V-O Species-Doped Carbon Frameworks Loaded with Ru Nanoparticles as Highly Efficient and CO-Tolerant Catalysts for Alkaline Hydrogen Oxidation.

Efficient and CO-tolerant catalysts for alkaline hydrogen oxidation (HOR) are vital to the commercial application of anion exchange membrane fuel cells (AEMFCs). Herein, a robust Ru-based catalyst (Ru/VOC) with ultrasmall Ru nanoparticles supported on carbon frameworks with atomically dispersed V-O species is prepared elaborately. The catalyst exhibits a remarkable mass activity of 3.44 mA µgPGM, which is 31.3 times that of Ru/C and even 4.7 times higher than that of Pt/C. Moreover, the Ru/VOC anode can achieve a peak power density (PPD) of 1.194 W cm-2, much superior to that of Ru/C anode and even better than that of Pt/C anode. In addition, the catalyst also exhibits superior stability and exceptional CO tolerance. Experimental results and density functional theory (DFT) calculations demonstrate that V-O species are ideal OH- adsorption sites, which allow Ru to release more sites for hydrogen adsorption. Furthermore, the electron transfer from Ru nanoparticles to the carbon substrate regulates the electronic structure of Ru, reducing the hydrogen binding energy (HBE) and the CO adsorption energy on Ru, thus boosting the alkaline HOR performance and CO tolerance of the catalyst. This is the first report that oxophilic single atoms distributed on carbon frameworks serve as OH- adsorption sites for efficient hydrogen oxidation, opening up new guidance for the elaborate design of high-activity catalysts for the alkaline HOR.

Modulating tumor mechanics with nanomedicine for cancer therapy.

Over the past several decades, the importance of the tumor mechanical microenvironment (TMME) in cancer progression or cancer therapy has been recognized by researchers worldwide. The abnormal mechanical properties of tumor tissues include high mechanical stiffness, high solid stress, and high interstitial fluid pressure (IFP), which form physical barriers resulting in suboptimal treatment efficacy and resistance to different types of therapy by preventing drugs infiltrating the tumor parenchyma. Therefore, preventing or reversing the establishment of the abnormal TMME is critical for cancer therapy. Nanomedicines can enhance drug delivery by exploiting the enhanced permeability and retention (EPR) effect, so nanomedicines that target and modulate the TMME can further boost antitumor efficacy. Herein, we mainly discuss the nanomedicines that can regulate mechanical stiffness, solid stress, and IFP, with a focus on how nanomedicines change abnormal mechanical properties and facilitate drug delivery. We first introduce the formation, characterizing methods and biological effects of tumor mechanical properties. Conventional TMME modulation strategies will be briefly summarized. Then, we highlight representative nanomedicines capable of modulating the TMME for augmented cancer therapy. Finally, current challenges and future opportunities for regulating the TMME with nanomedicines will be provided.

Doxorubicin and erastin co-loaded hydroxyethyl starch-polycaprolactone nanoparticles for synergistic cancer therapy.

Cancer stem cells (CSCs), enabled to self-renew, differentiate, and initiate the bulk tumor, are recognized as the culprit of treatment resistance, metastasis, and recurrence. Simultaneously eradicating CSCs and bulk cancer cells is crucial for successful cancer therapy. Herein, we reported that doxorubicin (Dox) and erastin co-loaded hydroxyethyl starch-polycaprolactone nanoparticles (DEPH NPs) eliminated CSCs and cancer cells by regulating redox status. We found that an excellently synergistic effect existed when Dox and erastin were co-delivered by DEPH NPs. Specifically, erastin could deplete intracellular glutathione (GSH), thereby inhibiting the efflux of intracellular Dox and boosting Dox-induced reactive oxygen species (ROS) to amplify redox imbalance and oxidative stress. The high ROS levels restrained CSCs self-renewal via downregulating Hedgehog pathways, promoted CSCs differentiation, and rendered differentiated cancer cells vulnerable to apoptosis. As such, DEPH NPs significantly eliminated not only cancer cells but more importantly CSCs, contributing to suppressed tumor growth, tumor-initiating capacity, and metastasis, in various tumor models of triple negative breast cancer. This study demonstrates that the combination of Dox and erastin is potent in elimination of both cancer cells and CSCs, and that DEPH NPs represent a promising treatment against CSCs-rich solid tumors.

Mechano-boosting nanomedicine antitumour efficacy by blocking the reticuloendothelial system with stiff nanogels.

Nanomedicine has been developed for cancer therapy over several decades, while rapid clearance from blood circulation by reticuloendothelial system (RES) severely limits nanomedicine antitumour efficacy. We design a series of nanogels with distinctive stiffness and investigate how nanogel mechanical properties could be leveraged to overcome RES. Stiff nanogels are injected preferentially to abrogate uptake capacity of macrophages and temporarily block RES, relying on inhibition of clathrin and prolonged liver retention. Afterwards, soft nanogels deliver doxorubicin (DOX) with excellent efficiency, reflected in high tumour accumulation, deep tumour penetration and outstanding antitumour efficacy. In this work, we combine the advantage of stiff nanogels in RES-blockade with the superiority of soft nanogels in drug delivery leads to the optimum tumour inhibition effect, which is defined as mechano-boosting antitumour strategy. Clinical implications of stiffness-dependent RES-blockade are also confirmed by promoting antitumour efficacy of commercialized nanomedicines, such as Doxil and Abraxane.

Hydroxyethyl starch-folic acid conjugates stabilized theranostic nanoparticles for cancer therapy.

Small molecular prodrug-based nanomedicines with high drug-loading efficiency and tumor selectivity have attracted great attention for cancer therapy against solid tumors, including triple negative breast cancers (TNBC). However, abnormal tumor mechanical microenvironment (TMME) severely restricts antitumor efficacy of prodrug nanomedicines by limiting drug delivery and fostering cancer stem cells (CSCs). Herein, we employed carbamate disulfide bridged doxorubicin dimeric prodrug as pharmaceutical ingredient, marketed IR780 iodide as photothermal agent, and biocompatible hydroxyethyl starch-folic acid conjugates as amphiphilic surfactant to prepare a theranostic nanomedicine (FDINs), which could actively target at TNBC 4T1 tumor tissues and achieve reduction-responsive drug release with high glutathione concentration in cancer cells and CSCs. Importantly, in addition to directly causing damage to cancer cells and sensitizing chemotherapy, FDINs-mediated photothermal effect regulates aberrant TMME via reducing cancer associated fibroblasts and depleting extracellular matrix proteins, thereby normalizing intratumor vessel structure and function to facilitate drug and oxygen delivery. Furthermore, FDINs potently eliminate CSCs by disrupting unique CSCs niche and consuming intracellular GSH in CSCs. As a result, FDINs significantly suppress tumor growth in both subcutaneous and orthotopic 4T1 tumors. This study provides novel insights on rational design of prodrug nanomedicines for superior therapeutic effect against stroma- and CSCs-rich solid malignancies.

Precise fibrin decomposition and tumor mechanics modulation with hydroxyethyl starch-based smart nanomedicine for enhanced antitumor efficacy.

Chemotherapy is a conventional cancer treatment in clinical settings. Although numerous nano drug delivery systems have been developed, the chemotherapeutic effect is greatly limited by abnormal tumor mechanics in solid tumors. Tumor stiffening and accumulated solid stress compress blood vessels and inhibit drug delivery to tumor cells, becoming critical challenges for chemotherapy. By loading doxorubicin (DOX), tissue plasminogen activator (tPA), and fibrin targeting peptide CREKA (Cys-Arg-Glu-Lys-Ala) within pH responsive amphiphilic block polymers, pyridyldithio-hydroxyethyl starch-Schiff base-polylactic acid (PA-HES-pH-PLA), we report a smart nanomedicine, DOX@CREKA/tPA-HES-pH-PLA (DOX@CREKA/tPA-HP), which exhibits a potent antitumor efficacy. In triple-negative breast cancer (TNBC) 4T1 tumors, DOX@CREKA/tPA-HP precisely targeted and effectively decomposed fibrin matrix. By measuring Young's Modulus of tumor slices and quantifying tumor openings, we demonstrated that DOX@CREKA/tPA-HP remarkably reduced tumor stiffness and solid stress. Consequently, the alleviated tumor mechanics decompressed tumor blood vessels, promoted drug delivery, and led to amplified antitumor effect. Our work reveals that decomposing fibrin is a significant means for modulating tumor mechanics, and DOX@CREKA/tPA-HP is a promising smart nanomedicine for treating TNBC.

Tumor-specific activatable biopolymer nanoparticles stabilized by hydroxyethyl starch prodrug for self-amplified cooperative cancer therapy.

Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required. Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu2+ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer. Results: Interestingly, the pre-doped Cu2+ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu2+ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively. Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.

Transforming growth factor-ß blockade modulates tumor mechanical microenvironments for enhanced antitumor efficacy of photodynamic therapy.

Photodynamic therapy (PDT) is frequently used in cancer treatment in clinical settings. However, its applications in stroma-rich solid tumors, e.g., triple negative breast cancer, are limited by abnormal mechanical microenvironments. Solid stress accumulated in stroma-rich solid tumors compresses tumor blood vessels, hampers the delivery of photosensitizers (PSs) in tumor tissues, and poses a major challenge for potent PDT. Here, we report a novel combination strategy to augment PDT based cancer therapy by combining hydroxyethyl starch-chlorin e6 conjugate self-assembled nanoparticles (HES-Ce6 NPs) with the transforming growth factor-ß (TGFß) inhibitor LY2157299 (LY). HES-Ce6 conjugates, as synthesized by one step esterification reaction, could self-assemble into uniform HES-Ce6 NPs, which exhibited enhanced photostability and generated more reactive oxygen species (ROS) under 660 nm laser irradiation than free Ce6. Prior to PDT, intragastric administration of LY decreased collagen deposition, alleviated solid stress, and decompressed tumor blood vessels. As a result, the reconstructed tumor mechanical microenvironment promoted accumulation and penetration of HES-Ce6 NPs into tumor tissues, contributing to augmented antitumor efficacy of HES-Ce6 NP mediated PDT. Modulating tumor mechanical microenvironments using TGFß blockade to enhance the delivery of PSs in tumors with excessive extracellular matrix represents an efficient strategy for treating stroma-rich solid tumors.

Targeting transforming growth factor-ß signaling for enhanced cancer chemotherapy.

During the past decades, drugs targeting transforming growth factor-ß (TGFß) signaling have received tremendous attention for late-stage cancer treatment since TGFß signaling has been recognized as a prime driver for tumor progression and metastasis. Nonetheless, in healthy and pre-malignant tissues, TGFß functions as a potent tumor suppressor. Furthermore, TGFß signaling plays a key role in normal development and homeostasis by regulating cell proliferation, differentiation, migration, apoptosis, and immune evasion, and by suppressing tumor-associated inflammation. Therefore, targeting TGFß signaling for cancer therapy is challenging. Recently, we and others showed that blocking TGFß signaling increased chemotherapy efficacy, particularly for nanomedicines. In this review, we briefly introduce the TGFß signaling pathway, and the multifaceted functions of TGFß signaling in cancer, including regulating the tumor microenvironment (TME) and the behavior of cancer cells. We also summarize TGFß targeting agents. Then, we highlight TGFß inhibition strategies to restore the extracellular matrix (ECM), regulate the tumor vasculature, reverse epithelial-mesenchymal transition (EMT), and impair the stemness of cancer stem-like cells (CSCs) to enhance cancer chemotherapy efficacy. Finally, the current challenges and future opportunities in targeting TGFß signaling for cancer therapy are discussed.

A Simple Glutathione-Responsive Turn-On Theranostic Nanoparticle for Dual-Modal Imaging and Chemo-Photothermal Combination Therapy.

Constructing a tumor microenvironment stimuli activatable theranostic nanoparticle with simple components and preparation procedures for multimodality imaging and therapy remains a major challenge for current theranostic systems. Here we report a novel and simple glutathione (GSH)-responsive turn-on theranostic nanoparticle for dual-modal imaging and combination therapy. The theranostic nanoparticle, DHP, consisting of a disulfide-bond-linked hydroxyethyl starch paclitaxel conjugate (HES-SS-PTX) and a near-infrared (NIR) cyanine fluorophore DiR, is prepared with a simple one-step dialysis method. As DiR is encapsulated within the hydrophobic core formed by HES-SS-PTX, the fluorescence of DiR is quenched by the aggregation-caused quenching (ACQ) effect. Nonetheless, once DHP is internalized by cancer cells, the disulfide bond of HES-SS-PTX can be cleaved by intracellular GSH, leading to the synchronized release of conjugated PTX and loaded DiR. The released PTX could exert its therapeutic effect, while DiR could adsorb onto nearby endosome/lysosome membranes and regain its fluorescence. Thus, DHP could monitor the release and therapeutic effect of PTX through the fluorescence recovery of DiR. Remarkably, DHP can also be used as an in vivo probe for both fluorescent and photoacoustic imaging and at the same time achieves potent antitumor efficacy through chemo-photothermal combination therapy. This study provides novel insights into designing clinically translatable turn-on theranostic systems.

Potentiating photodynamic therapy of ICG-loaded nanoparticles by depleting GSH with PEITC.

Photodynamic therapy (PDT) is a clinically approved cancer treatment which utilizes reactive oxygen species (ROS) to eradicate cancer cells. But the high concentration of GSH inside tumor cells can neutralize the generated ROS during PDT, resulting in an insufficient therapeutic effect. To address this issue, we combined ICG-loaded nanoparticles with PEITC for potent PDT. ICG encapsulated in novel hydroxyethyl starch-oleic acid conjugate (HES-OA) nanoparticles (∼50 nm) exhibited excellent stability and efficient singlet oxygen generation under laser irradiation, promoted cellular uptake, and enhanced tumor accumulation, whilst PEITC depleted intracellular GSH significantly. As a result, PDT based on ICG-loaded NPs combined with PEITC synergistically suppressed cancer cells both in vitro and in vivo. Potentiating ICG-loaded NPs with PEITC represents a novel and efficient strategy to enhance PDT efficacy.

Antioxidative Effects and Mechanism Study of Bioactive Peptides from Defatted Walnut ( Juglans regia L.) Meal Hydrolysate.

The peptide components of defatted walnut ( Juglans regia L.) meal hydrolysate (DWMH) remain unclear, hindering the investigation of biological mechanisms and exploitation of bioactive peptides. The present study aims to identify the peptide composition of DWMH, followed by to evaluate in vitro antioxidant effects of selected peptides and investigate mechanisms of antioxidative effect. First, more than 1 000 peptides were identified by de novo sequencing in DWMH. Subsequently, a scoring method was established to select promising bioactive peptides by structure based screening. Eight brand new peptides were selected due to their highest scores in two different batches of DWMH. All of them showed potent in vitro antioxidant effects on H2O2-injured nerve cells. Four of them even possessed significantly stronger effects than DWMH, making the selected bioactive peptides useful for further research as new bioactive entities. Two mechanisms of hydroxyl radical scavenging and ROS reduction were involved in their antioxidative effects at different degrees. The results showed peptides possessing similar capacity of hydroxyl radical scavenging or ROS reduction may have significantly different in vitro antioxidative effects. Therefore, comprehensive consideration of different antioxidative mechanisms were suggested in selecting antioxidative peptides from DWMH.

Tuning the Activity of Carbon for Electrocatalytic Hydrogen Evolution via an Iridium-Cobalt Alloy Core Encapsulated in Nitrogen-Doped Carbon Cages.

Graphene, a 2D material consisting of a single layer of sp2 -hybridized carbon, exhibits inert activity as an electrocatalyst, while the incorporation of heteroatoms (such as N) into the framework can tune its electronic properties. Because of the different electronegativity between N and C atoms, electrons will transfer from C to N in N-doped graphene nanosheets, changing inert C atoms adjacent to the N-dopants into active sites. Notwithstanding the achieved progress, its intrinsic activity in acidic media is still far from Pt/C. Here, a facile annealing strategy is adopted for Ir-doped metal-organic frameworks to synthesize IrCo nanoalloys encapsulated in N-doped graphene layers. The highly active electrocatalyst, with remarkably reduced Ir loading (1.56 wt%), achieves an ultralow Tafel slope of 23 mV dec-1 and an overpotential of only 24 mV at a current density of 10 mA cm-2 in 0.5 m sulfuric acid solution. Such superior performance is even superior to the noble-metal catalyst Pt. Surface structural and computational studies reveal that the superior behavior originates from the decreased ΔGH* for HER induced by the electrons transferred from the alloy core to the graphene layers, which is beneficial for enhancing CH binding.

Nanoporous PtFe Nanoparticles Supported on N-Doped Porous Carbon Sheets Derived from Metal-Organic Frameworks as Highly Efficient and Durable Oxygen Reduction Reaction Catalysts.

Designing and exploring catalysts with high activity and stability for oxygen reduction reaction (ORR) at the cathode in acidic environments is imperative for the industrialization of proton exchange membrane fuel cells (PEMFCs). Theoretical calculations and experiments have demonstrated that alloying Pt with a transition metal can not only cut down the usage of scarce Pt metal but also improve performance of mass activity compared with pure Pt. Herein, we exhibit the preparation of nanoporous PtFe nanoparticles (np-PtFe NPs) supported on N-doped porous carbon sheets (NPCS) via facile in situ thermolysis of a Pt-modified Fe-based metal-organic framework (MOF). The np-PtFe/NPCS exhibit a more positive half-wave potential (0.92 V) compared with commercial Pt/C catalyst (0.883 V). The nanoporous structure allows our catalyst to possess high mass activity, which is found to be 0.533 A·mgPt-1 and 3.04 times better than that of Pt/C (0.175 A·mgPt-1). Moreover, the conversion of PtFe NPs from porous to hollow structure can maintain the activity of electrocatalyst. Our strategy provides a facile design and synthesis process of noble-transition metal alloy electrocatalysts via noble metal modified MOFs as precursors.

Erratum: Ruthenium-cobalt nanoalloys encapsulated in nitrogen-doped graphene as active electrocatalysts for producing hydrogen in alkaline media.

This corrects the article DOI: 10.1038/ncomms14969.

Corrigendum: Ruthenium-cobalt nanoalloys encapsulated in nitrogen-doped graphene as active electrocatalysts for producing hydrogen in alkaline media.

This corrects the article DOI: 10.1038/ncomms14969.

Ruthenium-cobalt nanoalloys encapsulated in nitrogen-doped graphene as active electrocatalysts for producing hydrogen in alkaline media.

The scalable production of hydrogen could conveniently be realized by alkaline water electrolysis. Currently, the major challenge confronting hydrogen evolution reaction (HER) is lacking inexpensive alternatives to platinum-based electrocatalysts. Here we report a high-efficient and stable electrocatalyst composed of ruthenium and cobalt bimetallic nanoalloy encapsulated in nitrogen-doped graphene layers. The catalysts display remarkable performance with low overpotentials of only 28 and 218 mV at 10 and 100 mA cm-2, respectively, and excellent stability of 10,000 cycles. Ruthenium is the cheapest platinum-group metal and its amount in the catalyst is only 3.58 wt.%, showing the catalyst high activity at a very competitive price. Density functional theory calculations reveal that the introduction of ruthenium atoms into cobalt core can improve the efficiency of electron transfer from alloy core to graphene shell, beneficial for enhancing carbon-hydrogen bond, thereby lowing ΔGH* of HER.

Enhanced Activity for Hydrogen Evolution Reaction over CoFe Catalysts by Alloying with Small Amount of Pt.

The hydrogen evolution reaction highly relied on Pt electrocatalysts, with high activity and stability. In the past few years, a host of efforts have been made in the development of novel platinum nanostructures with a low amount of Pt because the scarcity and high price of Pt hinder its practical applications. Here, we report the preparation of PtCoFe@CN electrocatalysts with a remarkably reduced Pt loading amount of 4.60% by annealing Pt-doped metal-organic frameworks (MOFs). The electrocatalyst demonstrated an outstanding performance with only 45 mV overpotential to achieve the 10 mA cm-2 current density, which is quite close to that of the commercial 20% Pt/C catalyst. The enhanced catalytic capability is originated from the modification of the electronic structures of CoFe by alloying with Pt. The results indicate that robust and superstable alloy electrocatalysts which contain a very small amount of noble metal could be prepared by annealing noble metal-doped MOFs.

Active and Durable Hydrogen Evolution Reaction Catalyst Derived from Pd-Doped Metal-Organic Frameworks.

The water electrolysis is of critical importance for sustainable hydrogen production. In this work, a highly efficient and stable PdCo alloy catalyst (PdCo@CN) was synthesized by direct annealing of Pd-doped metal-organic frameworks (MOFs) under N2 atmosphere. In 0.5 M H2SO4 solution, PdCo@CN displays remarkable electrocatalytic performance with overpotential of 80 mV, a Tafel slope of 31 mV dec(-1), and excellent stability of 10 000 cycles. Our studies reveal that noble metal doped MOFs are ideal precursors for preparing highly active alloy electrocatalysts with low content of noble metal.

[Study on preparations and fluorescent properties of rare earth complex with property of fluorescence sensor].

Europium chloride, 2-thienylformyltrifluoroacetone and sodium silicate were used to synthesize new-style rare earth complex (Eu-TNS). By adding into dichloromethane solution containing Eu-TNS, the fluorescent intensities were enhanced gradually and regularly. High-resolution mass spectrometry was used to detect the formula of Eu-TNS, which belongs to multi-core rare-earth complex. Polarity of solution increasing by adding absolute ethanol will cause Eu-TNS to dissociate, which enhances the fluoresceot intensities of Eu-TNS solution. This rare earth complex Eu-TNS can be employed as fluorescence sensor to detect the content of ethanol in organic solvent.