Dual-Stimuli Regulation of DNAzyme Cleavage Reaction by Coordination-Driven Nanoprobes for Cancer Cell Imaging.

Endowing current artificial chemical reactions (ACRs) with high specificity and intricate activation capabilities is crucial for expanding their applications in accurate bioimaging within living cells. However, most of the reported ACR-based evaluations relied on either single biomarker stimuli or dual activators without obvious biological relevance, still limiting their accuracy and fidelity. Herein, taking the metal-ion-dependent DNAzyme cleavage reaction as a model ACR, two regulators, glutathione (GSH) and telomerase (TE) activated DNAzyme cleavage reactions, were exploited for precise discrimination of cancerous cells from normal cells. DNA probe was self-assembled into the ZIF-90 nanoparticle framework to construct coordination-driven nanoprobes. This approach enhances the stability and specificity of tumor imaging by utilizing biomarkers associated with rapid tumor proliferation and those commonly overexpressed in tumors. In conclusion, the research not only paves the way for new perspectives in cell biology and pathology studies but also lays a solid foundation for the advancement of biomedical imaging and disease diagnostic technologies.

Orthogonally Sequential Activation of Self-Powered DNAzymes Cascade for Reliable Monitoring of mRNA in Living Cells.

Ratiometric imaging of tumor-related mRNA is significant, yet spatiotemporally resolved regulation on the ratiometric signals to avoid non-specific activation in the living cells remains challenging. Herein, orthogonally sequential activation of concatenated DNAzyme circuits is, first, developed for Spatio Temporally regulated Amplified and Ratiometric (STAR) imaging of TK1 mRNA inside living cells with enhanced reliability and accuracy. By virtue of the synthesized CuO/MnO2 nanosheets, orthogonally regulated self-powered DNAzyme circuits are operated precisely in living cells, sequentially activating two-layered DNAzyme cleavage reactions to achieve the two ratiometric signal readouts successively for reliable monitoring of low-abundance mRNA in living cells. It is found that the ratiometric signals can only be derived from mRNA over-expressed tumor cells, also irrespective of probes' delivery concentration. The presented approach could provide new insight into orthogonally regulated ratiometric systems for reliable imaging of specific biomarkers in living cells, benefiting disease precision diagnostics.

Correction: A poly(thymine)-templated fluorescent copper nanoparticle hydrogel-based visual and portable strategy for an organophosphorus pesticide assay.

Correction for 'A poly(thymine)-templated fluorescent copper nanoparticle hydrogel-based visual and portable strategy for an organophosphorus pesticide assay' by Jihua Chen et al., Analyst, 2019, 144, 2423-2429, https://doi.org/10.1039/C9AN00017H.

Self-propelled assembly of nanoparticles with self-catalytic regulation for tumour-specific imaging and therapy.

Targeted assembly of nanoparticles in biological systems holds great promise for disease-specific imaging and therapy. However, the current manipulation of nanoparticle dynamics is primarily limited to organic pericyclic reactions, which necessitate the introduction of synthetic functional groups as bioorthogonal handles on the nanoparticles, leading to complex and laborious design processes. Here, we report the synthesis of tyrosine (Tyr)-modified peptides-capped iodine (I) doped CuS nanoparticles (CuS-I@P1 NPs) as self-catalytic building blocks that undergo self-propelled assembly inside tumour cells via Tyr-Tyr condensation reactions catalyzed by the nanoparticles themselves. Upon cellular internalization, the CuS-I@P1 NPs undergo furin-guided condensation reactions, leading to the formation of CuS-I nanoparticle assemblies through dityrosine bond. The tumour-specific furin-instructed intracellular assembly of CuS-I NPs exhibits activatable dual-modal imaging capability and enhanced photothermal effect, enabling highly efficient imaging and therapy of tumours. The robust nanoparticle self-catalysis-regulated in situ assembly, facilitated by natural handles, offers the advantages of convenient fabrication, high reaction specificity, and biocompatibility, representing a generalizable strategy for target-specific activatable biomedical imaging and therapy.

Reusable carboxylesterase immobilized in ZIF for efficient degradation of chlorpyrifos in enviromental water.

The past few decades have witnessed biodegradation of pesticides as a significant method in remediation of the environment for its specificity, efficiency and biocompatibility. However, the tolerability and recyclability of the enzymes in pesticide degradation and the development of enzymes that biodegrad pesticides are still urgent problems to be solved so far. Herein, a novel hyper-thermostable and chlorpyrifos-hydrolyzing carboxylesterase EstC was immobilized by biomineralization using zeolitic imidazolate framework (ZIF), one of the metal-organic frameworks (MOFs) with highly diverse structure and porosity. Compared with free enzyme, EstC@ZIF with a cruciate flower-like morphology presented scarcely variation in catalytic efficiency and generally improved the tolerance to organic solvents or detergents. Furthermore, there was scarcely decrease in the catalytic efficiency of EstC@ZIF and it also showed good reusability with about 50% residual activity after 12 continuous uses. Notably, EstC@ZIF could be used in actual water environment with an excellent value of degradation rate of 90.27% in 120 min, and the degradation efficiency remained about 50% after 9 repetitions. The present strategy of immobilizing carboxylesterase to treat pesticide-contaminated water broadens the method of immobilized enzymes on MOFs, and envisions its recyclable applicability in globe environmental remediation.

Advances in Meta-Optics and Metasurfaces: Fundamentals and Applications.

Meta-optics based on metasurfaces that interact strongly with light has been an active area of research in recent years. The development of meta-optics has always been driven by human's pursuits of the ultimate miniaturization of optical elements, on-demand design and control of light beams, and processing hidden modalities of light. Underpinned by meta-optical physics, meta-optical devices have produced potentially disruptive applications in light manipulation and ultra-light optics. Among them, optical metalens are most fundamental and prominent meta-devices, owing to their powerful abilities in advanced imaging and image processing, and their novel functionalities in light manipulation. This review focuses on recent advances in the fundamentals and applications of the field defined by excavating new optical physics and breaking the limitations of light manipulation. In addition, we have deeply explored the metalenses and metalens-based devices with novel functionalities, and their applications in computational imaging and image processing. We also provide an outlook on this active field in the end.

The impact of adolescent achievement goal orientation on learning anxiety: The mediation effect of peer interaction.

Learning anxiety is one of the most critical emotional disturbances, which also has a high incidence rate in adolescents. Peer interaction is critical and unique for adolescents. Although previous studies have found that achievement goal orientation has an important role in the development of learning anxiety, its mechanism has not been clarified. This study surveyed 470 adolescents (191 middle school students and 279 high school students; 211 boys) and established a structural equation model to explore the mediating role of peer interaction in the influence of achievement goal orientation on learning anxiety. Results showed that (1) there were significant gender differences in mastery-avoidance goal orientation, peer interaction, and learning anxiety, and there were grade differences in performance-approach goal and performance-avoidance goal orientations; (2) mastery-approach, mastery-avoidance, and performance-avoidance goal orientations directly predicted learning anxiety; and (3) social anxiety in peer interactions had a mediating effect on the influence of mastery-approach, mastery-avoidance, and performance-avoidance goal orientations on learning anxiety. The findings extend theoretical considerations by teasing out the process of peer interaction affecting the relationship between achievement goal orientation and learning anxiety. Additionally, the results have practical implications for the effective use of peer interaction to reduce learning anxiety.

Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy.

PURPOSE: Development of B-cell lymphoma 2 (BCL-2)-specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein-protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575). EXPERIMENTAL DESIGN: Computational modeling was used to design "lead" compounds. Biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays were used to determine the selectivity and potency of BCL-2 inhibitor lisaftoclax. The antitumor effects of lisaftoclax were also evaluated in several xenograft models. RESULTS: Lisaftoclax selectively binds BCL-2 (Ki < 0.1 nmol/L), disrupts BCL-2:BIM complexes, and compromises mitochondrial outer membrane potential, culminating in BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong antitumor activity in hematologic cancer cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. After lisaftoclax treatment, prodeath proteins BCL-2‒like protein 11 (BIM) and Noxa increased, and BIM translocated from cytosol to mitochondria. Consistent with these apoptotic activities, lisaftoclax entered malignant cells rapidly, reached plateau in 2 hours, and significantly downregulated mitochondrial respiratory function and ATP production. Furthermore, lisaftoclax inhibited tumor growth in xenograft models, correlating with caspase activation, poly (ADP-ribose) polymerase 1 cleavage, and pharmacokinetics of the compound. Lisaftoclax combined with rituximab or bendamustine/rituximab enhanced antitumor activity in vivo. CONCLUSIONS: These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2-selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.

Zn(ii)-Coordination-driven self-assembled nanoagents for multimodal imaging-guided photothermal/gene synergistic therapy.

Synergistic photothermal therapy (PTT) with gene therapy (GT) has drawn emerging interest in the improvement of cancer therapeutic efficiency, while the co-delivery of photothermal agents (PTAs) and therapeutic genes by an integrated nanoplatform, with controllability and biodegradability, is still challenging and urgently desired. Herein, a multi-functional metal-organic framework (MOF) based PTT-GT platform (siRNA@PT-ZIF-8) was developed, which was constructed with siRNA, a near-infrared (NIR) responsive organic dye IR780 derivative (IR780-1), and 2-methylimidazole (2-MIM) by a facile one-pot self-assembly method. This "all-in-one" system of siRNA@PT-ZIF-8 enabled not only photothermal/photoacoustic/fluorescence multimodal imaging but also tumor microenvironment responsiveness for specific and on-demand release of therapeutic cargos, overcoming the inherent limitations of free gene or organic PTA molecules (e.g., short blood circulation half-life and weak stability) in conventional PTT and GT. This nanoplatform provides an efficient and safe strategy for cancer theranostics, and the one-step assembly strategy favors personalized formulation design for diverse demands in cancer management.

Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. METHODS: KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic-pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. RESULTS: In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. CONCLUSIONS: Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK+ NSCLC refractory to earlier-generation ALK inhibitors. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).

FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia.

INTRODUCTION: FLT3-ITD mutations occur in approximately 25% of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Despite initial efficacy, short duration of response and high relapse rates limit clinical use of selective FLT3 inhibitors. Combination approaches with other targeted therapies may achieve better clinical outcomes. MATERIALS AND METHODS: Anti-leukemic activity of multikinase inhibitor olverembatinib (HQP1351), alone or in combination with BCL-2 inhibitor lisaftoclax (APG-2575), was evaluated in FLT3-ITD mutant AML cell lines in vitro and in vivo. A patient-derived FLT3-ITD mutant AML xenograft model was also used to assess the anti-leukemic activity of this combination. RESULTS: HQP1351 potently induced apoptosis and inhibited FLT3 signaling in FLT3-ITD mutant AML cell lines MV-4-11 and MOLM-13. HQP1351 monotherapy also significantly suppressed growth of FLT3-ITD mutant AML xenograft tumors and prolonged survival of tumor-bearing mice. HQP1351 and APG-2575 synergistically induced apoptosis in FLT3-ITD mutant AML cells and suppressed growth of MV-4-11 xenograft tumors. Combination therapy improved survival of tumor bearing-mice in a systemic MOLM-13 model and showed synergistic anti-leukemic effects in a patient-derived FLT3-ITD mutant AML xenograft model. Mechanistically, HQP1351 downregulated expression of myeloid-cell leukemia 1 (MCL-1) by suppressing FLT3-STAT5 (signal transducer and activator of transcription 5) signaling and thus enhanced APG-2575-induced apoptosis in FLT3-ITD mutant AML cells. CONCLUSIONS: FLT3 inhibition by HQP1351 downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 to potentiate cellular apoptosis in FLT3-ITD mutant AML. Our findings provide a scientific rationale for further clinical investigation of HQP1351 combined with APG-2575 in patients with FLT3-ITD mutant AML.

A Novel Four-Gene Signature as a Potential Prognostic Biomarker for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high incidence and mortality rates. However, a reliable prognostic signature has not yet been confirmed. Thus, the purpose of the present study was to develop a biomarker with high specificity and sensitivity for the diagnosis and prognosis of patients with HCC. The mRNA expression profiles of HCC were obtained from the GSE19665, GSE41804, and TCGA databases. Subsequently, 193 differentially expressed genes (DEGs) were identified from the intersection of the data from the three datasets. Bioinformatics analysis showed that the identified DEGs are related to the cell cycle, oocyte meiosis, and p53 signaling pathway, among other factors, in cancers. A protein-protein interaction (PPI) and a functional analysis were performed to investigate the biological function of the DEGs and obtain the candidate genes using the MCODE of Cytoscape. The candidate genes were introduced into the TCGA database for survival analysis, and the four candidate genes that were hub genes and meaningful for survival were retained for further verification. We validated the gene and protein expression and determined the prognosis of our patient cohort. In addition, we evaluated the biological functions regulating tumor cell proliferation and metastasis in vitro. According to the ROC curve analysis of gene expression in clinical samples, it was found that the four genes can be used to predict the diagnosis. A survival analysis based on data from the TCGA database and clinical samples showed that the four genes may be used as biomarkers for providing prognoses for patients. The cell functional experiments revealed that these four genes were related to tumor proliferation, migration, and invasion. In conclusion, the genes identified in the present study could be used as markers to diagnose and predict the prognosis of patients with HCC and guide targeted therapy.

A DNAzyme-Based Dual-Stimuli Responsive Electrochemiluminescence Resonance Energy Transfer Platform for Ultrasensitive Anatoxin-a Detection.

An effective and precise electrochemiluminescence resonance energy transfer (ECL-RET), including the efficient regulation over the proximity of a donor and an acceptor and the reliable stimuli responsive as well as the avoidance of undesirable probes leakage, etc., is significant for the development of an accurate and sensitive ECL detection method; yet, the current literature in documentation involves only a limited range of such ECL-RET systems. Herein, we propose an ECL-RET strategy with dually quenched ultralow background signals and a dual-stimuli responsive, accurate signal output for the ultrasensitive and reliable detection of anatoxin-a (ATX-a). The dual quenching is accomplished by an integrated ECL-RET probe of metal organic frameworks (MOFs) encapsulated into Ru(bpy)32+ (Ru-MOF) (donor) coated with silver nanoparticles (AgNPs) shell (acceptor 1) and close proximity with DNA-ferrocene (Fc) (acceptor 2). Multistimuli responsive DNAzyme facilitated the accurate signal switch by both target ATX-a and hydrogen peroxide (H2O2). Because of the specific recognition of the aptamer toward ATX-a, an intricate design of the DNA sequence enabled the exposure of the Ag+-dependent DNAzyme sequence and H2O2 in situ generated Ag+ triggering a catalytic cleavage reaction to freely release the two ECL-RET energy acceptors, thus switching the ECL signal significantly and achieving ultrasensitive detection. It is noteworthy that AgNPs are key in this ECL-RET strategy, serving both as the gate-keepers for avoiding ECL probes leakage and also the ECL energy acceptors, and mostly importantly serving as the redox substrate for the subsequent DNAzyme catalytic signal switch. The proposed ECL-RET aptasensor for ATX-a detection displayed splendid monitoring performance with a quite low detection limit of 0.00034 mg mL-1. This sensor not only led to the development of a dual-quenching ECL-RET system but also provided meaningful multistimuli responsive ECL biosensing platform construction, which shows a promising application prospect in complicated sample analysis.

Autonomous operation of 3D DNA walkers in living cells for microRNA imaging.

Three dimensional (3D) DNA walkers hold great potential in serving as an ideal candidate for signal transduction and amplification in bio-assays. However, the autonomous operation of 3D DNA walkers inside living cells is still few and far between, which could be attributed to the lack of suitable driving forces and moderate efficiency in terms of the cellular uptake of such complex 3D DNA components. Herein, a newly updated autonomously operated and highly integrated 3D DNA walker on Au nanoparticles (Au NPs)/zeolitic imidazolate framework-8 (ZIF-8) was activated in a tumor microenviroment and its signal amplified assay capability in living cells was demonstrated using miRNA as a sensing model biomolecule. Specifically, we assembled a 3D DNA motor, including Zn2+-dependent DNAzyme and substrates on the AuNPs grafted on ZIF-8. After being delivered into a living cell, ZIF-8 was efficiently degraded in the tumor microenvironment (low pH value), locally releasing the Zn2+ and DNA motor. Then, a self-sufficient DNA motor autonomously performed the bio-analytical task of imaging miRNA-10b, with a low detection limit of 34 pM. Also, such self-sufficient 3D walkers allowed real-time imaging of MDA-MB-231 cells by intracellular operation. This method demonstrates the self-sufficient 3D DNA motor's bioanalytical application in living cells which may inspire various other biological applications including gene delivery, therapy, etc.

Target triggered ultrasensitive electrochemical polychlorinated biphenyl aptasensor based on DNA microcapsules and nonlinear hybridization chain reaction.

In this work, we demonstrated an ultrasensitive detection platform for polychlorinated biphenyls (PCBs) based on DNA microcapsules and a nonlinear hybridization chain reaction (NHCR). In the process, first, electrochemical signal molecules (Methylene Blue, MB) were sealed in the prepared DNA microcapsules. In the presence of PCB-72, DNA microcapsules could be dissociated with the conjugation of the aptamer and target, and meanwhile, the released DNA strand could initiate the NHCR and trigger the chain branching growth of DNA dendrimers. Because the released MBs were intercalated into the DNA dendrimer, enhanced electrochemical responses could be detected. This method exhibited ultrahigh sensitivity to PCB-72 with a detection limit of 0.001 ng mL-1. Furthermore, the present aptasensor was also capable of discriminating different PCB congeners. Therefore, the devised label-free and enzyme-free amplification electrochemical aptasensor strategy has great potential for the detection of PCB-72 in real samples, and this strategy may also become an attractive alternative for sensitive and selective small molecule, protein, nucleic acid and nuclease activity detection.

Photocontrolled Thermosensitive Electrochemiluminescence Hydrogel for Isocarbophos Detection.

Endowing specificity and controllability with the electrochemiluminescence (ECL) thermosensitive hydrogels is vitally crucial to expanding their sensing applications. Herein, a novel photocontrolled thermosensitive electrochemiluminescence hydrogel (PT-ECL hydrogel) sensing platform with sufficient simplicity, specificity, and precise controllability is proposed, for the first time, by the integration of Ru(bpy)32+ (bpy = 2,2'-bipyridine) derivatives (signal reporter), split aptamers (recognition unites), and Au nanorods (AuNRs) (photothermal energy converter) into the poly(N-isopropylacrylamide) (pNIPAM) matrix. In the presence of the model target isocarbophos (ICP), the conjugation of two split aptamers initiated the ECL-resonance energy transfer (ECL-RET) between the Au nanorods and the Ru(bpy)32+ centers. Surprisingly, under the irradiation of near-infrared (NIR) light, the photothermal effect of AuNRs prompted the shrinkage of the hydrogel, resulting in the enhancement of the ECL-RET and further ∼7 times signal amplification. Consequently, the PT-ECL hydrogel sensing platform performed well for ICP detection with a low detection limit of 20 pM (S/N = 3) and a wide linear range from 50 pM to 4 µM, with great stability and repeatability. Obviously, the results showed that AuNRs utilized in this study served the role as not only the ECL-RET acceptor but also the photothermal converter to prompt the phase change of the PT-ECL hydrogel precisely and simply controlled by NIR light. Use of the proposed PT-ECL hydrogel detection scheme is a first step toward enabling a newly upgraded highly sensitive and selective hydrogel-based assay and also paving the way for the application of smart photothermal reagents.

A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma.

Despite therapeutic advances, the effective treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge. Evasion of apoptosis through upregulating antiapoptotic B-cell lymphoma-2 (BCL-2) family members and p53 inactivation, and abnormal activation of B-cell receptor signaling pathway are two important pathogenic factors for DLBCL. In this study, our aim is to explore a rational combination of BCL-2 inhibitor plus Brutons tyrosine kinase (BTK) blockade or p53 activation for treating DLBCL with the above characteristics. We demonstrated that a novel BCL-2 selective inhibitor APG-2575 effectively suppressed DLBCL with BCL-2 high expression via activating the mitochondrial apoptosis pathway. BTK inhibitor ibrutinib combined with BCL-2 inhibitors showed synergistic antitumor effect in DLBCL with mean expression of BCL-2 and myeloid cell leukemia-1 (MCL-1) through upregulating the expression level of BIM and modulating MCL-1 and p-Akt expression. For p53 wild-type DLBCL with high expression of BCL-2, APG-2575 showed strong synergic effect with mouse double minute 2 (MDM2)p53 inhibitor APG-115 that can achieve potent antitumor effect and markedly prolong survival in animal models. Collectively, our data provide an effective and precise therapeutic strategy through rational combination of BCL-2 and BTK or MDM2p53 inhibitors for DLBCL, which deserves further clinical investigation.

Flexible and self-healing electrochemical hydrogel sensor with high efficiency toward glucose monitoring.

The commercial sensor of a continuous glucose monitoring system suffers from restricted penetration of glucose in the dense sensing coating, uncontrolled leakage of the glucose oxidase and electrocatalytic medium, and susceptibility to mechanical damage. Herein, a self-healing hydrogel based on quaternized chitosan and oxidized dextran was designed, and CeO2/MnO2 hollow nanospheres were covalently linked in the hydrogel as the electrocatalytic medium. Glucose oxidase was loaded via the strong electrostatic interactions with the CeO2/MnO2 hollow nanospheres. An extra covering agent was coated on the hydrogel to prevent the leakage of the glucose oxidase and electrocatalytic medium. Covalent linkage of the hydrogel on a bendable chip formed a flexible glucose sensor, which showed a wide linear range (1-111 mM), fast response (less than 3 s), and high sensitivity (176 µA mM-1 cm-2). The hydrogel-based sensor was self-healable, and could continuously work for over 30 days. Thus, this study provides a method to simultaneously prevent the leakage of the electrocatalytic medium, promote the sensitivity of glucose detection, and tolerate the mechanical damage, which shows great potential for continuous glucose monitoring.

In Situ Cation Exchange Generated ZnS-Ag2S Nanoparticles for Photothermal Detection of Transcription Factor.

The photothermal reagent (PTA)-mediated point-of-care detection of disease biomarkers using thermometers as readout has attracted increasing attention, but complex modification or generation process of PTAs still limited their further applications. Herein, we report a photothermal detection platform in which the target recognition triggered the in situ generation of the PTA and ZnS-Ag2S nanoparticles (NPs) by one-step autonomous cation exchange reaction (ACER). As a proof of concept, NF-kB1, a kind of disease biomarker, was used to demonstrate the photothermal detection platform. First, a triplex-like DNA structure containing the recognition part of NF-kB1 and cytosine-Ag+-cytosine (C-Ag+-C) unit was designed. With the recognition of NF-kB1, abundant C-Ag+-C units were released to take ACER with the prepared ZnS NPs. In addition, because of the intrinsic detecting limitation of the thermometer, hybridization chain reaction (HCR) was introduced to load more Ag+ for the enhancement of the photothermal signal. After the irradiation of 808 nm laser toward the generated ZnS-Ag2S NPs dispersions, its temperature increased with the increased concentration of NF-kB1 in the range from 10 to 1000 nM with a detection limit of 2.31 nM. The signal-amplifying role of HCR was confirmed by the control experiment. This platform of in situ generation of PTA not only integrated the recognition process with detection but also avoided the complex process of modification or generation, which has remarkable potential to be extended for the detections of other different disease biomarkers.

Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors.

BACKGROUND: Imatinib shows limited efficacy in patients with gastrointestinal stromal tumors (GISTs) carrying secondary KIT mutations. HQP1351, an orally bioavailable multikinase BCR-ABL inhibitor, is currently in clinical trials for the treatment of T315I mutant chronic myelogenous leukemia (CML), but the potential application in imatinib-resistant GISTs carrying secondary KIT mutations has not been explored. METHODS: The binding activities of HQP1351 with native or mutant KIT were first analyzed. Imatinib-sensitive GIST T1 and imatinib-resistant GIST 430 cells were employed to test the in vitro antiproliferative activity. Colony formation assay, cell migration assay and cell invasion assay were performed to evaluate the clonogenic, migration and invasion ability respectively. Flow cytometry and western blot analysis were used to detect cell apoptosis, cell cycle and signaling pathway. In vivo antitumor activity was evaluated in mouse xenograft models derived from GIST cell lines. RESULTS: HQP1351 potently inhibited both wild-type and mutant KIT kinases. In both imatinib-resistant and sensitive GIST cell lines, HQP1351 exhibited more potent or equivalent antiproliferative activity compared with ponatinib, a third generation BCR-ABL and KIT inhibitor. HQP1351 led to more profound inhibition of cell colony formation, cell migration and invasion, cell cycle arrest and cell apoptosis than ponatinib. Furthermore, HQP1351 also inhibited p-KIT, p-AKT, p-ERK1/2, and p-STAT3 to a higher extent than ponatinib. Finally, in xenograft tumor models derived from imatinib-resistant GIST cancer cell lines, HQP1351 exhibited antitumor activity superior to ponatinib. CONCLUSIONS: Collectively, our in vitro and in vivo results suggest that the therapeutic application of HQP1351 in imatinib-resistant GIST patients deserves further investigation in clinical trials.