Biocompatible Copper-Based Nanocomposites for Combined Cancer Therapy.

Copper (Cu) and Cu-based nanomaterials have received tremendous attention in recent years because of their unique physicochemical properties and good biocompatibility in the treatment of various diseases, especially cancer. To date, researchers have designed and fabricated a variety of integrated Cu-based nanocomplexes with distinctive nanostructures and applied them in cancer therapy, mainly including chemotherapy, radiotherapy (RT), photothermal therapy (PTT), chemodynamic therapy (CDT), photodynamic therapy (PDT), cuproptosis-mediated therapy, etc. Due to the limited effect of a single treatment method, the development of composite diagnostic nanosystems that integrate chemotherapy, PTT, CDT, PDT, and other treatments is of great significance and offers great potential for the development of the next generation of anticancer nanomedicines. In view of the rapid development of Cu-based nanocomplexes in the field of cancer therapy, this review focuses on the current state of research on Cu-based nanomaterials, followed by a discussion of Cu-based nanocomplexes for combined cancer therapy. Moreover, the current challenges and future prospects of Cu-based nanocomplexes in clinical translation are proposed to provide some insights into the design of integrated Cu-based nanotherapeutic platforms.

Correction: Cell Therapy: A Safe and Efficacious Therapeutic Treatment for Alzheimer's Disease in APP+PS1 Mice.

[This corrects the article DOI: 10.1371/journal.pone.0049468.].

Multi-strategy orthogonal enhancement and analysis of aldo-keto reductase thermal stability.

Given their outstanding efficiency and selectivity, enzymes are integral in various domains such as drug synthesis, the food industry, and environmental management. However, the inherent instability of natural enzymes limits their widespread industrial application. In this study, we underscore the efficacy of enhancing protein thermal stability through comprehensive protein design strategies, encompassing elements such as the free energy of protein folding, internal forces within proteins, and the overall structural design. We also demonstrate the efficiency and precision of combinatorial screening in the thermal stability design of aldo-keto reductase (AKR7-2-1). In our research, three single-point mutations and five combinatorial mutations were strategically introduced into AKR7-2-1, using multiple computational techniques. Notably, the E12I/S235I mutant showed a significant increase of 25.4 °C in its melting temperature (Tm). Furthermore, the optimal mutant, E12V/S235I, maintained 80 % of its activity while realizing a 16.8 °C elevation in Tm. Remarkably, its half-life at 50 °C was increased to twenty times that of the wild type. Structural analysis indicates that this enhanced thermal stability primarily arises from reduced oscillation in the loop region and increased internal hydrogen bonding. The promising results achieved with AKR7-2-1 demonstrate that our strategy could serve as a valuable reference for enhancing the thermal stability of other industrial enzymes.

Specific coenzyme preference switching for an aldo-keto reductase that synthesizes the chiral intermediate of duloxetine.

The synthesis of chiral intermediates for the traditional antidepressant duloxetine has gained significant attention as the number of depressed patients continues to grow. S-N, N-Dimethyl-3-hydroxy-3-(2-thienyl)-1-propanamide (S-DHTP) is a critical intermediate in the synthesis of duloxetine, and the chemical synthesis process is complex and environmentally unfriendly. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a major cost driver in the biocatalytic production of S-DHTP from N, N-Dimethyl-3-keto-3-(2-thienyl)-1-propanamide (DKTP). Here, we successfully modified the coenzyme preference of an aldo-keto reductase (AKR7-2-1) to use the cheaper reduced nicotinamide adenine dinucleotide (NADH) through a coenzyme preference modification approach. We utilized protein engineering to create a superior mutant, Y53F, which increased the coenzyme specificity of AKR7-2-1 by 875-fold and improved its thermal stability, enhancing its potential for industrial applications. Molecular dynamics simulations were performed to demonstrate the effect of mutations at key sites on the protein, revealing the altered coenzyme preference and increased thermal stability from structural and energetic changes. This study validates the viability of the coenzyme preference modification strategy for aldo-keto reductase, offering valuable insights for fellow researchers and guiding future investigations.

Construction of Immobilized Enzymes with Yeast and Metal-Organic Frameworks for Enhanced Biocatalytic Activities.

Metal-organic frameworks (MOFs) have become promising host materials for enzyme immobilization and protection. Herein, ZIF-8 nanocubes were successfully self-assembled onto yeast as a biological template to obtain hybrid Y@ZIF-8. The size, morphology, and loading efficiency of ZIF-8 nanoparticles assembled on yeast templates can be well-regulated by adjusting the various synthetic parameters. Particularly, the amount of water significantly affected the particle size of ZIF-8 assembled on yeast. Through using a cross-linking agent, the relative enzyme activity of Y@ZIF-8@t-CAT could be greatly enhanced and remained the highest even after seven consecutive cycles, with improved cycling stability, as compared to that of Y@ZIF-8@CAT. In addition to the effect of the physicochemical properties of Y@ZIF-8 on the loading efficiency, the temperature tolerance, pH tolerance, and storage stability of Y@ZIF-8@t-CAT were also systematically investigated. Importantly, the catalytic activity of free catalase was decreased to 72% by 45 days, while the activity of the immobilized catalase remained above 99%, suggesting good storage stability. The present work demonstrates that yeast-templated ZIF-8 nanoparticles have a high potential to be used as biocompatible immobilization materials and are promising candidates for the preparation of effective biocatalysts in biomedicine applications.

A Minireview for Recent Development of Nanomaterial-Based Detection of Antibiotics.

Antibiotics are considered a new type of organic pollutant. Antibiotic residues have become a global issue due to their harm to human health. As the use of antibiotics is increasing in human life, such as in medicine, crops, livestock, and even drinking water, the accurate analysis of antibiotics is very vital. In order to develop rapid and on-site approaches for the detection of antibiotics and the analysis of trace-level residual antibiotics, a high-sensitivity, simple, and portable solution is required. Meanwhile, the rapid nanotechnology development of a variety of nanomaterials has been achieved. In this review, nanomaterial-based techniques for antibiotic detection are discussed, and some reports that have employed combined nanomaterials with optical techniques or electrochemical techniques are highlighted.

Fabrication of supported Pt/CeO2 nanocatalysts doped with different elements for CO oxidation: theoretical and experimental studies.

Supported Pt/CeO2 catalysts have been widely used in carbon monoxide (CO) oxidation; however, the high oxygen vacancy formation energy (Evac) in the process leads to the poor performance of these catalysts. Herein, we explored different element (Pr, Cu, or N) doped CeO2 supports using Ce-based metal-organic frameworks (MOFs) as precursors via calcination treatment. The obtained CeO2 supports were used to load Pt nanoparticles. These catalysts were systematically characterized by various techniques, and they showed superior catalytic activity for CO oxidation compared to undoped catalysts which could be attributed to the formation of Ce3+, and high amounts of Oads/(Oads + Olat) and Ptδ+/Pttotal. Moreover, density functional theory calculations with on-site Coulomb interaction correction (DFT+U) were performed to provide atomic-scale insights into the reaction process by the Mars-van Krevelen (M-vK) mechanism, which revealed that the element-doped catalysts could simultaneously reduce the adsorption energies of CO and lower reaction energy barriers in the *OOCO associative pathway.

Afterglow Electrochemiluminescence from Nitrogen-Deficient Graphitic Carbon Nitride.

Almost all current electrochemiluminescent reagents require real-time electrochemical stimulation to emit light. Here, we report a novel electrochemiluminescent reagent, nitrogen-deficient graphitic carbon nitride (CNx), that can emit afterglow electrochemiluminescence (ECL) after cessation of electric excitation. CNx obtained by post-thermal treatment of graphitic carbon nitride (CN) with KSCN has a cyanamide group and a nitrogen vacancy, which created defects to trap electrically injected electrons. The trapped electrons can slowly release and react with coreactants to emit light with longevity. The cathodic afterglow ECL lasts for 70 s after pulsing the CNx nanosheet (CNxNS-1.6)-modified glassy carbon electrode at -1.0 V for 20 s in 2.0 M PBS containing 1 mM K2S2O8. The afterglow ECL mechanism is revealed by investigation of its influencing factors and ECL wavelength. The discovery of afterglow ECL may open a new doorway for new significant applications of the ECL technique and provide a deeper understanding of the structure-property relationships of CN.

Hierarchically Annular Mesoporous Carbon Derived from Phenolic Resin for Efficient Removal of Antibiotics in Wastewater.

Antibiotics have become a new type of environmental pollutant due to their extensive use. High-performance adsorbents are of paramount significance for a cost-effective and environmentally friendly strategy to remove antibiotics from water environments. Herein, we report a novel annular mesoporous carbon (MCN), prepared by phenolic resin and triblock copolymer F127, as a high-performance adsorbent to remove penicillin, streptomycin, and tetracycline hydrochloride from wastewater. The MCNs have high purity, rich annular mesoporosity, a high surface area (605.53 m2/g), and large pore volume (0.58 cm3/g), improving the adsorption capacity and facilitating the efficient removal of penicillin, streptomycin, and tetracycline hydrochloride from water. In the application of MCNs to treat these three kinds of residual antibiotics, the adsorption amounts of tetracycline hydrochloride were higher than penicillin and streptomycin, and the adsorption capacity was up to 880.6 mg/g. Moreover, high removal efficiency (99.6%) and excellent recyclability were achieved. The results demonstrate that MCN adsorbents have significant potential in the treatment of water contaminated with antibiotics.

Visible light-induced selenylative spirocyclization of biaryl ynones toward the formation of selenated spiro[5.5]trienones.

A visible-light induced dearomative cascade cyclization of biaryl ynones with diselenides under photocatalyst and external additive-free conditions has been explored, giving a series of selenated spiro[5.5]trienones in moderate to good yields. The Se-Se bond in diselenides could be cleaved to generate arylselenyl radicals under visible light irradiation in the absence of a photocatalyst. This protocol provides a facile and green method for the synthesis of spiro[5.5]trienones.

Tumor Cell-Specific and Lipase-Responsive Delivery of Hydrogen Sulfide for Sensitizing Chemotherapy of Pancreatic Cancer.

The inability of small molecule drugs to diffuse into tumor interstitium is responsible for the relatively low effectiveness of chemotherapy. Herein, a hydrogen sulfide (H2S) gas-involved chemosensitization strategy is proposed for pancreatic cancer treatment by developing a tumor-specific lipase-responsive nanomedicine based on aptamer-conjugated DATS/Dox co-loaded PCL-b-PEO micelle (DA/D@Ms-A). After receptor-mediated endocytosis and subsequent digestion of PCL blocks by intracellular lipase, the nanomedicine releases Dox and DATS, which then react with intracellular glutathione to produce H2S. The cytotoxicity result indicates that H2S can enhance Dox chemotherapy efficiency owing to the synergetic therapeutic effect of Dox and H2S. Moreover, the nanomedicine is featured with well tumor penetration capability benefitting from the targeting ability of aptamers and high in vivo biocompatibility due to the high density of PEO and biodegradable PCL. The nanomedicine capable of synergetic gas-chemotherapy holds great potential for pancreatic cancer treatment.

CXCR4 knockdown enhances sensitivity of paclitaxel via the PI3K/Akt/mTOR pathway in ovarian carcinoma.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy. EOC control remains difficult, and EOC patients show poor prognosis regarding metastasis and chemotherapy resistance. The aim of this study was to estimate the effect of CXCR4 knockdown-mediated reduction of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) stemness and enhancement of chemotherapy sensitivity in EOC. Mechanisms contributing to these effects were also explored. Our data showed distinct contribution of CXCR4 overexpression by dependent PI3K/Akt/mTOR signaling pathway in EOC development. CXCR4 knockdown resulted in a reduction in CSCs and EMT formation and enhancement of chemotherapy sensitivity in tumor cells, which was further advanced by blocking CXCR4-PI3K/Akt/mTOR signaling. This study also documented the critical role of silencing CXCR4 in sensitizing ovarian CSCs to chemotherapy. Thus, targeting CXCR4 to suppress EOC progression, specifically in combination with paclitaxel (PTX) treatment, may have clinical application value.

Enhancing the biocatalytic synthesis of chiral drug intermediate by rational design an aldo-keto reductase from Bacillus megaterium YC4-R4.

In recent years, with the increasing number of patients with depression, the efficient synthesis of the first-line antidepressant drug duloxetine intermediate (S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propanamine, S-DHTP) has attracted great attention. The wild-type AKR3-2-9 from Bacillus megaterium YC4-R4 exhibits high application potential of catalyzing N,N-dimethyl-3-keto-3-(2-thienyl)-1-propanamine (DKTP) to prepare S-DHTP, but there is still much room for improvement. In this work, rational design was carried out to enhance the catalytic potential of AKR3-2-9. Notably, compared to the wild-type AKR3-2-9, three mutants (Ile189Val, Asn256Asp, and Ile189Val + Asn256Asp) were obtained, and their catalytic efficiencies were increased by 1.3 times, 2.3 times, and 1.31 times, respectively. Besides, the thermal stability and organic solvent resistance were improved. More importantly, when the concentration of the substrate DKTP was 0.5 g/L, the catalytic yields of Ile189Val, Asn256Asp and Ile189Val + Asn256Asp were increased by 1.45 times, 1.86 times, and 2.05 times, respectively. Besides, the corresponding optical purities of the three mutants were 92.7 %, 94.3 % and 93.8 %. The above results indicated that the rational design of the AKR of Bacillus megaterium YC4-R4 enhanced its potential for biocatalytic preparation of S-DHTP.

Biocompatible 2D Cu-TCPP Nanosheets Derived from Cu2O Nanocubes as Multifunctional Nanoplatforms for Combined Anticancer Therapy.

Two-dimensional (2D) metal-organic frameworks (MOFs) could serve as multifunctional nanoplatforms to load small-molecule drugs and enzyme-mimicking nanoparticles (NPs) with a high efficiency for combined cancer therapy. Herein, we have prepared novel 2D Cu-tetrakis (4-carboxyphenyl) porphyrin (TCPP) nanosheets with an average thickness of 1.2 ± 0.1 nm using Cu2O nanocubes (50 nm) as a template and solid copper ion supplier. Cu2O nanocubes can be consumed and hybridized with the obtained Cu-TCPP, depending on the molar ratio of Cu2O and TCPP linker. The resultant Cu2O/Cu-TCPP could serve as nanoplatforms for co-loading of Pt and Au NPs to construct multifunctional Cu2O/Cu-TCPP/(Pt-Au) nanomedicines, which showed a superior anticancer effect via multiple therapeutic modes. For instance, Cu(II)-TCPP can produce 1O2 in the presence of acidic H2O2 by the Russell mechanism and the intrinsic Cu(I) ions (derived from the residual Cu2O) could mediate a Fenton-like reaction in tumorous tissues to generate toxic hydroxyl radicals (•OH). Moreover, the loaded Pt NPs with catalase (CAT)-mimic activity could decompose hydrogen peroxide (H2O2) into O2 within the tumor cells, increasing the local O2 concentration, modulating the tumorous hypoxia atmosphere, and promoting the O2-dependent glucose oxidation reaction. Furthermore, Au NPs with glucose oxidase (GOx)-mimic activity could accelerate the consumption of glucose and cut nutrient supply to induce starvation therapy. Consequently, our designed 2D MOF-based therapeutic nanomedicines would be a promising candidate for future smart and combined cancer therapy.

Cobalt Phthalocyanine Supported on Mesoporous CeO2 as an Active Molecular Catalyst for CO Oxidation.

Heterogenization of biomolecules by immobilizing on a metal oxide support could greatly enhance their catalytic activity and stability, but their interactions are generally weak. Herein, cobalt phthalocyanine (CoPc) molecules were firmly anchored on a Ce-based metal-organic framework (Ce-BTC) due to π-π stacking interaction between CoPc and aromatic frameworks of the BTC linker, which was followed by a calcination treatment to convert Ce-BTC to mesoporous CeO2 and realize a molecular-level dispersion of CoPc on the surface of CeO2. Various characterization results confirm the successful fabrication of molecular-based CoPc/CeO2 catalysts which exhibited good CO oxidation performance. Importantly, we found that the mixing manner of Ce-BTC and CoPc remarkably affects the physicochemical properties which then determined the catalytic performance of the resultant CoPc/CeO2 catalysts. In contrast, the direct physical mixing of CoPc and CeO2 led to poor performance toward CO oxidation, manifesting that the Ce-BTC-mediated CoPc loading strategy is promising for the heterogenization of catalytic biomolecules.

3D printing of recombinant Escherichia coli/Au nanocomposites as agitating paddles towards robust catalytic reduction of 4-nitrophenol.

Three-dimensional (3D) printing technology has received remarkable attention in manufacturing catalysts with tailored shapes and high precision, particularly facilitating catalyst recovery, maximizing heat/mass transfer, as well as enhancing catalytic performance. Herein, an engineered recombinant Escherichia coli strain (denoted as e-E. coli) with overexpressing metallothionein (a metal-binding protein) was explored to synthesize Au nanoparticles serving as both reducing and stabilizing agents. Then, the mixed inks containing e-E. coli/Au composite and biocompatible polymers (sodium alginate and gelatin) were extruded based on a direct ink writing method followed by chemical crosslinking to form robust 3D grids with square symmetry. To boost the mass transfer and minimize pressure drop, the monolith catalysts were assembled into agitating paddles and used for liquid-phase batch reactions (volume: 1 L). As such, the reaction solutions were mixed internally via the powered "catalytic paddles" with high mechanical strength, excellent reactivity, and easy recyclability, which could be reused at least 7 cycles without performance loss. Our work provides a novel strategy for the fabrication of supported Au catalysts, and the proof-of-concept "catalytic paddles" by 3D printing technology can be applied to other industrial solution-based reactions.

Metal-Free Sulfonylative Spirocyclization of Indolyl-ynones via Insertion of Sulfur Dioxide: Access to Sulfonated Spiro[cyclopentenone-1,3'-indoles].

A three-component sulfonylative spirocyclization of indolyl ynones with aryldiazonium salts and a sulfur dioxide surrogate of DABCO·(SO2)2 has been developed, providing a range of sulfonated spiro[cyclopentenone-1,3'-indoles] in moderate to good yields. This transformation was initiated by an in situ generated arylsulfonyl radical and proceeded efficiently under metal-free conditions, involving a radical-induced dearomative cascade cyclization accompanied by the insertion of sulfur dioxide. This protocol provides an efficient and convenient method to access sulfonated spiroindolenines, and tolerant various functional groups.

Fabrication of Versatile Hollow Metal-Organic Framework Nanoplatforms for Folate-Targeted and Combined Cancer Imaging and Therapy.

Metal-organic frameworks (MOFs) have received extensive attention in the field of biomedicine, particularly serving as multifunctional theranostic nanoplatforms by integrating chemodrugs, imaging agents, and targeting agents. Herein, we report a facile strategy for the fabrication of a hollow and monodisperse MOF (denoted hMIL-88B(Fe)@ZIF-8) consisting of ZIF-8 nanoparticles loaded on the external shell of hollow MIL-88B(Fe). In particular, the hybrid hollow MOF was constructed by partially etching spindlelike MIL-88B(Fe) nanoparticles with 2-methylimidazole in the presence of zinc ions. The obtained hMIL-88B(Fe)@ZIF-8 was then used as a drug/cargo delivery vehicle for loading doxorubicin (DOX), manganese oxide (MnOx) nanoparticles, and folic acid (FA), forming a multifunctional nanoplatform (denoted hM@ZMDF). Importantly, the resulting hM@ZMDF exhibited a specific targeting property for the FA receptor-overexpressed cancer cells (MCF-7 and HepG-2 cells) and then it unloaded DOX and Fe3+ in the tumor microenvironment. Consequently, DOX played dual roles as a chemotherapeutic drug and a fluorescent imaging agent. Also, the released Fe3+ could mediate the Fenton reaction and intracellularly generate toxic hydroxyl radicals in the presence of high glutathione in cancer cells. In addition, MnOx nanoparticles could participate in magnetic resonance imaging. Therefore, the versatile hM@ZMDF nanoplatforms have great potential for smart cancer therapy.