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The increased risk of breast cancer metastasis is closely linked to the effects of platelets. Our previously light-switchable diphtheria toxin A fragment (DTA) gene system, known as the LightOn system, has demonstrated significant therapeutic potential; it lacks antimetastatic capabilities. In this study, we devised an innovative system by combining cell membrane fusion liposomes (CML) loaded with the light-switchable transgene DTA (pDTA) and a ticagrelor (Tig) prodrug. This innovative system, named the sequential rocket-mode bioactivating drug delivery system (pDTA-Tig@CML), aims to achieve targeted pDTA delivery while concurrently inhibiting platelet activity through the sequential release of Tig triggered by reactive oxygen species with the tumor microenvironment. In vitro investigations have indicated that pDTA-Tig@CML, with its ability to sequentially release Tig and pDTA, effectively suppresses platelet activity, resulting in improved therapeutic outcomes and the mitigation of platelet driven metastasis in breast cancer. Furthermore, pDTA-Tig@CML exhibits enhanced tumor aggregation and successfully restrains tumor growth and metastasis. It also reduces the levels of ADP, ATP, TGF-β, and P-selectin both in vitro and in vivo, underscoring the advantages of combining the bioactivating Tig prodrug nanoplatform with the LightOn system. Consequently, pDTA-Tig@CML emerges as a promising light-switchable DTA transgene system, offering a novel bioactivating prodrug platform for breast cancer treatment.

Epidemiology shows that more than 6.8 million people in the world are influenced by inflammatory bowel disease (IBD) each year. IBD is a refractory inflammatory disease, and the disease mainly affects the colon. Shikonin (SK) was originally extracted from traditional Chinese medicine “Zicao” (with an English name Lithospermum erythrorhizon) and found to inhibit inflammation, regulate immunity, and be involved in healing wounds. Herein, we used chitosan (CS), hyaluronic acid (HA), and pH-responsive polymer Eudragits S100 (ES100) to design SK-loaded ES100/HA/CS nanoparticles (SK@SAC) as an oral delivery system to treat the colitis mice. Particle size of SK@SAC was 190.3 nm and drug loading efficiency was 6.6%. SAC nanoparticles accumulated in RAW264.7 macrophages and exhibited colitis-targeted ability by increasing the local drug concentration as well as reducing nonspecific distribution after oral gavage. In TNBS-induced IBD mice, SK@SAC treatment had significant therapeutic effects, regulated of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and anti-inflammatory cytokines (IL-10 and TGF-β), and also inhibited COX-2 and iNOS activity. SK@SAC also increased tight junction protein ZO-1 and occludin to some extent. These promising results showed that this novel oral SK-loaded nanoparticle drug delivery system for targeted treatment provides a new strategy for the management of IBD.

Protein methylation is one of the most common and important post-translational modifications, and it plays vital roles in epigenetic regulation, signal transduction, and chromatin metabolism. However, due to the diversity of methylation forms, slight difference between methylated sites and nonmodified ones, and ultralow abundance, it is extraordinarily challenging to capture and separate methylated peptides from biological samples. Here, we introduce a simple and highly efficient method to separate methylated and nonmethylated peptides using 18-crown-6 as a mobile phase additive in high-performance liquid chromatography. Selective complexation between lysine and 18-crown-6 remarkably increases the retention of the peptides on a C18 stationary phase, leading to an excellent baseline separation between the lysine methylated and nonmethylated peptides. A possible binding mechanism is verified by nuclear magnetic resonance titration, biolayer interferometry technology, and quantum chemistry calculation. Through establishment of a simple enrichment methodology, a good selectivity is achieved and four methylated peptides with greatly improved signal-to-noise (S/N) ratios are successfully separated from a complex peptide sample containing 10-fold bovine serum albumin tryptic digests. By selecting rLys N as an enzyme to digest histone, methylation information in the histone could be well identified based on our enrichment method. This study will open an avenue and provide a novel insight for selective enrichment of lysine methylated peptides in post-translational modification proteomics.

In view of the size and hydrophilicity of glycopeptides, materials having suitable channels (size-exclusion) and strong hydrophilic surface (hydrophilic interaction) are preferred to enrich the glycopeptides in biological samples. Metal–organic frameworks (MOFs) are good candidates. However, their smaller microporous channels and low chemical stability have limited the application. Herein, a facile strategy was established to construct hydrophilic mesoporous MOF via synergistic etching and surface functionalization by using phytic acid (PA). Besides, polyvinylpyrrolidone (PVP) was added during MOF synthesis to enhance the water stability of the MOF. Owing to the expanded hydrophilic mesoporous channels, the PA-modified Ce-MOF effectively and selectively captured 422 glycopeptides from 155 glycoproteins in tryptic digests of human serum (2 μL). The present work sheds light on the easy fabrication of hydrophilic mesoporous materials, and this established material holds unique advantages for glycopeptides analysis in biological samples.

The controversy surrounding the use of diphtheria toxin (DT) as a therapeutic agent against tumor cells arises mainly from its unexpected harmfulness to healthy tissues. We encoded the cytotoxic fragment A of DT (DTA) as an objective gene in the Light-On gene-expression system to construct plasmids pGAVPO (pG) and pU5-DTA (pDTA). Meanwhile, a cRGD-modified ternary complex comprising plasmids, chitosan, and liposome (pG&pDTA@cRGD-CL) was prepared as a nanocarrier to ensure transfection efficiency. Benefiting from spatiotemporal control of this light-switchable transgene system and the superior tumor targeting of the carrier, toxins were designed to be expressed selectively in illuminated lesions. In vitrostudies suggested that pG&pDTA@cRGD-CL exerted arrest of the S phase in B16F10 cells upon blue light irradiation and, ultimately, induced the apoptosis and necrosis of tumor cells. Such DTA-based treatment exerted enhanced antitumor activity in mice bearing B16F10 xenografts and displayed prolonged survival time with minimal side effects. Hence, we described novel DTA-based therapy combined with nanotechnology and the Light-On gene-expression system: such treatment could be a promising strategy against melanoma.

Photodynamic therapy (PDT) utilizes photosensitizers to convert innoxious oxygen to cytotoxic reactive oxygen species under an appropriate light, thus inducing cancer cells necrosis. However, PDT performs in an oxygen-dependent method to destroy cells while hypoxia is a feature for most solid tumors. To effectively improve the PDT effect against solid tumors, an oxygen self-supplying and pH-sensitive therapeutic nanoparticle (PTFC) has been developed by the self-assembly of a tetrakis(pentafluorophenyl) chlorin (TFPC)-conjugated block copolymer (POEGMA-b-P(DEAEMA-co-GMA)). PTFC nanoparticles can transport oxygen to a tumor site with their accumulation in the tumor on account of the good oxygen solubility, therefore relieving the oxygen deficiency of a solid tumor and enhancing the PDT efficacy. It is worth noting that the oxygen loading was realized by the fluorinated photosensitizer itself. In addition, the phototoxicity of PTFC nanoparticles is greatly improved in an acidic aqueous environment due to the DEAEMA unit protonation, which not only enhanced the cellular uptake of nanoparticles but also weakened the aggregation of photosensitizers. Taking the hypoxia and acidic microenvironment of solid tumors, PTFC nanoparticles could be efficiently taken up and disassembled to release oxygen upon accumulation at tumor sites, thus significantly improving the PDT efficacy against solid tumors.

Developing reliable and facile approaches for alkaline phosphatase (ALP) sensing is important due to its role as a clinical biomarker for many diseases. In this study, we proposed a new and convenient colorimetric assay based on the pyrophosphate (PPi)-mediated oxidase-mimicking activity switching of nanosized MnFe2O4for the detection of ALP. The synthesized MnFe2O4exhibited high oxidase-like activity to catalyze the oxidation of colorless 3,3′,5,5′-tetramethylbenzidine (TMB) to its blue product TMBox in the presence of dissolved O2, leading to a color reaction rapidly and remarkably; PPi could significantly inhibit the activity of the MnFe2O4nanozyme via the strong interaction between PPi and the Fe(III) species in MnFe2O4, resulting in the suppression of the TMB color reaction; when ALP was added, it hydrolyzed the PPi substrate to phosphate (Pi) that had no obvious effect on the MnFe2O4activity, and such that the TMB color reaction catalyzed by the nanozyme could be observed again. With the above principle, linear colorimetric determination of ALP in the scope of 0.6–55 U L−1was achieved, giving the limit of detection down to 0.27 U L−1. Besides, the developed assay could provide selective response toward ALP against other co-existing biological species. Furthermore, reliable detection of ALP in human serum samples was verified by our assay, revealing its great promise as an effective and facile tool for ALP monitoring in clinical practice.

A hydrophilic nanocomposite was synthesized by an easy route to improve glycopeptides enrichment efficiency. This new composite, prepared with a method based on electrostatic interaction, was demonstrated to be efficient for immobilization of carrageenan on graphene oxide/poly(ethylenimine) support (denoted as GO–PEI–Carr). Carrageenan, which has a large number of hydroxyl groups and is fully negatively charged, is a new modified phase of hydrophilic materials in glycoproteomics. The introduction of carrageenan provided the composite not only a perfect surface charge but also a greater ability to enrich glycosylated peptides. Thirty-four glycopeptides from human serum immunoglobulin G (IgG) tryptic digests were obviously observed with greatly improved signal-to-noise (S/N) ratio. A good selectivity was still kept even when the molar ratio of IgG and bovine serum albumin (BSA) tryptic digest mixtures reached to 1:500. Meanwhile, 76 glycopeptides derived from 56 glycoproteins with 83 N-glycosylation sites were identified from human serum and 149 glycopeptides derived from 129 glycoproteins with 157 N-glycosylation sites were identified from mouse liver tissues, which showed the ability to enrich glycopeptides from complex biological samples. In addition, GO–PEI–Carr exhibited a unique repeatability and stability even after enrichment of glycopeptides for 20 times. It also performed a higher sensitivity (1 fmol/μL IgG), a better enrichment capacity (up to ∼300 mg/g), and an ideal enrichment recovery (90.8% and 109.5%) for glycopeptides enrichment, indicating a great potential for the application of glycoproteomic research.

In this work, multifunctional Ti4+-immobilized phytic acid-modified magnetic graphene (denoted as MagG@PEI@PA-Ti4+) nanocomposites were fabricated through a facile route for simultaneous/respective enrichment of N-glyco- and phosphopeptides. Phytic acid (PA), with six phosphate groups, possesses excellent hydrophilicity and metal ion coordination ability, which endowed the MagG@PEI@PA-Ti4+with combined properties of immobilized metal ion affinity chromatography (IMAC)- and hydrophilic interaction liquid chromatography (HILIC)-based materials. On the basis of the different binding ability of N-glyco- and phosphopeptides on MagG@PEI@PA-Ti4+, the MagG@PEI@PA-Ti4+nanocomposites could enrich N-glyco- and phosphopeptides simultaneously or respectively by using different enrichment conditions, achieving controllable selective enrichment of N-glyco- and phosphopeptides. The proposed nanocomposites demonstrated an outstanding performance for selective enrichment of N-glycopeptides (selectivity, 1:1000 molar ratios of IgG/BSA; sensitivity, 0.5 fmol/μL IgG; loading capacity, 300 mg g–1; recovery, >90%) and phosphopeptides (selectivity, 1:5000 molar ratios of α-casein/BSA; sensitivity, 0.1 fmol/μL α-casein; loading capacity, 100 mg g–1; recovery, >90%). Taking advantage of these merits, a total of 393 N-glycopeptides derived from 259 glycoproteins and 574 phosphopeptides derived from 341 phosphoproteins were identified from 200 μg of HeLa cell extracts through a single-step enrichment using MagG@PEI@PA-Ti4+.

Here, the combination of Nafion with microporous hollow carbon spheres (MHCS) is first proposed to fabricate a disposable metal-free electrode for heavy metal stripping sensing. The MHCS-Nafion composite film electrode is prepared by drop-casting a mixture of MHCS and Nafion onto the lab-made screen-printed carbon electrode (SPCE*). Results demonstrate that the interfusion of MHCS into Nafion offers enhanced performance for the electro-enrichment and stripping of lead and cadmium over the only Nafion film: 1) abundant MHCS immobilized on the electrode surface serve as effective nucleation sites for metal ion reduction; 2) the mixing of MHCS into Nafion enlarges the active surface of negative-charged Nafion for the electrostatic adsorption of metal cations. The proposed MHCS-Nafion/SPCE* provides linear responses for Pb2+and Cd2+in the range of 2–200 μg/L, with a detection limit of 1.37 and 1.63 μg/L, respectively. Practical applications of the sensor in water sample detection with good accuracy have also been confirmed.

The analysis of circulating tumor DNA (ctDNA) turns to be increasingly significant considering its potential value in the clinical diagnosis of cancer. Herein, a ctDNA electrochemical biosensor was developed with a low detection limit and high selectivity by using three-dimensional graphene-like homogeneous carbon architecture (3D-GHC600) loaded with gold-platinum (AuPt). The 3D-GHC600was derived from the annealing process of copper-based metal-organic framework (denoted as Cu-BTC) at the optimal temperature (600 °C), which includes the merits of large area, rich mesopores, homogeneous size and morphology, and 3D structure. AuPt was formed on the 3D-GHC600surface via an in-situ reduction reaction. Characterizations demonstrated that the resultant composite catalyst (AuPt/3D-GHC600) was prepared successfully and exhibited remarkable electrochemical properties. Further, the catalyst was used as a label of signal probes (SPs) to form SPs-label. The hybridization reactions were completed by layer-by-layer recognition of capture probes (CPs), target DNA (tDNA), and SPs-label on the electrode, thus forming a sandwich-like structure. The current signals of the SPs-label towards the electrocatalytic reduction of H2O2were recorded in all tests for tDNA analysis. Accordingly, this recommended biosensor of tDNA showed good performance including a wide linear range of 10-8M - 10-17M with a detection limit of 2.25×10-18M (S/N=3), excellent selectivity for the recognition of different interferences, satisfying reproducibility, good stability, and outstanding recovery. These results demonstrated the promising application of the biosensor in the detection of ctDNA.

The effect of mercury(ii) ion on the exonucleolytic activity of Exo III was investigated by using microchip-based microfluidic electrophoresis coupled with polyacrylamide gel electrophoresis. This is the first report of this inhibitory effect with qualitative and quantitative analysis. With a series concentration of Exo III, the inhibition was quantitatively examined at various concentrations of mercuric ion ranging from 0 to 1 μM. For a given concentration of Exo III, the inhibition increased with increasing concentration of mercuric ions, whereas increasing concentration of Exo III hindered the inhibition activity. The inhibiting effect of 1 μM Hg2+dropped significantly from (84.7 ± 1.95)% to (3.9 ± 1.25)% when the concentration of Exo III was increased from 0.02 to 0.5 units per μL. This study expands the application of microfluidic analytical methods to biochemistry and lays the foundation for the development of environmental research and genetic studies.

Integrating the advantages of screen printing technology with the encouraging electroanalytical characteristic of metallic bismuth, we developed an ultrasensitive and disposable screen-printed bismuth electrode (SPBE) modified with multi-walled carbon nanotubes (MWCNTs) for electrochemical stripping measurements. Metallic bismuth powders and MWCNTs were homogeneously mixed with graphite-carbon ink to mass-prepare screen-printed bismuth electrode doped with multi-walled carbon nanotubes (SPBE/MWCNT). The electroanalytical performance of the prepared SPBE/MWCNT was intensively evaluated by measuring trace Hg(II) with square-wave anodic stripping voltammetry (SWASV). The results indicated that the SPBE modified with 2 wt% MWCNTs could offer a more sensitive response to trace Hg(II) than the bare SPBE. The stripping current obtained at SPBE/MWCNT was linear with Hg(II) concentration in the range from 0.2 to 40 µg/L (R2= 0.9976), with a detection limit of 0.09 µg/L (S/N =3) under 180 s accumulation. The proposed “mercury-free” electrode, with extremely simple preparation and ultrahigh sensitivity, holds wide application prospects in both environmental and industrial monitoring.

Abstract: The screen-printed three-electrode system was applied to fabricate a new type of disposable amperometric xanthine oxidase biosensor. Carbon-working, carbon-counter and Ag/AgCl reference electrodes were all manually printed on the polyethylene terephthalate substrate forming the screen-printed three-electrode system by the conventional screen-printing process. As a mediator, Prussian blue could not only catalyze the electrochemical reduction of hydrogen peroxide produced from the enzyme reaction, but also keep the favorable potential around 0 V. The optimum operational conditions, including pH, potential and temperature, were investigated. The sensitivities of xanthine and hypoxanthine detections were 13.83 mA/M and 25.56 mA/M, respectively. A linear relationship was obtained in the concentration range between 0.10 μM and 4.98 μM for xanthine and between 0.50 μM and 3.98 μM for hypoxanthine. The small Michaelis-menten constant value of the xanthine oxidase biosensor was calculated to be 3.90 μM. The results indicate that the fabricated xanthine oxidase biosensor is effective and sensitive for the detection of xanthine and hypoxanthine.

Abstract: An electrochemical DNA biosensor for specific-sequences detection of Vibrio parahaemolyticus (VP) was fabricated. A single-stranded 20-mer oligonucleotide (ssDNA) and 6-mercapto-1-hexanol (MCH) were immobilized via a thiol linker on gold disk electrodes by self-assembling. The ssDNA underwent hybridization in a hybridization solution containing complementary or non-complementary or single base pair mismatched DNA sequences of VP. Examination of changes in response to these three target DNAs showed that the developed biosensor had a high selectivity and sensitivity.

Novel paramagnetic materials (3a, 3b, 4aand 4b) based on heterocyclic dyes (2aand 2b) and one stable nitroxide radical (4‐NH2‐TEMPO) were synthesized. EI‐MS, elemental analysis and FT‐IR spectral data confirmed the structures of the newly synthesized compounds. In addition, the cyclic voltammetry, the antioxidant activity and reactive oxygen species (ROS) scavenging properties of these compounds are discussed in this paper.

A newly synthesized nitroxide radical, 4-ferrocenecarboxyl-2,2,6,6-tetramethyl piperidine-1-oxyl (FC-TEMPO), was firstly encapsulated in the poly(Dl-lactic acid) (PLA) nanoparticles by the modified spontaneous emulsification solvent diffusion method. The formation of the nanoparticles with diameters of 120 ± 15 nm has been confirmed by a laser particle size analyzer. The morphology of the nanoparticles exhibited a fine spherical shape without aggregation or adhesion by the scanning electron microscopy (SEM). The electron paramagnetic resonance (EPR) spectra indicated that FC-TEMPO was mainly encapsulated into PLA nanoparticle core.

To develop a new family of Langmuir-Blodgett (LB) films of charge-transfer (CT) complexes, a long alkyl chain is attached to N,N′-dicyanoquinodiimine (DCNQI). Although no reaction in mixed solutions of the obtained alkylDCNQI and CuI were detected, it has been found that the alkylDCNQI is reduced by CuI when mixed solutions are spread on to the water surface. The optical characterization of LB films of pure alkylDCNQI and those of alkylDCNQI-CuI mixtures indicates the formation of CT complexes in the latter case.

To develop a new family of Langmuir-Blodgett (LB) films of charge-transfer (CT) complexes, a long alkyl chain is attached to N,N′-dicyanoquinodiimine (DCNQI). Although no reaction in mixed solutions of the obtained alkylDCNQI and CuI were detected, it has been found that the alkylDCNQI is reduced by CuI when mixed solutions are spread on to the water surface. The optical characterization of LB films of pure alkylDCNQI and those of alkylDCNQI-CuI mixtures indicates the formation of CT complexes in the latter case.

design and synthesis of (I)

All synthesized compounds (I) and (II) exhibit much higher in vitro cytotoxicity against human leukemia cell line K562 than their parent compounds.

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