Boosting Energy Deprivation by Synchronous Interventions of Glycolysis and Oxidative Phosphorylation for Bioenergetic Therapy Synergetic with Chemodynamic/Photothermal Therapy.

Bioenergetic therapy is emerging as a promising therapeutic approach. However, its therapeutic effectiveness is restricted by metabolic plasticity, as tumor cells switch metabolic phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) to compensate for energy. Herein, Metformin (MET) and BAY-876 (BAY) co-loaded CuFe2O4 (CF) nanoplatform (CFMB) is developed to boost energy deprivation by synchronous interventions of glycolysis and OXPHOS for bioenergetic therapy synergetic with chemodynamic/photothermal therapy (CDT/PTT). The MET can simultaneously restrain glycolysis and OXPHOS by inhibiting hexokinase 2 (HK2) activity and damaging mitochondrial function to deprive energy, respectively. Besides, BAY blocks glucose uptake by inhibiting glucose transporter 1 (GLUT1) expression, further potentiating the glycolysis repression and thus achieving much more depletion of tumorigenic energy sources. Interestingly, the upregulated antioxidant glutathione (GSH) in cancer cells triggers CFMB degradation to release Cu+/Fe2+ catalyzing tumor-overexpressed H2O2 to hydroxyl radical (∙OH), both impairing OXPHOS and achieving GSH-depletion amplified CDT. Furthermore, upon near-infrared (NIR) light irradiation, CFMB has a photothermal conversion capacity to kill cancer cells for PTT and improve ∙OH production for enhanced CDT. In vivo experiments have manifested that CFMB remarkably suppressed tumor growth in mice without systemic toxicity. This study provides a new therapeutic modality paradigm to boost bioenergetic-related therapies.

An efficient strategy with a synergistic effect of hydrophilic and electrostatic interactions for simultaneous enrichment of N- and O-glycopeptides.

N- and O-glycosylation modifications of proteins are closely linked to the onset and development of many diseases and have gained widespread attention as potential targets for therapy and diagnosis. However, the low abundance and low ionization efficiency of glycopeptides as well as the high heterogeneity make glycosylation analysis challenging. Here, an enrichment strategy, using Knoevenagel copolymers modified with polydopamine-adenosine (denoted as PDA-ADE@KCP), was firstly proposed for simultaneous enrichment of N- and O-glycopeptides through the synergistic effects of hydrophilic and electrostatic interactions. The adjustable charged surface and hydrophilic properties endow the material with the capability to achieve effective enrichment of intact N- and O-glycopeptides. The experimental results exhibited excellent selectivity (1 : 5000) and sensitivity (0.1 fmol µL-1) of the prepared material for N-glycopeptides from standard protein digest samples. Moreover, it was further applied to simultaneous capturing of N- and O-glycopeptides from mouse liver protein digests. Compared to the commercially available zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) material, the number of glycoproteins corresponding to all N- and O-glycopeptides enriched with PDA-ADE@KCP was much more than that with ZIC-HILIC. Furthermore, PDA-ADE@KCP captured more O-glycopeptides than ZIC-HILIC, revealing its superior performance in O-glycopeptide enrichment. All these results indicated that the strategy holds immense potential in characterizing N- and O-intact glycopeptides in the field of proteomics.

Overlapping peak separation algorithm for ion mobility spectra based on multistrategy JAYA.

RATIONALE: In the field of separation science, ion mobility spectrometry (IMS) plays an important role as an analytical tool. However, the lack of sufficient structural resolution is a common problem in qualitative and quantitative analysis using IMS. A method is needed to solve the problem of overlapping peaks caused by insufficient resolution. METHODS: The method uses multiple strategies to more effectively use population information to balance exploration and exploitation capabilities, prevent local optimization, accurately resolve overlapping peaks, quickly obtain optimal spectral peak model coefficients, and accurately identify compounds. RESULTS: Multistrategy JAYA algorithm's (MSJAYA) performance is compared with improved particle swarm optimization (IPSO), dynamic inertia weight particle swarm optimization (DIWPSO), and multiobjective dynamic teaching-learning-based optimization (MDTLBO). The analysis shows that MSJAYA's maximum separation error is within 0.6%, a level of accuracy not guaranteed by the other algorithms. In addition, the separation error fluctuates within a much smaller range, demonstrating MSJAYA's superior robustness. CONCLUSIONS: Compared with other overlapping peak separation algorithms, MSJAYA is more applicable because no special parameters are used. The method allows fast deconvolution analysis of strong overlapping peaks with multiple components, which greatly improves the resolution of IMS.

O2 self-sufficient and glutathione-depleted nanoplatform for amplifying phototherapy synergistic thermodynamic therapy.

Tumor hypoxia and high levels of intracellular glutathione (GSH) significantly limit the efficacy of photodynamic therapy (PDT). In addition, a single PDT treatment strategy is relatively insufficient to eliminate tumor, further limiting its application in biomedicine. Therefore, we demonstrated an omnipotent nanoplatform based on 2,2'-azobis [2-(2 imidazolin-2-yl)propane] dihydrochloride (AIPH) loaded manganese dioxide (MnO2) nanoflower (abbreviated as MnO2-AIPH) with simultaneously self-supplying oxygen (O2), depleting GSH, performing PDT, photothermal (PTT) and thermodynamic therapy (TDT) for boosting antitumor effects. By 808 nm near infrared (NIR) light irradiation, MnO2-AIPH not only reveals highly toxic reactive oxygen species (ROS) generation and excellent photothermal conversion ability for PDT and PTT, but also generates alkyl radicals by decomposing AIPH for TDT simultaneously to eliminate tumor effectively. Once internalized into the tumor, MnO2 will be degraded to Mn2+ which catalyzes endogenous hydrogen peroxide (H2O2) into O2 for enhanced PDT. Moreover, MnO2 can facilitate GSH oxidation to amplify oxidative stress, further enhancing ROS and alkyl radicals mediated cancer cell killing. In brief, this study provides a paradigm of antitumor efficiency amplification by the combination of sustained oxygen supply, potent GSH depletion, and phototherapy synergistic TDT.

Hydrogen peroxide self-sufficient and glutathione-depleted nanoplatform for boosting chemodynamic therapy synergetic phototherapy.

Chemodynamic therapy (CDT), which suppresses tumors via the conversion of endogenous hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals (•OH), is deemed as a cutting-edge antitumor strategy. However, the insufficient endogenous H2O2 and up-regulated antioxidant glutathione (GSH) in the tumor microenvironment (TME) greatly impede the therapeutic effect of CDT. Herein, a versatile nanoplatform MgO2@SnFe2O4@PEG (MSnFeP) is elaborately fabricated for boosting CDT synergetic phototherapy. In the TME, the activation of MSnFeP contributes to in situ supply of H2O2, generation of •OH and consumption of GSH for boosted CDT. Furthermore, photothermal therapy (PTT) and photodynamic therapy (PDT) are simultaneously stimulated by near-infrared (NIR) light exposure on MSnFeP to increase the toxic free radical yield. This strategy not only amplifies the CDT efficacy hindered by H2O2 deficiency and GSH overexpression, but also further enhances the therapeutic effect with the combination of phototherapy.

H2O2 self-sufficient nanoplatform based on CeO2 QDs decorated MgO2 nanosheet for amplified chemodynamic therapy.

Chemodynamic therapy (CDT), which employs Fenton/Fenton-like agents to decompose hydrogen peroxide (H2O2) into toxic hydroxyl radical (•OH) to induce cancer cell apoptosis and necrosis, holds great promise in tumor therapy due to its high selectivity. Nevertheless, its efficiency is impaired by the insufficient intracellular H2O2 concentration and/or the insensitive response of Fenton/Fenton-like agents to the slightly acid tumor microenvironment (pH∼7.0-6.5). Herein, we develop a novel CDT reagent based on CeO2 quantum dot (QD) decorated MgO2 nanosheets engineered with cascade reactions to boost the intracellular H2O2 level and high pH-activated (pH = 6.5) characteristic for an enhanced CDT. Under the tumor microenvironment (pH = 6.5), MgO2 nanosheets that are highly reactive can react with H2O to produce nontoxic Mg2+ and abundant H2O2, boosting the intracellular H2O2 level. The self-generated H2O2 is subsequently converted into •OH by CeO2 QD, which is served as a relatively high pH-activated (pH = 6.5) Fenton-like agent. The sufficient intracellular H2O2 supply and sensitive response to the slightly acid tumor sites significantly improve the Fenton reaction, leading to the excellent in vivo CDT results with tumor growth inhibition effect. Our work presents a distinctive paradigm for self-boosting CDT efficacy.

A novel hydrophilic hydrogel with a 3D network structure for the highly efficient enrichment of N-glycopeptides.

Protein glycosylation is of great significance in various physiological processes. Nevertheless, it remains a huge challenge to identify glycopeptides in complex biosamples by the direct mass spectrometry analysis due to the low ion efficiency and low abundance of glycopeptides. In this study, a novel hydrogel (denoted as ZIF-8/SAP) with a stable three-dimensional (3D) network structure and excellent hydrophilicity was successfully fabricated to capture glycopeptides with high efficiency. Owing to the unique characteristics, ZIF-8/SAP exhibited great selectivity (1 : 1000), great sensitivity (1 fmol µL-1), large binding capacity (300 mg g-1) and satisfactory reusability (seven cycles). Inspired by the great enrichment performance of the as-prepared material toward glycopeptides, ZIF-8/SAP was further applied to capture glycopeptides from a real human serum sample. The experimental results demonstrated that 217 N-glycosylation sites were identified in 283 N-glycopeptides, corresponding to 95 glycoproteins identified from 10 µL human serum by the nano-LC-MS/MS analysis, revealing the great potential of the novel ZIF-8/SAP hydrogel for glycopeptide enrichment and glycoproteomic research.

CeO2 QDs anchored on MnO2 nanoflowers with multiple synergistic effects for amplified tumour therapy.

Chemodynamic therapy (CDT) is an emerging tumour-specific therapeutic technology. However, the relatively insufficient catalytic activity of CDT agents in the tumour microenvironment (TME) limits their biomedical application. In addition, severe hypoxia and glutathione (GSH) overexpression in the TME greatly limit the antitumour efficiency of monotherapy. Herein, a cancer cell membrane-camouflaged and ultrasmall CeO2-decorated MnO2 (mMC) composite is developed for amplified CDT, photodynamic therapy (PDT) and photothermal therapy (PTT). Due to the homotypic targeting ability of cancer cell membranes, mMC nanoparticles preferentially accumulate in tumour tissue. In the TME, CeO2 acts as a highly efficient CDT agent to convert endogenous H2O2 to toxic reactive oxygen species (ROS) for killing cancer cells. Meanwhile, MnO2 irradiated with near-infrared (NIR) light displays prominent hyperthermia and ROS generation performance to perform PTT and PDT. Moreover, MnO2 can produce oxygen to ameliorate hypoxia and deplete GSH to relieve the antioxidant capability of tumours, which is beneficial to the simultaneous augmentation of PDT and CDT. Most importantly, the catalytic activity of CeO2 was greatly improved by hyperthermia. Consequently, a significantly enhanced therapeutic efficiency was obtained by the above multiple synergistic effects. This work provides a proof of concept for amplified tumour therapy by synchronously self-supplying oxygen, consuming GSH, and enhancing catalytic activity.

Bowl-like mesoporous polydopamine with size exclusion for highly selective recognition of endogenous glycopeptides.

It has been confirmed that endogenous glycopeptide plays an important role in a variety of pathological and physiological processes. However, direct analysis of endogenous glycopeptide is still a great challenge owing to the low abundance of endogenous glycopeptides and the presence of a large number of interfering substances such as large-sized proteins and heteropeptides in complex biological sample. Herein, we reported a novel bowl-like mesoporous polydopamine nanoparticle modified by carrageenan (denoted as MPDA@PEI@CA) with strong hydrophilicity and size-exclusion effect for high specificity enrichment of endogenous glycopeptides. Thanks to the suitable pore channel structure as well as strong hydrophilic surface, the as-prepared MPDA@PEI@CA nanoparticles exhibited prominent performance in enrichment of N-linked glycopeptide with ultrahigh selectivity (1:5000 M ratio of horseradish peroxidase (HRP) digests/bovine serum albumin (BSA) digests), low detection limit (5 fmol µL-1), outstanding size-exclusion ability (1:1000 mass of HRP/BSA), and unique reusability (five times). 125 N-glycosylation sites of 134 glycopeptides from 65 glycoproteins were identified from 2 µL sample of human serum treated with the MPDA@PEI@CA nanoparticles, which manifested the ability to enrich endogenous N-linked glycopeptides from complex biological samples. These results indicated that the bowl-like MPDA@PEI@CA nanoparticles with novel structure prepared in this work had great potential for glycopeptidome analysis.

Biodegradable flower-like manganese for synergistic photothermal and photodynamic therapy applications.

A flower-like nanostructured MnO2 with near-infrared (NIR) light-triggered high photothermal conversion capability of 30% and reactive oxygen species (ROS) generation ability was successfully developed. Different from the reported MnO2 nanomaterials those were used in the nanomedicine field for only relieving tumor hypoxia and/or imaging, the flower-like MnO2 inherently acts as a competent agent for simultaneously enhanced photothermal and photodynamic therapy. A flower-like nanostructured MnO2 with near-infrared (NIR) light triggered high photothermal conversion capability of 30% and reactive oxygen species (ROS) generation ability was successfully developed.

Blood circulation stable doxorubicin prodrug nanoparticles containing hydrazone and thioketal moieties for antitumor chemotherapy.

Prodrug nanoparticles with cleavable moieties sensitive to intracellular stimuli have drawn great attention on cancer chemotherapy. Herein, a reactive oxygen species (ROS)-responsive doxorubicin prodrug mPEG-Phe-TK-Phe-hyd-DOX was synthesized, in which hydrophilic methoxy poly(ethylene glycol) (mPEG) and hydrophobic anticancer drug doxorubicin (DOX) were conjugated with hydrazone (hyd) and ROS-responsive thioketal (TK) moieties. The ROS-responsiveness of prodrug was confirmed by proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). Unexpectedly, the results of in vitro drug release indicated that the hydrazone bond of prodrug nanoparticles was insensitive to pH, which may be due to the strong hydrophobicity, π-π interactions and cation-π interactions jointly inhibited the hydrolysis of hydrazone bonds under acidic conditions. The cellular uptake and in vitro anticancer study showed that ROS-responsive prodrug nanoparticles exhibited faster cellular uptake and better anticancer efficacy. The in vivo experiments showed that the ROS-responsive prodrug nanoparticles had comparable antitumor efficacy with free anticancer drug DOX and reduced organ toxicity. Our results provide novel idea of successfully design multi-stimuli-responsive nano-drug carrier.

Ultralow-intensity near infrared light synchronously activated collaborative chemo/photothermal/photodynamic therapy.

Although combined chemotherapy (Chemo), photothermal (PTT) and photodynamic (PDT) in cancer therapy has drawn significant attention due to its superior anticancer ability, the required high intensity of irradiation results in serious photo-toxicity to healthy neighboring cells, and thus limits its biomedical applications. Herein, we developed an ultralow-intensity near infrared (NIR) light synchronously activated collaborative Chemo/PTT/PDT nanoplatform. The nanoplatform is composed of a highly emissive upconversion (UC) core, chlorin e6 (Ce6) photosensitizer and the anticancer drug doxorubicin hydrochloride (DOX) co-loaded in a mesoporous silica (MS) shell, and polyethylene glycol-modified graphene (PGO) acts as both the photothermal reagent and smart switch for promoted drug release. Upon 808 nm NIR light exposure with ultralow intensity (0.25 W cm-2), which is below the maximum permissible exposure (MPE, 0.33 W cm-2) for skin, the mild hyperpyrexia of PGO induced both cancer cell irreversible death for PTT and greatly promoted drug release for enhanced Chemo. On the other hand, the upconverted 660 nm light from UC activated Ce6 to generate reactive oxygen species for PDT, while the upconverted 540 nm light from UC could be employed for visualizing the treatment process. The in vitro and in vivo anticancer experiments demonstrate that the ultralow-intensity NIR light synchronously activated Chemo/PTT/PDT nanoplatform exhibits remarkable therapeutic efficacy with minimal photodamage.

Significantly enhanced energy storage performance in BiFeO3/BaTiO3/BiFeO3 sandwich-structured films through crystallinity regulation.

With the increasing demand of high energy density dielectric films, macrostructure design, for instance the construction of sandwich-structured films, has been attracting much attention due to its promise in raising the discharge energy density along with an enhanced electric breakdown strength. However, the contrast of dielectric constants between neighboring layers plays a dominate role in the distribution of the electric field, which might decrease the electric breakdown strength, and has attracted little attention up to now. Additionally, high energy storage efficiency with low energy dissipation should also be considered for dielectric applications despite enhancing the discharge energy density. In this study, the effects of dielectric constant contrast between neighboring layers have been proposed and investigated in the BiFeO3/BaTiO3/BiFeO3 sandwich-structured films through regulating the annealing temperature, in which the polarization behavior has also been tuned by partially crystallizing BiFeO3 and BaTiO3 films. As a result, the BiFeO3/BaTiO3/BiFeO3 sandwich-structured film annealed at 550 °C exhibits a favorable discharge energy density of 18.5 J cm-3 and a high energy storage efficiency of 82.3%, which result from the synergetic effect of the polarization behavior (Pm - Pr = 12.1 µC cm-2) and enhanced electric breakdown strength (EBDS = 2320 kV cm-1). By rational design of the dielectric and ferroelectric properties of individual layers, both excellent discharge energy density and energy storage efficiency could be simultaneously obtained in the sandwich-structured films.

Near-Infrared Light-Triggered Hydrophobic-to-Hydrophilic Switch Nanovalve for On-Demand Cancer Therapy.

An on-demand drug delivery nanoplatform based on mesoporous silica (mSiO2) coated upconversion nanoparticles (UCNP@mSiO2) with a novel near-infrared (NIR) light-triggered hydrophobic-to-hydrophilic switch nanovalve was fabricated. The surface of UCNP@mSiO2 was first immobilized with hydrophobic 2-diazo-1,2-naphthoquinones (DNQ) guest molecules. After doxorubicin hydrochloride (DOX, a universal anticancer drug) was loaded into channels of mSiO2 shell, ß-cyclodextrin (ß-CD) host molecules with a hydrophobic cavity were added as gatekeepers to cap DNQ stalk molecules via hydrophobic affinity, which may play a role in the OFF state of the nanovalve to prevent the drug from being released. Upon 980 nm light irradiation, a NIR light-triggered hydrophobic-to-hydrophilic switch, that transformed the hydrophobic guest DNQ into hydrophilic guest 3-indenecarboxylic acid (ICA), took place so that the capped ß-CD gatekeepers dissociated due to repulsion between ß-CD host (hydrophobic) and ICA guest (hydrophilic), activating the ON state of the nanovalves to release drug. The in vitro studies prove that the nanoplatform enables on-demand drug release to efficiently kill HeLa cell upon NIR light regulation. The in vivo experiment results further confirm that the nanoplatform with such fabricated nanovalves is able to inhibit tumor growth in mice. The designed nanovalves based on the novel NIR light-triggered hydrophobic-to-hydrophilic switch strategy therefore may shed new light on future development of on-demand cancer therapy.

Fabrication of Mesoporous-Silica-Coated Upconverting Nanoparticles with Ultrafast Photosensitizer Loading and 808†nm NIR-Light-Triggering Capability for Photodynamic Therapy.

A novel photodynamic therapy nanoplatform based on mesoporous-silica-coated upconverting nanoparticles (UCNP) with electrostatic-driven ultrafast photosensitizer (PS) loading and 808 nm near infrared (NIR)-light-triggering capabilities has been fabricated. By positively charging inner channels of the mesoporous silica shell with amino groups, a quantitative dosage of negatively charged PS, exemplified with Rose Bengal (RB) molecules, can be loaded in 2 min. In addition, the electrostatic-driven technique simultaneously provides the platform with both excellent PS dispersity and leak-proof properties due to the repulsion between the same-charged molecules and the electrostatic attraction between different-charged PS and silica channel walls, respectively. The as-coated silica shell with an ultrathin thickness of 12±2 nm is delicately fabricated to facilitate ultrafast PS loading and efficient energy transfer from UCNP to PS. The outside surface of the silica shell is capped with hydrophilic ß-cyclodextrin, which not only enhances the dispersion of resulting nanoparticles in water but also plays a role of "gatekeeper", blocking the pore opening and preventing PS leaking. The in vitro cellular lethality experiment demonstrates that RB molecules can be activated to effectively generate singlet oxygen and kill cancer cells upon 808 nm NIR light irradiation.

pH-Responsive drug release and NIR-triggered singlet oxygen generation based on a multifunctional core-shell-shell structure.

A multifunctional platform with pH-responsive drug release and near-infrared (NIR) light-triggered photodynamic therapy (PDT) was designed and prepared using the novel core-shell-shell structure. The multifunctional platform consists of an upconversion nanoparticle (UCNP) emission core, a photosensitizer methylene blue (MB) embedded dense silica sandwich shell, and a polyethyleneimine conjugated folic acid (PEI-FA) gated mesoporous silica (MS) outmost shell with doxorubicin hydrochloride (DOX) loaded inside. The simulated drug release experiments revealed that DOX will release from the nanoparticles because of the distortion in the PEI-FA layer under acidic conditions. Moreover, under 980 nm NIR irradiation, a 660 nm red light emission was excited, activating MB to generate a singlet oxygen (1O2), which acts as the PDT drug. The multifunctional platform integrated pH-responsive drug release and UCNP-based PDT drug together show promising potential in nanomedicine for future chemotherapy and NIR-triggered PDT.

Negative Capacitance in BaTiO3/BiFeO3 Bilayer Capacitors.

Negative capacitances provide an approach to reduce heat generations in field-effect transistors during the switch processes, which contributes to further miniaturization of the conventional integrated circuits. Although there are many studies about negative capacitances using ferroelectric materials, the direct observation of stable ferroelectric negative capacitances has rarely been reported. Here, we put forward a dc bias assistant model in bilayer capacitors, where one ferroelectric layer with large dielectric constant and the other ferroelectric layer with small dielectric constant are needed. Negative capacitances can be obtained when external dc bias electric fields are larger than a critical value. Based on the model, BaTiO3/BiFeO3 bilayer capacitors are chosen as study objects, and negative capacitances are observed directly. Additionally, the upward self-polarization effect in the ferroelectric layer reduces the critical electric field, which may provide a method for realizing zero and/or small dc bias assistant negative capacitances.

Design and Synthesis of Core-Shell-Shell Upconversion Nanoparticles for NIR-Induced Drug Release, Photodynamic Therapy, and Cell Imaging.

Novel core-shell-shell structured nanoparticles 75 nm in diameter with all-in-one "smart" functional capabilities for simultaneous photoresponsive drug release, photodynamic therapy, and cell imaging are designed and prepared. These nanoparticles consist of an upconversion (UC) emission core, a photosensitizer-embodied silica sandwich shell, and a ß-cyclodextrin (ß-CD) gated mesoporous silica outmost shell with drugs (Rhodamine B as a model) loaded inside. We show in this proof-of-concept demonstration that, under 980 nm near-infrared irradiation, UC 540 nm green light emissions were emitted for cell imaging, and 660 nm red light emissions were excited for activating photosensitizers to generate singlet oxygen, which could be exploited directly to kill cancer cells and simultaneously dissociate ß-CD gatekeeper to release drugs. The preliminary results reported here will shed new light on the future design and applications of multifunctional platforms for cancer therapy and diagnostic.

Triple-doped KMnF3:Yb3+/Er3+/Tm3+ nanocubes: four-color upconversion emissions with strong red and near-infrared bands.

Triple-doped (Yb(3+)/Er(3+)/Tm(3+)) KMnF3 nanocubes with uniform sizes of 250 nm were synthesized by a facile hydrothermal route using the oleic acid as the capping agent. It was found that these nanocubes can simultaneously exhibited four-color (blue, green, red and NIR) upconversion emissions under a single 980 nm near-infrared (NIR) laser excitation, which should have potential multicolor in vivo imaging applications. Specifically, the red (660 nm) and NIR (800 nm) peaks, known as two "optical windows" for imaging biological tissues, were strong. The spectral and pump analyses indicated the two-photon processes were responsible for the both red and NIR emissions.