Cascade Self-Generation of Carbon Monoxide Triggered by Photoinduced Holes for Efficient Hypoxic Tumors Therapy.

It still remains challenging to design multifunctional therapeutic reagents for effective cancer therapy under a unique tumor microenvironment including insufficient endogenous H2O2 and O2, low pH, and a high concentration of glutathione (GSH). In this work, a CO-based phototherapeutic system triggered by photogenerated holes, which consisted of ionic liquid (IL), the CO prodrug Mn2(CO)10, and iridium(III) porphyrin (IrPor) modified carbonized ZIF-8-doped graphitic carbon nitride nanocomposite (IL/ZCN@Ir(CO)), was designed for cascade hypoxic tumors. Upon light irradiation, the photogenerated holes on IL/ZCN@Ir(CO) oxidize water into H2O2, which subsequently induces Mn2(CO)10 to release CO. Meanwhile, IrPor can convert H2O2 to hydroxyl radical (•OH) and subsequent singlet oxygen (1O2), which further triggers CO release. Moreover, the degraded MnO2 shows activity for glutathione (GSH) depletion and mimics peroxidase, leading to GSH reduction and •OH production in tumors. Thus, this strategy can in situ release high concentrations of CO and reactive oxygen species (ROS) and deplete GSH to efficiently induce cell apoptosis under hypoxic conditions, which has a high inhibiting effect on the growth of tumors, offering an attractive strategy to amplify CO and ROS generation to meet therapeutic requirements in cancer treatment.

The Nonlinear Dynamics of a MEMS Resonator with a Triangular Tuning Comb.

The nonlinear dynamic response of a MEMS resonator with a triangular tuning comb is studied. The motion equation with dis-smooth tuning electrostatic force is derived according to Newton's second law. The analytical solution of the periodic response is obtained using the harmonic balance method and section integral method. The singularity theory is then applied to investigate the bifurcation of the periodic response of the untuned system. The transition sets on the DC-AC voltage plane dividing the planes into several persistent regions are obtained. The bifurcation diagrams' topological structures and jump phenomena corresponding to different parameter regions are analyzed. We explore the effects of tuning voltage on the response. This demonstrates that the amplitude-frequency curves present more hardening characteristics with increased tuning voltage. Many twists, bifurcation points, and unstable solutions appear, leading to complicated jump phenomena. Two bifurcation points exist on the response curves: the smooth and dis-smooth bifurcation points, with the latter occurring on the switching plane of non-uniform fingers.

pH-Responsive Multifunctional Nanoplatforms with Reactive Oxygen Species-Controlled Release of CO for Enhanced Oncotherapy.

Recently, various nanomaterials have drawn increasing attention for enhanced tumor therapy. However, a lack of tumor uptake and insufficient generation of cytotoxic agents have largely limited the antitumor efficacy in vivo. Herein, a multifunctional nanoplatform (IL@CPPor(CO)) was constructed with pH-responsive copper peroxide nanoparticles (CPNP) that are capable of self-supplying H2O2, a radical-sensitive carbonic oxide (CO) donor (Fe3(CO)12), photosensitizer Iridium(III) meso-tetra (N-methyl-4-pyridyl)porphyrin pentachloride (IrPor), and ionic liquid (IL) for enhanced oncotherapy. Under acidic conditions, the CPNP could decompose to release H2O2 and Cu2+. The concomitant generation of H2O2 could efficiently trigger Fe3(CO)12 to release the CO in situ. On the other hand, Cu2+ possesses both glutathione depletion and Fenton-like properties. In addition, IrPor has both peroxidase-like activity and photosensitizer properties to produce reactive oxygen species (ROS) in tumors. The released ROS could trigger the rapid intracellular release of CO. More importantly, released CO and ROS could promote cell apoptosis and improve the therapeutic efficacy. Moreover, due to the pH-dependent ROS generation property, the IL@CPPor(CO) exhibited high tumor accumulation, low toxicity, and good biocompatibility, which enabled effective tumor growth inhibition with minimal side effects in vivo. This work provides a novel multifunctional nanoplatform that combined photodynamic therapy with CDT and CO to improve therapeutic efficacy.

Sensitive Electrochemical Sensor for Glycoprotein Detection Using a Self-Serviced-Track 3D DNA Walker and Catalytic Hairpin Assembly Enzyme-Free Signal Amplification.

Approaches for the detection of targets in the cellular microenvironment have been extensively developed. However, developing a method with sensitive and accurate analysis for noninvasive cancer diagnosis has remained challenging until now. Here, we reported a sensitive and universal electrochemical platform that integrates a self-serviced-track 3D DNA walker and catalytic hairpin assembly (CHA) triggering G-Quadruplex/Hemin DNAzyme assembly signal amplification. In the presence of a target, the aptamer recognition initiated the 3D DNA walker on the cell surface autonomous running and releasing DNA (C) from the triple helix. The released DNA C as the target-triggered CHA moiety, and then G-quadruplex/hemin, was formed on the surface of electrode. Eventually, a large amount of G-quadruplex/hemin was formed on the sensor surface to generate an amplified electrochemical signal. Using N-acetylgalactosamine as a model, benefiting from the high selectivity and sensitivity of the self-serviced-track 3D DNA walker and the CHA, this designed method showed a detection limit of 39 cell/mL and 2.16 nM N-acetylgalactosamine. Furthermore, this detection strategy was enzyme free and exhibited highly sensitive, accurate, and universal detection of a variety of targets by using the corresponding DNA aptamer in clinical sample analysis, showing potential for early and prognostic diagnostic application.

Ionic liquid functionalized metal-organic framework nanowires for sensitive and real-time electrochemical monitoring of nitric oxide released from living cells.

Sensitive, selective, and real-time detection of nitric oxide (NO) is still challenging due to its rapid diffusion, short half-life, and low concentration in living systems. Herein, we synthesized well-defined ultralong metal-organic framework nanowires (MOFNWs) that were further uniformly covered with gold nanoparticle (AuNPs) and ionic liquids (ILs) and applied these NWs to detect and monitor NO released from living cells. In this system, ILs and AuNPs act as excellent catalysts for electrochemical oxidation of NO. By taking advantage of the synergetic effect between ILs, AuNPs and MOFNWs, the composite (IL@Au@MOFNWs) sensor probe displays excellent electrocatalytic activity toward NO oxidation with a detection limit as low as 2.28 nM for NO detection. The high levels of selectivity and sensitivity to NO in complex biological environments can be attributed to the exposed Ni2+ active sites, high ion-electron transport rates of NWs, and the high conductivity of ILs and AuNPs. Furthermore, the IL@Au@MOFNWs offer a biocompatible sensing interface enabling rapid real-time monitoring of NO released from living cells by drug stimulation. Collectively, these results demonstrate that functionalized ultralong MOFNWs exhibit a remarkable ability to quantify NO levels in cells and could therefore provide new potential of this sensor in electrochemical detection of living bodies.

ROS generation strategy based on biomimetic nanosheets by self-assembly of nanozymes.

Reactive oxygen species (ROS) play an important role in physiology and have been applied in tumor therapy. However, insufficient endogenous H2O2 and hypoxia in cancer cells can lead to limited ROS production and poor therapeutic efficacy. Herein, we develop a biomimetic nanosheet material based on the self-assembly of nanozymes that could supply H2O2 under acidic conditions and catalyze a cascade of intracellular biochemical reactions to produce ROS under both normoxic and hypoxic conditions without any external stimuli. In this system, the copper peroxide nanosheets (CPNS), which are pH-responsive, were prepared through coordination of H2O2 to Cu2+ and then modified using ultrafine Pt NPs to form CPNS@Pt. The CPNS could decompose under acidic conditions, allowing the simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. On the other hand, Pt NPs were also released. The released Pt NPs behave as an oxidase mimic and catalase mimic. In this way, the well-defined CPNS@Pt can not only relieve hypoxic conditions but also generate ROS to induce cell apoptosis, thereby paving the way for the development of a nanozyme with multienzyme activity as a therapeutic strategy.

Electrochemically classifying DNA structure based on the small molecule-DNA recognition.

Herein, we reported the differential binding ability of aminoglycosides to DNA structures using electrochemical method through principal component analysis (PCA) to classify different DNA secondary structures and understand the link between secondary structure and DNA conformation. In these analyses, the DNA with different secondary structure motifs: bulge, internal loop, hairpin loop and stem loop were designed. The aminoglycosides as receptors were modified on the surface of electrode. In the presence of DNA, the DNA will be absorbed on the surface of electrode via the recognition of DNA and aminoglycosides, resulting in the electrochemical signal observed in [Fe(CN)6]3-/4-. Furthermore, the DNA structures labeled with 2-aminopurine (2-AP) at the structural motif of interest were also employed to study the binding affinity between aminoglycosides and different DNA motifs. The PCA suggested that this method may achieve nucleotide-specific classification of two independent secondary structure motifs, and the structure and sequence of DNA and the size and structure of small molecule could affect the binding ability of the aminoglycosides and DNA. This approach presents a new approach to classify DNA structure and offers ideas for designing targeted drugs small molecule compounds for wound dressing and drug delivery.

Versatile metal-organic frameworks as a catalyst and an indicator of nitric oxide.

The imaging of nitric oxide (NO) and its donors is crucial to explore NO-related physiological and pathological processes. In this work, we demonstrate the use of Cu-based metal-organic frameworks (Cu-MOFs) as nanoprobes for NO detection and as a catalyst for the generation of NO from the biologically occurring substrate, S-nitrosothiols (RSNOs). The paramagnetic Cu2+ in the MOFs could quench the luminescence of triphenylamine; Cu-MOFs only exhibited weak emission at 450 nm. Upon the addition of NO, the paramagnetic Cu2+ was reduced to diamagnetic Cu+, and thus the luminescence was recovered directly. Cu-MOFs exhibited high selectivity for other species in the reaction system, including NO2-, H2O2, AA, NO3- and 1O2. More significantly, the Cu+ can react with s-nitrosoglutathione (GSNO), s-nitrosocysteine (CysNO), and s-nitrosocysteamine (CysamNO) to generate NO and then oxidize to Cu2+-MOFs with quenched luminescence, respectively, and thus the catalysis is inhibited, noted as a self-controlled process. The Cu-MOFs catalyst was confirmed by powder X-ray diffraction to remain structurally intact in aqueous environments. The Cu-MOFs have been successfully employed in the biological imaging of NO in living cells. The bifunctional MOFs could offer a novel platform for the real-time monitoring of NO species, provide potential for exploiting NO in cancer therapy and improve the methodologies to elucidate the NO-related biological processes.

Ultrasensitive electrochemical biosensor for protein detection based on target-triggering cascade enzyme-free signal amplification strategy.

Herein, a cost-effective, simple and sensitive electrochemical sensing platform was established based on aptamer - target recognition and target-triggering signal amplification strategy for protein detection. Due to the high affinity between the aptamer and target, the assistant DNA1 (a1) could release from a1-aptamer duplex and trigger the following DNA circuits. The strand displacement and branch migration reaction brought assistant DNA3 (a3) released. Eventually, a large number of duplex structures of a3-Hairpin DNA3 were formed on the surface of electrode. Consequently, the capture DNA on the surface of platinum nanoparticles could hybridize with the unfolded DNA fragment of Hairpin DNA3 on the sensor surface, resulting in the electrochemical signal readout of H2O2 reduction. Using thrombin as a model target, under the optimal conditions, this method exhibited a linear detection range from 0.5 pM to 300 nM with a detection limit of 0.17 pM. The proposed detection strategy was enzyme-free and exhibited good selectivity and sensitivity for a variety of protein targets detection by using corresponding DNA-based affinity probes, which makes it possible to apply the sensor for sensitivity detection of analytes in bioassays.

Porphyrin decorated Cu2O nanocrystals for electroanalytical detection of S-Nitrosothiols.

S-nitrosothiols (RSNO) as the potential nitric oxide (NO) storage, transfer and delivery vehicles under physiological condition have been identified as important in a number of disease states. However, a detection and quantification of RSNO method with simple and sensitive in biological media is currently lacking. A novel electrochemical sensing platform based on ionic liquid (IL) and copper porphyrin (PorCu) decorated cuprous oxide (Cu2O) nanocomposites was developed to detect RSNO under physiological condition. In this system, RSNO were decomposed by Cu(I) in IL/PorCu/Cu2O to release NO, following the generated NO could be oxidized on the electrode to generate current signal. By taking advantage of the synergetic effect of IL, PorCu and Cu2O, the sensor exhibited excellent sensitivity and linearity toward various RSNO species in phosphate buffer solution (PBS), pH 7.4. A low detection limit for N-Acetyl-3-(nitrososulfanyl)valine (SNAP), S-nitrosocysteine (CysNO) and S-nitrosoglutathione (GSNO) was 110 nM, 20 nM and 67 nM (S/N = 3), respectively. Furthermore, this method displayed good selectivity, which could be used in complex application. The detection scheme with the features of high sensitivity and ease of operation, implies the potential of IL/PorCu/Cu2O for further various complex physiological studies.

Understanding the Performance of Metal-Organic Frameworks for Modulation of Nitric Oxide Release from S-Nitrosothiols.

S-Nitrosothiols (RSNOs) which are important intermediates in circulating reservoirs of nitric oxide (NO), transport and numerous NO signaling pathways play intricate roles in the etiology of several pathologies. However, it is still a challenge to control the release of NO from nitrosylated compounds under physiological pH. In this paper, for the first time, we report the catalytic activity and kinetic study for the modulation of NO release from RSNOs by an array of metal-organic frameworks (MOFs) (M-MOF (M'); M=Zr, Cu; and M'=Cu, Pd, no metal) under physiological conditions via time-dependent absorbance spectra. The result showed that metal active sites as well as the morphology and pore size of MOFs exhibited different activities toward RSNOs. The order of catalytic activity of these MOFs toward RSNOs is ordered in the decreasing sequence: Cu-MOF(Pd)>Cu-MOF(Cu)>Cu-MOF(no metal)>Zr-MOF(Pd)>Zr-MOF(Cu)>Zr-MOF(no metal). In addition, Zr-MOF(Pd) was as model for cell experiment, demonstrated Zr-MOF(Pd) could react with RSNOs to generate NO in the complex environment of cell. Collectively, these findings establish a platform for MOFs-based, highly catalyze RSNOs in biological samples, a powerful tool for expanding the knowledge of the biology and chemistry of NO-mediated phenomena.

Electrochemical biosensor based on singlet oxygen generated by molecular photosensitizers.

Here a sensing strategy with the integration of photosensitizer and electrochemical analysis was present. The photosensitizer, Zinc(II) tetraphenylporphyrin (ZnTCPP), was functionalized graphene oxide (GO) to form complex (ZnTCPP/GO) as the electrode material and generated singlet-oxygen (1O2) in the presence of air under light illumination. Due to the special electronic structure of 1O2, hydroquinone (HQ) could react with 1O2 to produce electrochemically-detectable products, benzoquinone (BQ). Meanwhile, the formed BQ could be reduced on the electrode, completing the redox cycling. The ZnTCPP/GO modified ITO electrode produces a stable and enhanced photocurrent signal under 420 nm irradiation in air-saturated buffer, compared with in N2-saturated buffer. On the other hand, l-glutathione (GSH) as a signalling molecule plays important role in physiological process, which was employed as model to investigated the sensing performance. Coupling with HQ oxidized by 1O2, a GSH sensor was constructed on the basis the redox cycling of HQ. A sensitive reduction of photocurrent is observed with the addition of GSH, due to the GSH could be oxidized by the generated 1O2 to form GSSG. The biosensor displayed good performance in a broad concentration range of 0-150 µM, with a lower detection limit of 1.3 µM at an S/N ratio of 3, and could be used in practical application. This work affords a platform for constructing the biosensor with 1O2 instead of enzyme via on/off light switching.