Cu-BTC Derived Mesoporous CuS Nanomaterial as Nanozyme for Colorimetric Detection of Glutathione.

In this paper, Cu-BTC derived mesoporous CuS nanomaterial (m-CuS) was synthesized via a two-step process involving carbonization and sulfidation of Cu-BTC for colorimetric glutathione detection. The Cu-BTC was constructed by 1,3,5-benzenetri-carboxylic acid (H3BTC) and Cu2+ ions. The obtained m-CuS showed a large specific surface area (55.751 m2/g), pore volume (0.153 cm3/g), and pore diameter (15.380 nm). In addition, the synthesized m-CuS exhibited high peroxidase-like activity and could catalyze oxidation of the colorless substrate 3,3',5,5'-tetramethylbenzidine to a blue product. Peroxidase-like activity mechanism studies using terephthalic acid as a fluorescent probe proved that m-CuS assists H2O2 decomposition to reactive oxygen species, which are responsible for TMB oxidation. However, the catalytic activity of m-CuS for the oxidation of TMB by H2O2 could be potently inhibited in the presence of glutathione. Based on this phenomenon, the colorimetric detection of glutathione was demonstrated with good selectivity and high sensitivity. The linear range was 1-20 µM and 20-300 µM with a detection limit of 0.1 µM. The m-CuS showing good stability and robust peroxidase catalytic activity was applied for the detection of glutathione in human urine samples.

A two-photon fluorescent probe for highly selective detection of Cys over GSH and Hcy based on the Michael addition and transcyclization mechanism and its application in bioimaging and protein straining in SDS-PAGE.

BACKGROUND: Cysteine (Cys), glutathione (GSH), and homocysteine (Hcy), as three major biothiols are involved in a variety of physiological processes and play a crucial role in plant growth. Abnormal levels of Cys can cause plants to fail to grow properly. To date, although a very large number of fluorescent probes have been reported for the detection of biothiols, very few of them can be used for the selective discrimination of Cys from GSH and Hcy due to their structural similarity, and only a few of them can be used for plant imaging. RESULTS: Here, three fluorescent probes (o-/m-/p-TMA) based on TMN fluorophore and the ortho-/meta-/para-substituted maleimide recognition groups were constructed to investigate the selective response effect of Cys. Compared to the o-/m-TMA, p-TMA can selectively detect Cys over GSH and Hcy with a rapid response time (10 min) and a low detection limit (0.26 µM). The theoretical calculation confirmed that the intermediate p-TMA-Cys-int has shorter interatomic reaction distances (3.827 Å) compared to o-/m-TMA-Cys (5.533/5.287 Å), making it more suitable for further transcyclization reactions. Additionally, p-TMA has been employed for selective tracking of exogenous and endogenous Cys in Arabidopsis thaliana using both single-/two-photon fluorescence imaging. Furthermore, single cell walls produced obvious two-photon fluorescence signals, indicating that p-TMA can be used for high-concentration Cys analysis in single cells. Surprisingly, p-TMA can be used as a fluorescent dye for protein staining in SDS-PAGE with higher sensitivity (7.49 µg/mL) than classical Coomassie brilliant blue (14.11 µg/mL). SIGNIFICANCE: The outstanding properties of p-TMA make it a promising multifunctional molecular tool for the highly selective detection of Cys over GSH and Hcy in various complex environments, including water solutions, zebrafish, and plants. Additionally, it has the potential to be developed as a fluorescent dye for a simple and fast SDS-PAGE fluorescence staining method.

Development of Aptamer-DNAzyme based metal-nucleic acid frameworks for gastric cancer therapy.

The metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature. Furthermore, longer oligonucleotides facilitate functional expansion of nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, we build an interferon regulatory factor-1(IRF-1) loaded Ca2+/(aptamer-deoxyribozyme) MNF to target regulate glucose transporter (GLUT-1) expression in human epidermal growth factor receptor-2 (HER-2) positive gastric cancer cells. This MNF nanodevice disrupts GSH/ROS homeostasis, suppresses DNA repair, and augments ROS-mediated DNA damage therapy, with tumor inhibition rate up to 90%. Our work signifies a significant advancement towards an era of universal MNF application.

Nitrodopamine modified MnO2 NS-MoS2QDs hybrid nanocomposite for the extracellular and intracellular detection of glutathione.

We have developed a highly sensitive and reliable fluorescence resonance energy transfer (FRET) probe using nitro-dopamine (ND) and dopamine (DA) coated MnO2 nanosheet (ND@MnO2 NS and DA@MnO2 NS) as an energy acceptor and MoS2 quantum dots (QDs) as an energy donor. By employing surface-modified MnO2 NS, we can effectively reduce the fluorescence intensity of MoS2 QDs through FRET. It can reduce MnO2 NS to Mn2+ and facilitate the fluorescence recovery of the MoS2 QDs. This ND@MnO2 NS@MoS2 QD-based nanoprobe demonstrates excellent sensitivity to GSH, achieving an LOD of 22.7 nM in an aqueous medium while exhibiting minimal cytotoxicity and good biocompatibility. Moreover, our sensing platform shows high selectivity to GSH towards various common biomolecules and electrolytes. Confocal fluorescence imaging revealed that the nanoprobe can image GSH in A549 cells. Interestingly, the ND@MnO2 NS nanoprobe demonstrates no cytotoxicity in living cancer cells, even at concentrations up to 100 µg mL-1. Moreover, the easy fabrication and eco-friendliness of ND@MnO2 NS make it a rapid and simple method for detecting GSH. We envision the developed nanoprobe as an incredible platform for real-time monitoring of GSH levels in both extracellular and intracellular mediums, proving valuable for biomedical research and clinical diagnostics.

Magnetic Field-Optimized Paramagnetic Nanoprobe for T2/T1 Switchable Histopathological-Level MRI.

Traditional magnetic resonance imaging (MRI) contrast agents (CAs) are a type of "always on" system that accelerates proton relaxation regardless of their enrichment region. This "always on" feature leads to a decrease in signal differences between lesions and normal tissues, hampering their applications in accurate and early diagnosis. Herein, we report a strategy to fabricate glutathione (GSH)-responsive one-dimensional (1-D) manganese oxide nanoparticles (MONPs) with improved T2 relaxivities and achieve effective T2/T1 switchable MRI imaging of tumors. Compared to traditional contrast agents with high saturation magnetization to enhance T2 relaxivities, 1-D MONPs with weak Ms effectively increase the inhomogeneity of the local magnetic field and exhibit obvious T2 contrast. The inhomogeneity of the local magnetic field of 1-D MONPs is highly dependent on their number of primary particles and surface roughness according to Landau-Lifshitz-Gilbert simulations and thus eventually determines their T2 relaxivities. Furthermore, the GSH responsiveness ensures 1-D MONPs with sensitive switching from the T2 to T1 mode in vitro and subcutaneous tumors to clearly delineate the boundary of glioma and metastasis margins, achieving precise histopathological-level MRI. This study provides a strategy to improve T2 relaxivity of magnetic nanoparticles and construct switchable MRI CAs, offering high tumor-to-normal tissue contrast signal for early and accurate diagnosis.

Mucoadhesive phenylboronic acid-grafted carboxymethyl cellulose hydrogels containing glutathione for treatment of corneal epithelial cells exposed to benzalkonium chloride.

Benzalkonium chloride (BAK) is the most commonly-used preservative in topical ophthalmic medications that may cause ocular surface inflammation associated with oxidative stress and dry eye syndrome. Glutathione (GSH) is an antioxidant in human tears and able to decrease the proinflammatory cytokine release from cells and reactive oxygen species (ROS) formation. Carboxymethyl cellulose (CMC), a hydrophilic polymer, is one of most commonly used artificial tears and can promote the corneal epithelial cell adhesion, migration and re-epithelialization. However, most of commercial artificial tears provide only temporary relief of irritation symptoms and show the short-term treatment effects. In the study, 3-aminophenylboronic acid was grafted to CMC for increase of mucoadhesive properties that might increase the precorneal retention time and maintain the effective therapeutic concentration on the ocular surface. CMC was modified with different degree of substitution (DS) and characterized by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. Phenylboronic acid (PBA)-grafted CMC hydrogels have interconnected porous structure and shear thinning behavior. Modification of CMC with high DS (H-PBA-CMC) shows the strong bioadhesive force. The optimal concentration of GSH to treat corneal epithelial cells (CECs) was evaluated by cell viability assay. H-PBA-CMC hydrogels could sustained release GSH and decrease the ROS level. H-PBA-CMC hydrogels containing GSH shows the therapeutic effects in BAK-damaged CECs via improvement of inflammation, apoptosis and cell viability. After topical administration of developed hydrogels, there was no ocular irritation in rabbits. These results suggested that PBA-grafted CMC hydrogels containing GSH might have potential applications for treatment of dry eye disease.

Codelivery of CPT and siPHB1 with GSH/ROS Dual-Responsive Hybrid Nanoparticles Based on a [12]aneN3-Derived Lipid for Synergistic Lung Cancer Therapy.

The combination of small-interfering RNA (siRNA)-mediated gene silencing and chemotherapeutic agents for lung cancer treatment has attracted widespread attention in terms of a greater therapeutic effect, minimization of systemic toxicity, and inhibition of multiple drug resistance (MDR). In this work, three amphiphiles, CBN1-CBN3, were first designed and synthesized as a camptothecin (CPT) conjugate and gene condensation agents by the combination of CPT prodrugs and di(triazole-[12]aneN3) through the ROS-responsive phenylborate ester and different lengths of alkyl chains (with 6, 9, 12 carbon chains for CBN1-CBN3, respectively). CBN1-CBN3 were able to be self-assembled into liposomes with an average diameter in the range of 320-240 nm, showing the ability to effectively condense siRNA. Among them, CBN2, with a nine-carbon alkyl chain, displayed the best anticancer efficiency in A549 cells. In order to give nanomedicines a stealth property and PEGylation/dePEGylation transition, a GSH-responsive PEGylated TPE derivative containing a disulfide linkage (TSP) was further designed and prepared. A combination of CBN2/siRNA complexes and DOPE with TSP resulted in GSH/ROS dual-responsive lipid-polymer hybrid nanoparticles (CBN2-DP/siRNA NPs). In present GSH and H2O2, CBN2-DP/siRNA NPs were decomposed, resulting in the controlled release of CPT drug and siRNA. In vitro, CBN2-DP/siPHB1 NPs showed the best anticancer activity for suppression of about 75% of A549 cell proliferation in a serum medium. The stability of CBN2-DP/siRNA NPs was significantly prolonged in blood circulation, and they showed effective accumulation in the A549 tumor site through an enhanced permeability and retention (EPR) effect. In vivo, CBN2-DP/siPHB1 NPs demonstrated enhanced synergistic cancer therapy efficacy and tumor inhibition as high as 71.2%. This work provided a strategy for preparing lipid-polymer hybrid NPs with GSH/ROS dual-responsive properties and an intriguing method for lung cancer therapy.

Construction of a dual-signal readout platform for effective glutathione S-transferase sensing based on polyethyleneimine-capped silver nanoclusters and cobalt-manganese oxide nanosheets with oxidase-mimicking activity.

A novel dual-mode fluorometric and colorimetric sensing platform is reported for determining glutathione S-transferase (GST) by utilizing polyethyleneimine-capped silver nanoclusters (PEI-AgNCs) and cobalt-manganese oxide nanosheets (CoMn-ONSs) with oxidase-like activity. Abundant active oxygen species (O2•-) can be produced through the CoMn-ONSs interacting with dissolved oxygen. Afterward, the pink oxDPD was generated through the oxidation of colorless N,N-diethyl-p-phenylenediamine (DPD) by O2•-, and two absorption peaks at 510 and 551 nm could be observed. Simultaneously, oxDPD could quench the fluorescence of PEI-AgNCs at 504 nm via the inner filter effect (IFE). However, in the presence of glutathione (GSH), GSH prevents the oxidation of DPD due to the reducibility of GSH, leading to the absorbance decrease at 510 and 551 nm. Furthermore, the fluorescence at 504 nm was restored due to the quenching effect of oxDPD on decreased PEI-AgNCs. Under the catalysis of GST, GSH and1-chloro-2,4-dinitrobenzo (CDNB) conjugate to generate an adduct, initiating the occurrence of the oxidation of the chromogenic substrate DPD, thereby inducing a distinct colorimetric response again and the significant quenching of PEI-AgNCs. The detection limits for GST determination were 0.04 and 0.21 U/L for fluorometric and colorimetric modes, respectively. The sensing platform illustrated reliable applicability in detecting GST in real samples.

In vitro study on the competitive reactions between arsenite and selenite with glutathione.

Exposure to arsenic can cause various biological effects by increasing the production of reactive oxygen species (ROS). Selenium acts as a beneficial element by regulating ROS and limiting heavy metal uptake and translocation. There are studies on the interactive effects of As and Se in plants, but the antagonistic and synergistic effects of these elements based on their binding to glutathione (GSH) molecules have not been studied yet. In this study, we aimed to investigate the antagonistic or synergistic effects of As and Se on the binding mechanism of Se and As with GSH at pH 3.0, 5.0, or 6.5. The interaction of As and Se in Se(SG)2 + As(III) or As(SG)3 + Se(IV) binary systems and As(III) + Se(IV) + GSH ternary system were examined depending on their ratios via liquid chromatography diode array detector/electrospray mass spectrometry (LC-DAD/MS) and liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The results showed that the formation of As(GS)3 was not detected in the As(III) + Se(SG)2 binary system, indicating that As(III) did not affect the stability of Se(SG)2 complex antagonistically. However, in the Se(IV) + As(SG)3 binary system, the addition of Se(IV) to As(SG)3 affected the stability of As(SG)3 antagonistically. Se(IV) reacted with GSH, disrupting the As(SG)3 complex, and consequently, Se(SG)2 formation was measured using LC-MS/DAD. In the Se(IV) + GSH + As(III) ternary system, Se(SG)2 formation was detected upon mixing As(III), Se(IV), and GSH. The increase in the concentration of As(III) did not influence the stability of the Se(SG)2 complex. Additionally, Se(IV) has a higher affinity than As(III) to the GSH, regardless of the pH of the solution. In both binary and ternary systems, the formation of the by-product glutathione trisulfide (GSSSG) was detected using LC-ESI-MS/MS.

Nanoscale Evaluation of the Degradation Stability of Black Phosphorus Nanosheets Functionalized with PEG and Glutathione-Stabilized Doxorubicin Drug-Loaded Gold Nanoparticles in Real Functionalized System.

Two-dimensional black phosphorus (2D BP) has attracted significant research interest in the field of biomedical applications due to its unique characteristics, including high biocompatibility, impressive drug-loading efficiency, phototherapeutic ability, and minimal side effects. However, its puckered honeycomb lattice structure with lone-pair electrons of BP leads to higher sensitivity and chemical reactivity towards H2O and O2 molecules, resulting in the degradation of the structure with physical and chemical changes. In our study, we synthesize polyethylene glycol (PEG) and glutathione-stabilized doxorubicin drug-assembled Au nanoparticle (Au-GSH-DOX)-functionalized BP nanosheets (BP-PEG@Au-GSH-DOX) with improved degradation stability, biocompatibility, and tumor-targeting ability. Transmission electron microscopy, X-ray photoelectron spectroscopy, and Raman spectroscopy indicate the nanoscale degradation behavior of synthesized nanoconjugates in three different environmental exposure conditions, and the results demonstrate the remarkable nanoscale stability of BP-PEG@Au-GSH-DOX against the degradation of BP, which provides significant interest in employing 2D BP-based nanotherapeutic agents for tumor-targeted cancer phototherapy.

1H NMR based sulfonation reaction kinetics of wine relevant thiols in comparison with known carbonyls.

Sulfite addition is a common tool for ensuring wines' oxidative stability via the activity of its free and weakly bound molecular fraction. As a nucleophile, bisulfite forms covalent adducts with wine's most relevant electrophiles, such as carbonyls, polyphenols, and thiols. The equilibrium in these reactions is often represented as dissociation rather than formation. Recent studies from our laboratory demonstrate, first, the acetaldehyde sulfonate dissociation, and second, the chemical stability of cysteine and epicatechin sulfonates under wine aging conditions. Thus, the objective of this study was to monitor by 1H NMR the binding specificity of known carbonyl-derived SO2 binders (acetaldehyde and pyruvic acid) in the presence of S-containing compounds (cysteine and glutathione). We report that during simulated wine aging, the sulfur dioxide that is rapidly bound to carbonyl compounds will be released and will bind to cysteine and glutathione, demonstrating the long-term sulfur dioxide binding potential of S-containing compounds. These results are meant to serve as a complement to existing literature reviews focused on molecular markers related to wines' oxidative stability and emphasize once more the importance of S-containing compounds in wine aging chemical mechanisms.

Fe3O4 nanoparticles entrapped in the inner surfaces of N-doped carbon microtubes with enhanced biomimetic activity.

Tubular structured composites have attracted great interest in catalysis research owing to their void-confinement effects. In this work, we synthesized a pair of hollow N-doped carbon microtubes (NCMTs) with Fe3O4 nanoparticles (NPs) encapsulated inside NCMTs (Fe3O4@NCMTs) and supported outside NCMTs (NCMTs@Fe3O4) while keeping other structural features the same. The impact of structural effects on the catalytic activities was investigated by comparing a pair of hollow-structured nanocomposites. It was found that the Fe3O4@NCMTs possessed a higher peroxidase-like activity when compared with NCMTs@Fe3O4, demonstrating structural superiority of Fe3O4@NCMTs. Based on the excellent peroxidase-like catalytic activity and stability of Fe3O4@NCMTs, an ultra-sensitive colorimetric method was developed for the detection of H2O2 and GSH with detection limits of 0.15 µM and 0.49 µM, respectively, which has potential application value in biological sciences and biotechnology.

Preparation of Liposome Gel by Calcium Cross-Linking Induces the Long-Term Release of DOX to Improve the Antitumor Effect.

Doxorubicin (DOX) is one of the most commonly used anticancer drugs; however, its clinical application is greatly limited due to its toxicity and chemotherapy resistance. The delivery of DOX by liposomes (Lipos) can improve the blood circulation time in vivo and reduce toxic side effects, but the drug's accumulation in the tumor is often insufficient for effective treatment. In this study, we present a calcium cross-linked liposome gel for the encapsulation of DOX, demonstrating its superior long-term release capabilities compared to conventional Lipos. By leveraging this enhanced long-term release, we can enhance drug accumulation within tumors, ultimately leading to improved antitumor efficacy. Lipos were prepared using the thin-film dispersion method in this study. We utilized the ion-responsiveness of glutathione-gelatin (GSH-GG) to form the gel outside the Lipos and named the nanoparticles coated with GSH-GG on the outside of Lipos as Lipos@GSH-GG. The average size of Lipos@GSH-GG was around 342.9 nm, with a negative charge of -25.6 mV. The in vitro experiments revealed that Lipos@GSH-GG exhibited excellent biocompatibility and slower drug release compared to conventional Lipos. Further analysis of cellular uptake and cytotoxicity demonstrated that Lipos@GSH-GG loading DOX (DOX&Lipos@GSH-GG) exhibited superior long-term release effects and lower toxic side effects compared to Lipos loading DOX (DOX&Lipos). Additionally, the findings regarding the long-term release effect in vivo and the tumor accumulation within tumor-bearing mice of Lipos@GSH-GG suggested that, compared to Lipos, it demonstrated superior long-term release capabilities and achieved greater drug accumulation within tumors. In vivo antitumor efficacy experiments showed that DOX&Lipos@GSH-GG demonstrated superior antitumor efficacy to DOX&Lipos. Our study highlights Lipos@GSH-GG as a promising nanocarrier with the potential to enhance efficacy and safety by means of long-term release effects and may offer an alternative approach for effective antitumor therapy in the future.

Water-soluble silver nanoclusters with multicolor fluorescence generated by dialdehyde nanofibrillated cellulose for biological imaging.

Water-soluble silver nanoclusters (AgNCs) as a new type of fluorescent material have attracted much attention for their remarkable optical properties and excellent cytocompatibility. However, it is still challenging to synthesize water-soluble AgNCs with good cytocompatibility and excellent fluorescence. Herein, the dialdehyde nanofibrillated cellulose (DANFC)- reduced water-soluble AgNCs capped by glutathione (GSH) with tunable fluorescence emissions were first reported. The DANFC provides a mild reduction environment and crystal growth system for the coordination between silver ions and GSH compared to conventional methods using strong reducing agents. The AgNCs with intense red fluorescence (R-AgNCs@GSH, size ∼2.24 nm) and green fluorescence (G-AgNCs@GSH, size ∼1.93 nm) were produced by varying the ratios of silver sources and ligands, and could maintain stable fluorescence intensity over 6 months. Moreover, the CCK-8 study demonstrated that the R-AgNCs@GSH and G-AgNCs@GSH reduced by DANFC of excellent cytocompatibility (cell viability >90 %) and enable precise multicolor intracellular imaging of Hela cells in 1 h. This work proposes a novel method to synthesize water-soluble AgNCs with tunable fluorescence emission at room temperature based on the classical silver- mirror reaction (SMR) using DANFC as reducing agent, and the synthesized fluorescent AgNCs have great potential as novel luminescent nanomaterials in biological research.

A ROS storm generating nanocomposite for enhanced chemodynamic therapy through H2O2 self-supply, GSH depletion and calcium overload.

Catalytic generation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H2O2) is an effective strategy for tumor treatment in chemodynamic therapy (CDT). However, the intrinsic features of the microenvironment in solid tumors, characterized by limited H2O2 and overexpressed glutathione (GSH), severely impede the accumulation of intracellular ˙OH, posing significant challenges. To circumvent these critical issues, in this work, a CaO2-based multifunctional nanocomposite with a surface coating of Cu2+ and L-buthionine sulfoximine (BSO) (named CaO2@Cu-BSO) is designed for enhanced CDT. Taking advantage of the weakly acidic environment of the tumor, the nanocomposite gradually disintegrates, and the exposed CaO2 nanoparticles subsequently decompose to produce H2O2, alleviating the insufficient supply of endogenous H2O2 in the tumor microenvironment (TME). Furthermore, Cu2+ detached from the surface of CaO2 is reduced by H2O2 and GSH to Cu+ and ROS. Then, Cu+ catalyzes H2O2 to generate highly cytotoxic ˙OH and Cu2+, forming a cyclic catalysis effect for effective CDT. Meanwhile, GSH is depleted by Cu2+ ions to eliminate possible ˙OH scavenging. In addition, the decomposition of CaO2 by TME releases a large amount of free Ca2+, resulting in the accumulation and overload of Ca2+ and mitochondrial damage in tumor cells, further improving CDT efficacy and accelerating tumor apoptosis. Besides, BSO, a molecular inhibitor, decreases GSH production by blocking γ-glutamyl cysteine synthetase. Together, this strategy allows for enhanced CDT efficiency via a ROS storm generation strategy in tumor therapy. The experimental results confirm and demonstrate the satisfactory tumor inhibition effect both in vitro and in vivo.

PEGylated mesoporous silica core-shell redox-responsive nanoparticles for delivering paclitaxel to breast cancer cells.

Controlling the drug release and restricting its presence in healthy organs is extremely valuable. In this study, mesoporous silica nanoparticles (MSN) as the core, loaded with paclitaxel (PTX), were coated with a non-porous silica shell functionalized with disulfide bonds. The nanoparticles were further coated with polyethylene glycol (PEG) via disulfide linkages. We analyzed the physicochemical properties of nanoparticles, including hydrodynamic size via Dynamic Light Scattering (DLS), zeta potential, X-ray Diffraction (XRD) patterns, Fourier-Transform Infrared (FTIR) spectra, and imaging through Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). The drug release profile in two distinct glutathione (GSH) concentrations of 2 µM and 10 µM was measured. The cellular uptake of nanoparticles by MCF-7 cell line was determined using Confocal Laser Scanning Microscopy (CLSM) images and flow cytometry. Furthermore, the cell viability and the capability of nanoparticles to induce apoptosis in MCF-7 cell line were studied using the MTT assay and flow cytometry, respectively. Our investigations revealed that the release of PTX from the drug delivery system was redox-responsive. Also, results indicated an elevated level of cellular uptake and efficient induction of apoptosis, underscoring the promising potential of this redox-responsive drug delivery system for breast cancer therapy.

Injectable Chitosan Hydrogels Doped with 2D Peptide Nanosheet-Drug Conjugates for Glutathione-Responsive Sustained Drug Delivery.

The development of novel and effective drug delivery systems aimed at enhancing therapeutic profile and efficacy of therapeutic agents is a critical challenge in modern medicine. This study presents an intelligent drug delivery system based on self-assembled two-dimensional peptide nanosheets (2D PNSs). Leveraging the tunable properties of amino acid structures and sequences, we design a peptide with the sequence of Fmoc-FKKGSHC, which self-assembles into 2D PNSs with uniform structure, high biocompatibility, and excellent degradability. Covalent attachment of thiol-modified doxorubicin (DOX) drugs to 2D PNSs via disulfide bond results in the peptide-drug conjugates (PDCs), which is denoted as PNS-SS-DOX. Subsequently, the PDCs are encapsulated within the injectable, thermosensitive chitosan (CS) hydrogels for drug delivery. The designed drug delivery system demonstrates outstanding pH-responsiveness and sustained drug release capabilities, which are facilitated by the characteristics of the CS hydrogels. Meanwhile, the covalently linked disulfide bond within the PNS-SS-DOX is responsive to intracellular glutathione (GSH) within tumor cells, enabling controlled drug release and significantly inhibiting the cancer cell growth. This responsive peptide-drug conjugate based on a 2D peptide nanoplatform paves the way for the development of smart drug delivery systems and has bright prospects in the future biomedicine field.

Mononuclear η6-arene ruthenium(II) complexes with pyrazolyl-pyridazine ligands: synthesis, CT-DNA binding, reactivity towards glutathione, and cytotoxicity.

Organometallic η6-arene ruthenium(II) complexes with 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (Ru1, Ru2, and Ru5) and 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (Ru3-4) N,N' heterocyclic and η6-arene (cymene (Ru1-4) or toluene (Ru 5)) have been synthesized. The ruthenium(II) complexes have common "three-legged piano-stool" pseudo-octahedral structures known for half-sandwich complexes. Evolution of their UV-Visible absorption spectra in PBS buffer or DMSO over 24 h confirmed their good solvolysis stability. Titrations of the complexes with the calf thymus DNA (CT-DNA) were monitored using UV-Visible absorption and fluorescence spectroscopies. The complexes interact moderately with CT-DNA and their binding constants are in the order of 104 M-1. Competitive binding of the complexes to a DNA-Hoechst 33,258 depicted competitive displacement of Hoechst from DNA's minor grooves. These complexes bind to glutathione forming GSH-adducts through S coordination by replacement of a halide, with the iodo-analogues having higher binding constants than the chloro-complexes. Cyclic voltammograms of the complexes exhibited one electron-transfer quasi-reversible process. Trends in the molecular docking data of Ru1-5/DNA were similar to those for DNA binding constants. Of the five, only Ru1, Ru3 and Ru5 showed some activity (moderate) against the MCF-7 breast cancer cells with IC50 values in the range of 59.2-39.9 for which Ru5 was the most active. However, the more difficult-to-treat cell line, MDA-MB 231 cell was recalcitrant to the treatment by these complexes.

Reduction-sensitive polymeric carrier for the targeted delivery of a quinazoline derivative for enhanced generation of reactive oxygen species against cancer.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors and the development of effective therapeutics against HCC is urgently needed. A novel quinazoline derivative 04NB-03 (Qd04) has been proved to be highly effective against HCC without obvious toxic side-effects. However, the poor water solubility and low bioavailability in vivo severely limit its clinical application. In addition, Qd04 kills tumor cells by inducing an accumulation of endogenous reactive oxygen species (ROS), which is highly impeded by the overexpression of glutathione (GSH) in tumor cells. Herein, we designed a disulfide cross-linked polyamino acid micelle to deliver Qd04 for HCC therapy. The disulfide linkage not only endowed a tumor-targeted delivery of Qd04 by responding to tumor cell GSH but also depleted GSH to achieve increased levels of ROS generation, which improved the therapeutic efficiency of Qd04. Both in vitro and in vivo results demonstrated that the synthesized nanodrug exerted good anti-hepatoma effects, which provided a potential application for HCC therapy in clinics.

A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy.

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.