusion injury.

A novel mitochondria-targeted superoxide-responsive nitric oxide donor was developed by incorporation of diphenylphosphinyl and triphenylphosphonium groups into diazeniumdiolate, enabling remarkable protection against ischemia/reperfusion injury in H9c2 cells and isolated rat hearts.

Effects of core size and PEG coating layer of iron oxide nanoparticles on the distribution and metabolism in mice.

INTRODUCTION: In vivo distribution of polyethylene glycol (PEG)ylated functional nanoparticles is vital for determining their imaging function and therapeutic efficacy in nanomedicine. However, contradictory results have been reported regarding the effect of core size and PEG surface of the nanoparticles on biodistribution. METHODS: To clarify this ambiguous understanding, using iron oxide nanoparticles (IONPs) as a model system, we investigated the effect of core size and PEG molecule weights on in vivo distribution in mice. Three PEGylated IONPs, including 14 nm IONP@PEG2,000, 14 nm IONP@PEG5,000, and 22 nm IONP@PEG5,000, were prepared with a hydrodynamic size of 26, 34, and 81 nm, respectively. The blood pharmacokinetics and tissue distribution were investigated in detail. RESULTS: The results indicated that the PEG layer, rather than core size, played a dominant role in determining the half-life time of IONPs. Specifically, increased molecular weight of the PEG layer led to a longer half-life time. These PEGylated IONPs were mainly excreted by liver clearance. While the PEG molecular layer constituted the key factor to determine the clearance ratio, core size affected the clearance rate. CONCLUSION: Complete blood count analysis and histopathology suggested excellent biocompatibility of PEGylated IONPs for future clinical trials.

A photostable fluorescent probe for long-time imagining of lysosome in cell and nematode.

Lysosome fluorescent imaging has been widely used in the field of biological staining and diagnostics, which plays a key role in understanding intracellular metabolism and various physiological processes. However, for most currently used small-molecule lysotrackers, the photostability is often unsatisfactory when used for long-term and real-time visualization of lysosomal dynamics. Herein, we reported a new lysosome-targetable photostable fluorescent probe (i.e. MPL-NPA), and results showed that MPL-NAP possesses superior photostability, appreciable tolerance to pH change, low cytotoxicity and high lysosome targeting ability. These findings confirm that MPL-NAP is a well-suited imaging agent for targeting lysosome and enables long-term and real-time monitor of lysosome morphological changes under physiological processes.

AMF responsive DOX-loaded magnetic microspheres: transmembrane drug release mechanism and multimodality postsurgical treatment of breast cancer.

DOX-loaded magnetic alginate-chitosan microspheres (DM-ACMSs) were developed as a model system to evaluate alternating magnetic field (AMF)-responsive, chemo-thermal synergistic therapy for multimodality postsurgical treatment of breast cancer. This multimodality function can be achieved by the combination of DOX for chemotherapy, with superparamagnetic iron oxide nanoparticles (SPIONs) as magnetic hyperthermia agents and drug release trigger. Both moieties are encapsulated in ACMSs which also allow on-demand drug release. It is demonstrated that the optimized SPION content in DM-ACMSs is about 0.29 mg Fe, at which DM-ACMSs could exhibit the best hyperthermia performance. Under a remote AMF, DM-ACMs can quickly reach a 22.5% cumulative drug release in the tumor site within 10 min upon exposure under AMF, whereas only 0.2% DOX is released in the absence of AMF. Furthermore, a comparison study of AMF and water bath as heating source indicates that the cumulative drug release amount upon AMF exposure is twice that by water bath heating. Further analysis revealed that the AMF stimulated drug release is driven by both thermal and concentration gradient from inside to outside, which can be well-described by the coupling mechanism of mass and heat transfer using the Soret diffusion model. In vitro cytotoxicity tests on MCF-7 breast cancer cells show that the combined therapy based on DM-ACMSs leads to 95.5% cell death, about 1.5-fold and 1.1-fold higher than that of single magnetic hyperthermia or chemotherapy, respectively. The in vivo anti-tumor effect on tumor-bearing mice demonstrates that the residual tumor disappears in 12 days after chemo-thermal synergistic treatment using DM-ACMSs, and there is no recurrence in the entire experiment period (40 days) as compared to 25 days recurrence for single-modality treatment. Our results not only provide an innovative DM-ACMSs system as a stimuli-responsive, synergistic chemo-thermal therapy platform for efficient reduction in the recurrence of breast cancer, but also provide insight into the intricate interplay of the functional components in magnetic hydrogel microspheres.

Enhancement of membrane stability on magnetic responsive hydrogel microcapsules for potential on-demand cell separation.

It is of high interest to obtain hydrogel membranes with optimum mechanical stability, which is a prerequisite to the successful fabrication of hydrogel microcapsules for cell separation. In this work, we developed magnetic responsive alginate/chitosan (MAC) hydrogel microcapsules by co-encapsulation of microbial cells and superparamagnetic iron oxide nanoparticles (SPIONs) reacting under a high voltage electrostatic field. We investigated the influence of the molecular weight of chitosan, microcapsules size, and membrane crosslinking time on the swelling behavior of microcapsules as an indicator of stability of the membranes. The results demonstrated that the suitable membrane stability conditions were obtained by a crosslinking of the microspheres with a chitosan presenting a molecular weight of 70kDa for 15-30min resulting in a membrane thickness of approximately 30mm. Considering the need of maintaining the cells inside the microcapsules, fermentation at 37°C and at neutral pH was favorable. Moreover, the MAC microcapsules sizing between 300 and 380µm were suitable for immobilizing Bacillus licheniformis in a 286h multiple fed-bath operation with no leakage of the SPIONs and cells. Overall, the results of this study provided strategies for the rational design of magnetic microcapsules exhibiting suitable mechanical stable membranes.

New photostable naphthalimide-based fluorescent probe for mitochondrial imaging and tracking.

Monitoring mitochondria morphological changes temporally and spatially exhibits significant importance for diagnosing, preventing and treating various diseases related to mitochondrial dysfunction. However, the application of commercially available mitochondria trackers is limited due to their poor photostability. To overcome these disadvantages, we designed and synthesized a mitochondria-localized fluorescent probe by conjugating 1,8-naphthalimide with triphenylphosphonium (i.e. NPA-TPP). The structure and characteristic of NPA-TPP was characterized by UV-vis, fluorescence spectroscopy, (1)HNMR, (13)CNMR, FTIR, MS, etc. The photostability and cell imaging were performed on the laser scanning confocal microscopy. Moreover, the cytotoxicity of NPA-TPP on cells was evaluated using (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The results showed that NPA-TPP not only has high sensitivity and specificity to mitochondria, but also exhibits super-high photostability, negligible cytotoxicity and good water solubility. In short, NPA-TPP indicates great potential for targeting mitochondria and enables a real-time and long-term tracking mitochondrial dynamics changes.

Highly sensitive free radical detection by nitrone-functionalized gold nanoparticles.

The detection of free radicals and related species has attracted significant attention in recent years because of their critical roles in physiological and pathological processes. Among the methods for the detection of free radicals, electron spin resonance (ESR) coupled with the use of the spin trapping technique has been an effective approach for characterization and quantification of these species due to its high specificity. However, its application in biological systems, especially in in vivo systems, has been greatly limited partially due to the low reaction rate between the currently available spin traps with biological radicals. To overcome this drawback, we herein report the first example of nitrone functionalized gold nanoparticles (Au@EMPO) as highly efficient spin traps in which the thiolated EMPO (2-(ethoxycarbonyl)-2-methyl-3,4-dihydro-2H-pyrrole 1-oxide) derivative was self-assembled on gold nanoparticles. Kinetic studies showed that Au@EMPO has a 137-fold higher reaction rate constant with ˙OH than PBN (N-tert-butyl-α-phenylnitrone). Owing to the high rate of trapping ˙OH by Au@EMPO as well as the high stability of the resulting spin adduct (t½ ∼ 56 min), Au@EMPO affords 124-fold higher sensitivity for ˙OH than EMPO. Thus, this new nanospin trap shows great potential in trapping the important radicals such as ˙OH in various biological systems and provides a novel strategy to design spin traps with much improved properties.