Injury of Macrophages Induced by Clostridium perfringens Type C Exotoxins.

Clostridium perfringens is a kind of anaerobic Gram-positive bacterium that widely exists in the intestinal tissue of humans and animals. And the main virulence factor in Clostridium perfringens is its exotoxins. Clostridium perfringens type C is the main strain of livestock disease, its exotoxins can induce necrotizing enteritis and enterotoxemia, which lead to the reduction in feed conversion, and a serious impact on breeding production performance. Our study found that treatment with exotoxins reduced cell viability and triggered intracellular reactive oxygen species (ROS) in human mononuclear leukemia cells (THP-1) cells. Through transcriptome sequencing analysis, we found that the levels of related proteins such as heme oxygenase 1 (HO-1) and ferroptosis signaling pathway increased significantly after treatment with exotoxins. To investigate whether ferroptosis occurred after exotoxin treatment in macrophages, we confirmed that the protein expression levels of antioxidant factors glutathione peroxidase 4/ferroptosis-suppressor-protein 1/the cystine/glutamate antiporter solute carrier family 7 member 11 (GPX4/FSP1/xCT), ferroptosis-related protein nuclear receptor coactivator 4/transferrin/transferrin receptor (NCOA4/TF/TFR)/ferritin and the level of lipid peroxidation were significantly changed. Based on the above results, our study suggested that Clostridium perfringens type C exotoxins can induce macrophage injury through oxidative stress and ferroptosis.

Copper Nanosheet-Based Wash-Free Fluorescence Imaging of Cancer Cells.

Near-infrared fluorescence (NIRF) probes greatly facilitate in vivo imaging of various biologically important species. However, there are several significant limitations such as consuming washing steps, photobleaching, and low signal intensity. Herein, we synthesized fluorescent copper nanosheets templated with DNA scaffolds (DNS/CuNSs). We employ them and Cy5.5 of the fluorescence resonance energy transfer (FRET) system, which have a larger Stokes shift (∼12-fold) than the traditional NIRF dye Cy5.5. Based on their excellent fluorescence properties, we employ DNS/CuNSs-Cy5.5 for fluorescence probes in cancer cell imaging. Compared with the free Cy5.5 fluorescence probe, the novel fluorescence imaging probe implements wash-free imaging and exhibits enhanced anti-photobleaching ability (∼5.5-fold). Moreover, the FRET system constructed by DNS/CuNSs has a higher signal amplification ability (∼4.17-fold), which is more similar to that of Cu nanoclusters prepared with DNA nanomonomers as a template. This work provides a new idea for cancer cell MCF-7 imaging and is expected to promote the development of cancer cell fluorescence imaging.

DNA Framework-Templated Fabrication of Ultrathin Electroactive Gold Nanosheets.

Generally, two-dimensional gold nanomaterials have unique properties and functions that offer exciting application prospects. However, the crystal phases of these materials tend to be limited to the thermodynamically stable crystal structure. Herein, we report a DNA framework-templated approach for the ambient aqueous synthesis of freestanding and microscale amorphous gold nanosheets with ultrathin sub-nanometer thickness. We observe that extended single-stranded DNA on DNA nanosheets can induce site-specific metallization and enable precise modification of the metalized nanostructures at predefined positions. More importantly, the as-prepared gold nanosheets can serve as an electrocatalyst for glucose oxidase-catalyzed aerobic oxidation, exhibiting enhanced electrocatalytic activity (~3-fold) relative to discrete gold nanoclusters owing to a larger electrochemical active area and wider band gap. The proposed DNA framework-templated metallization strategy is expected to be applicable in a broad range of fields, from catalysis to new energy materials.

Association between Yili goose sperm motility and expression profiles of mRNA and miRNA in testis.

BACKGROUND: The study was conducted to find out the candidate microRNA (miRNA) and genes that associated with sperm motility of Yili goose through small RNA sequencing of testicular tissue of Yili goose, and provide a theoretical basis for the study of the regulation mechanism of sperm motility of Yili goose gander. RESULTS: In this study, five male geese with high sperm motility and five male geese with low sperm motility were slaughtered to obtain their testis tissues for small RNA sequencing, and biological information methods were used for data analysis. The results showed that a total of 1575 known miRNAs and 68 novel miRNAs were identified in the testis tissue of Yili goose, and 71 differentially expressed miRNAs and 660 differentially expressed genes were screened. GO functional analysis showed that miRNAs target genes were mainly involved in the binding, kinase activity, structural constituent of cytoskeleton and intermediate filament cytoskeleton. KEGG functional analysis showed that miRNAs target genes were significantly enriched in arginine and proline metabolism, glycolysis / gluconeogenesis, fructose and mannose metabolism and beta-Alanine metabolism and other pathways. miRNAs-mRNAs interaction network suggests miR-140/miR-140-3p/miR-140-3p-NKAIN3, let-7d-BTG1 and miR-145-5p/miR -145a-5p-CLEC2E may play an important role in testis development and spermatogenesis. CONCLUSIONS: The results of this study suggest that the sperm motility of Yili goose may be regulated by different miRNAs, and the target genes are significantly enriched in pathways related to sperm metabolism, indicating that miRNAs affect the sperm motility of Yili goose by regulating the metabolic process of sperm and the expression of related genes. This study can provide a reference for revealing the regulation mechanism of Yili goose sperm motility at the molecular level.

Self-assembly Induced Enhanced Electrochemiluminescence of Copper Nanoclusters Using DNA Nanoribbon Templates.

Copper nanoclusters (CuNCs) are attractive electrochemiluminescence (ECL) emitters as Cu is comparatively inexpensive, nontoxic, and highly abundant. However, their ECL yield is relatively low. Herein, we report that orderly self-assembly of CuNCs using DNA nanoribbon as the template (DNR/CuNCs) conferred the CuNCs with improved ECL properties compared with individual CuNCs in both annihilation and co-reactant processes. The DNR/CuNCs resulted in a high ECL yield of 46.8 % in K2 S2 O8 , which was ≈68 times higher than that of individual CuNCs. This strategy was successfully extended to other ECL emitters, such as gold nanoclusters and the Ru(bpy)3 2+ /TPrA system. Furthermore, as an application of DNR/CuNCs, a DNR/CuNC-based ECL biosensor with higher sensitivity was constructed for dopamine determination (two orders of magnitude lower than that previously reported), showing that DNR/CuNCs have a potential for application in ECL bioanalysis as a new type of superior luminophore candidate.

Role of PAX2 in breast cancer verified by bioinformatics analysis and in vitro validation.

Background: Breast cancer (BC) is the most frequently diagnosed cancer in women and the second most common cancer among newly diagnosed cancers worldwide. Studies have shown that paired box 2 (PAX2) participates in the tumorigenesis of some cancer cells, but its role in BC is still unclear. Methods: Transcriptome expression profiles and clinicopathological information of BC were downloaded from The Cancer Genome Atlas (TCGA) database to explore the expression level and prognostic value of PAX2. Gene set enrichment analysis (GSEA) and functional enrichment analysis were performed to investigate the functions and pathways of PAX2. Moreover, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to determine the expression of PAX2 in BC tissues, and the predictive value of PAX2 in clinical samples was assessed. Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell growth. The migration and invasive capacities of cells were assessed by wound healing assay and Transwell assay. Results: PAX2 was upregulated in the TCGA-BC datasets. GSEA suggested that PAX2 may be involved in the regulation of signaling pathways such as MAPK. Moreover, PAX2 was overexpressed in BC tissues, and PAX2 expression was associated with tumor size and lymph node metastasis. PAX2 deficiency could promote the growth, migration, and invasion of BC cells. Conclusions: Upregulation of PAX2 inhibited BC cell growth, migration, and invasion, making PAX2 a potential therapeutic target for BC.

CAMSAP2 promotes colorectal cancer cell migration and invasion through activation of JNK/c-Jun/MMP-1 signaling pathway.

CAMSAP2 has been reported to act as an oncogene in hepatocellular carcinoma. However, the expression CAMSAP2 and its potential roles in colorectal cancer remain unclear. In this study, qRT-PCR and immunoblotting analysis were used to detect the mRNA and protein levels of CAMSAP2 in colorectal cancer tissues and cell lines. Wound-healing, transwell migration and invasion assay were performed to determine whether CAMSAP2 promotes the capabilities of migration and invasion of colorectal cancer cells. The results showed that CAMSAP2 was highly elevated in colorectal cancer tissues and cell lines. Moreover, the high CAMSAP2 expression was positively correlated with tumor invasion depth, lymph node metastasis, distant metastasis, and the poor prognosis of colorectal cancer. Additionally, ectopic expression of CAMSAP2 in colorectal cancer cells promoted the migration and invasion in vitro and enhanced the lung metastasis in nude mice. Conversely, silencing CAMSAP2 resulted in an opposite phenomenon. By gain- and loss-of function experiments, we demonstrated that MMP-1 was a substantial downstream target of CAMSAP2, and it played a crucial role in regulating the migration and invasion induced by CAMSAP2 in colorectal cancer cells. Mechanistically, CAMSAP2 promoted the activation of JNK/c-Jun signaling pathway and subsequently upregulated the transcription activity of MMP-1. Taken together, our findings demonstrated that CAMSAP2 promoted colorectal cancer cell migration, invasion and metastasis through activation of JNK/c-Jun/MMP-1 signaling pathway, indicating CAMSAP2 is a promising therapeutic target for the treatment of metastatic colorectal cancer patients.

A structure change-induced fluorescent biosensor for uracil-DNA glycosylase activity detection based on the substrate preference of Lambda exonuclease.

As one of the initiating DNA glycosylases in the base excision repair pathway, Uracil-DNA glycosylase (UDG) plays a pivotal role in maintaining genomic integrity. The abnormal expression of UDG in the organism is highly relevant to multiple diseases. Thus, rapid and sensitive detection of UDG activity is essential to aid early clinical diagnosis and biomedical research. Here we developed a rapid, sensitive and selective biosensor for UDG activity detection based on the substrate preference of Lambda exonuclease (λ exo). The protruding end in the substrate produced by UDG could be digested at a markedly high rate by λ exo, generating a detectable fluorescence signal. This proposed strategy for UDG detection exhibited high selectivity and high sensitivity (0.0001 U/mL) in a short time. It has also been successfully applied to detect UDG in real biological samples and the screening of UDG inhibitors.

[Analysis of Clinical Characteristics of JAK2 V617F and BCR-ABL Double-Mutant Myeloproliferative Neoplasms].

OBJECTIVE: To analyze the disease types, clinical manifestations, efficacy and outcome of JAK2 V617F and BCR-ABL double-mutant myeloproliferative neoplasms (MPN), and provide a reference for the diagnosis, treatment and prognosis of MPN. METHODS: The clinical characteristics, diagnosis, therapeutic efficacy and outcome of JAK2 V617F and BCR-ABL double-mutant MPN were analyzed comprehensitively by combining a clinical case diagnosed and treated in our hospital with literature cases from CNKI and PubMed databases. RESULTS: A total of 38 related literatures were retrieved from the two databases by searching "JAK2 V617F" and "BCR-ABL" as key words from 1990 to 2019, and 59 cases were involved. Among all the 60 cases, 41 were males (68.3%) with a median age of 61 (32-77) years old, while 19 were females (31.7%) with a median age of 58 (21-82) years old. The BCR-ABL fusion gene and JAK2 V617F mutation were found simultaneously in 21 cases (35%), 19 cases (31.7%) with JAK2 V617F mutation were found during the treatment of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Ph+CML was detectable in 20 cases (33.3%) during the treatment of JAK2 V617F mutation positive MPN. Polycythemia vera (PV) was the most common MPN coexisting with CML (30%), followed by essential thrombocythemia (ET) (26.7%) and primary myelofibrosis (PMF) (21.7%). In addition, there were 13 cases (21.7%) not classified in the literature. Among the 60 cases, 35 CML patients were clearly staged, including 31 in the chronic phase, 3 in the accelerated phase, and 1 in the blast crisis phase. As for the subtypes of BCR-ABL fusion gene, there were 30 cases with clear classification, including 28 cases of p210, 1 case of p190 and 1 case of p230. CONCLUSION: As cases of BCR-ABL and JAK2 V617F double-mutant MPN are reported, simultaneous detection of JAK2 V617F mutation and BCR-ABL fusion gene in MPN patients is necessary to avoid misdiagnosis and missed diagnosis.

Core-shell magnetic zeolite imidazolate framework-8 as adsorbent for magnetic solid phase extraction of brucine and strychnine from human urine.

Core-shell magnetic zeolite imidazolate framework-8 (Fe3O4@PAA@ZIF-8) was successfully synthesized and first employed as adsorbent of magnetic solid-phase extraction (MSPE) for the determination of brucine and strychnine in human urine sample coupled with high performance liquid chromatography. The as-prepared Fe3O4@PAA@ZIF-8 was characterized by transmission electron microscopy, Fourier-transform infrared spectrometry, X-ray diffraction, vibrating sample magnetometer and zeta potential analysis. Main parameters affecting the MSPE efficiency, including amount of adsorbent, sample solution pH, extraction time, ionic strength, desorption solvent, desorption time and desorption volume were further optimized. Under the optimized conditions, the proposed method provided good linearity (5.0-1000.0 µg L-1) with determination coefficients between 1.0000 and 0.9998, low limits of detection in the range of 1.1-1.2 µg L-1, and excellent reproducibility with relative standard deviations of less than 7.7%. The intra-day and inter-day precision were 1.5-3.2% and 2.1-7.2%, respectively. Satisfactory spiked recoveries were between97.2% and 115.4% with the relative standard deviations less than 6.3%. The results demonstrated that Fe3O4@PAA@ZIF-8 composite was a promising magnetic adsorbent for the preconcentration of brucine and strychnine in human urine sample.

Copper-Based Nanoscale Coordination Polymers Augmented Tumor Radioimmunotherapy for Immunogenic Cell Death Induction and T-Cell Infiltration.

Insufficient T-cell infiltration seriously hinders the efficacy of tumor immunotherapy. Induction of immunogenic cell death (ICD) is a potentially feasible approach to increase T-cell infiltration. Since ionizing radiation can only induce low-level ICD, this study constructs Cu-based nanoscale coordination polymers (Cu-NCPs) with mixed-valence (Cu+ /Cu2+ ), which can simultaneously and independently induce the generation of Cu+ -triggered hydroxyl radicals and Cu2+ -triggered GSH elimination, to synergize with radiation therapy for potent ICD induction. Markedly, this synergetic therapy remarkably enhances dendritic cell maturation and promotes antitumor CD8+ T-cell infiltration, thereby potentiating the development of checkpoint blockade immunotherapies against primary and metastatic tumors.

Recognition of the organ-specific mutations in metastatic breast cancer by circulating tumor cells isolated in vivo.

The failure to treat and control the growth of metastases is the main cause of death in breast cancer (BC) patients. Compared to the traditional method of analyzing circulating tumor DNA (ctDNA), capturing intact circulating tumor cells (CTCs) allows us to more accurately characterize mutations and identify suitable targeted therapies. We used CellCollector to collect peripheral CTCs. Thirty metastatic breast cancer (MBC) patients were enrolled, and 17 were analyzed with next-generation sequencing (NGS) methods. Clinical characteristics were analyzed along with the CTCs enumeration and detection rates. Whole-genome amplification (WGA) was used to amplify the CTC genomic DNA of 127 genes. Patients younger than 45 years old, with brain metastasis, with three or more metastatic sites, or with HER2-positive had the highest number of CTCs collected. The CTCs detection rate was also correlated to the number of metastasis sites. Different metastasis sites such as the brain, viscus, bone, and soft tissue contained specific high-frequency gene mutations. AKT3, MYC, and NT5C2 mutations were only found in brain metastases. APC, BCL2L11, ESRP1, FLT3 mutations were only in the visceral metastases. KEAP1, KIT, MET were the specific mutation genes in patients with bone and soft tissue metastases. These findings provide evidence that we can detect gene mutation information for obtaining the biological characteristics by CTCs using CellCollector. Different metastasis sites contain specific high-frequency mutation genes, which provide guidance to the accurate gene therapy.

Novel copper-based and pH-sensitive nanomedicine for enhanced chemodynamic therapy.

We utilized albumin as a reducing agent to establish novel copper-based and pH-sensitive nanocarrier CuNPs with abundant Cu+, which can encapsulate histone deacetylase (HDAC) inhibitor vorinostat to form uniform and stable nanomedicine V-CuNPs for synergistic chromatin remodelling and chemodynamic therapy.

Synergy of hypoxia relief and chromatin remodeling to overcome tumor radiation resistance.

Radiotherapy (RT) is one of the most extensive and effective approaches available for clinical tumor treatment. However, tumor microenvironments including hypoxia and histone deacetylase (HDAC) overexpression could induce radiation resistance, leading to tumor recurrence. Herein, nanoparticles (CAT-SAHA@PLGA) encapsulating catalase and HDAC inhibitor SAHA exhibited protected catalytic activity of catalase and prolonged the pharmacokinetic exposure of the HDAC inhibitor. Overall, the established CAT-SAHA@PLGA nanoparticles could overcome radiation resistance by synergistically increasing tumor oxygenation and inhibiting HDAC activity.

Clinical significance of sHER2­ECD and calpain­10 expression in tumor tissues of patients with breast cancer.

Human epidermal growth factor receptor 2 (HER2) is composed of an extracellular domain (ECD), a lipophilic transmembrane region and an intracellular domain (ICD). The most commonly used method to determine the status of HER2 is immunohistochemistry. However, false­negative results are sometimes given, which causes some patients to lose the opportunity for anti­HER2 therapy. We found that calpain­10 may prohibit HER2­ECD into peripheral blood resulting in a HER2­negative result by the immunohistochemical method. We enrolled 289 patients into our experiment to assess the relationship between sHER2­ECD and calpain­10. The results showed that there was a positive correlation between sHER2­ECD and calpain­10. Moreover, we also investigated the prognostic values of sHER2­ECD and calpain­10 in breast cancer patients. According to the follow­up results, positive sHER2­ECD and tissue calpain­10 were indicative of a poor prognosis in breast cancer patients. Subsequently, we further validated the relationship between the two molecules in in vitro experiments. In the in vitro experiments, the level of HER2­ECD in the culture medium was increased or decreased with a decrease or increase in calpain­10 by transfection technology, showing an inverse association. The results indicated that sHER2­ECD and tissue calpain­10 levels were powerful factors to assess the status of HER2. In combination with tissue HER2 detection, the occurrence of false­negative HER2 was reduced, providing patients with additional treatment opportunities. In conclusion, sHER2­ECD and tissue calpain­10 may be used as new prognostic indices for breast cancer.

Bifunctional liposomes reduce the chemotherapy resistance of doxorubicin induced by reactive oxygen species.

Doxorubicin (DOX) liposome is a widely used nano-medicine for colorectal cancer treatment. However, doxorubicin therapy increases the level of reactive oxygen species (ROS) in tumor cells, such as hydrogen peroxide (H2O2), which can stabilize hypoxia-inducible-factor-1α (HIF-1α). In a tumor hypoxic microenvironment, HIF-1 can up-regulate tumor-resistance related proteins, including P-glycoprotein (P-gp), glucose transporter 1 (GLUT-1), and matrix metalloproteinase 9 (MMP-9), leading to tumor tolerance to chemotherapy. The functional inhibition of HIF-1 can overcome this resistance and enhance the efficacy of tumor therapy. Here, we encapsulated one of the most effective HIF-1 inhibitors, acriflavine (ACF), and DOX in liposomes (DOX-ACF@Lipo) to construct bifunctional liposomes. ACF and DOX, released from DOX-ACF@Lipo, could effectively suppress the function of HIF-1 and the process of DNA replication, respectively. Consequently, the bifunctional liposome has great potential to be applied in clinics to overcome chemotherapy resistance induced by hypoxia.

Analysis of Pesticide Residue in Tomatoes by Carbon Nanotubes/ß-Cyclodextrin Nanocomposite Reinforced Hollow Fiber Coupled with HPLC.

For addressing the issues of pesticide residue analysis characterized by the trace levels of target analytes and the complexity of sample matrices, a selective extracting material, carbon nanotubes (CNTs)/ß-cyclodextrin (ß-CD) nanocomposite reinforced hollow fiber (HF), was developed. CNTs were chemically modified with ß-CD and then the resultant nanocomposite was immobilized into the wall pores and lumen of HF by sol-gel technology. The reinforced HF was applied to direct-immersion mode of solid phase microextraction for the determination of carbaryl and 1-naphthol in tomatoes, coupled with high performance liquid chromatography. The proposed method provided 240- and 215-fold enrichment factors, good linearity in the range of 0.6 to 600 ng/g and 0.2 to 600 ng/g, good repeatability with RSDs of 4.5% and 6.9%, and batch-to-batch reproducibility with RSDs of 7.4% and 8.3% for 1-naphthol and carbaryl, respectively. Moreover, the low limits of detection at 0.05 and 0.15 ng/g for 1-naphthol and carbaryl, respectively, along with the high recovery in the range of 84.2% to 108.9% were obtained. The results showed that the material combined the respective advantages of CNTs, ß-CD, and HF, thus, exhibiting efficient adsorption property, outstanding molecular recognition performance, and excellent sample clean-up effect, and it is applicable for pesticide residue analysis in complex matrices. PRACTICAL APPLICATION: The developed extracting material can be used for pesticide residue analysis of tomatoes. Pesticides, carbaryl, and 1-naphthol were detected in tomatoes, the most popular vegetable grown and consumed globally. The results supported the necessity to monitor pesticide residue for public health.

Oxygen-rich chemotherapy via modified Abraxane to inhibit the growth and metastasis of triple-negative breast cancer.

Abraxane® (Abx), an FDA approved albumin-bound paclitaxel nano-formulation, is one of the most common chemical drugs for the treatment of metastatic triple-negative breast cancer (mTNBC). However, acquired resistance and metastasis are critical factors that limit the treatment of mTNBC by Abx. In particular, both the tumor hypoxic microenvironment and the increase in hydrogen peroxide (H2O2) levels via paclitaxel stimulation primarily mediate the resistance to chemotherapy, where multiple drug resistance proteins such as P-gp and tumor invasion-related cytokines such as VEGF are continuously activated to pump out chemical drugs and aggravate tumor metastasis, respectively. Therefore, it is of great importance to combine tumor oxygenation with commercial chemical drugs for overcoming the acquired resistance and metastasis. In this study, a facile method was developed to deposit manganese dioxide (MnO2) onto the surface of Abraxane® (Abx) to form MnO2-modified Abx (M-Abx). The modification process did not change the critical characteristics of the parent Abx, which might have great potential for application in clinics for the treatment of mTNBC. Tumor oxygenation mediated by M-Abx specifically occurs within the H2O2-overexpressed tumor microenvironment, and significantly downregulates the content of tumor progression-related proteins, such as HIF-1α, P-gp, and VEGF. Ultimately, M-Abx treatment results in about a 2-fold increase in inhibition efficiency of tumor growth in both primary and metastatic tumors compared with traditional Abx therapy. Therefore, oxygen-rich chemotherapy was realized to efficiently sensitize paclitaxel, relieve acquired resistance and inhibit tumor metastasis.

Identification of potential prognostic long non­coding RNA signatures based on a competing endogenous RNA network in lung adenocarcinoma.

A number of experimental and computational studies have demonstrated the key roles of long non­coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in the tumorigenesis of lung adenocarcinoma (LUAC). However, there remains a requirement for prognostic candidate biomarkers acting as ceRNAs for the prediction of overall survival in patients with LUAC. The main goal of the present study was to identify novel lncRNAs associated with LUAC overall survival and assess their prognostic values. The study analyzed coding RNA and ncRNA expression profiles of patients with LUAC by retrieving existing RNA­sequencing datasets from The Cancer Genome Atlas database, and 2,507 differentially expressed mRNAs, 1,633 lncRNAs and 113 miRNAs were screened from patients with LUAC compared with those of adjacent normal samples (P<0.01 and |logFC|>2). Of these LUAC­specific RNAs, 134 lncRNAs, 21 miRNAs and 34 mRNAs were used to build an lncRNA­mRNA­miRNA ceRNA network, among which 8 lncRNAs and 9 mRNAs were associated with overall survival in patients with LUAC by acting as ceRNAs. Next, an lncRNA­based prognostic signature was constructed by risk scoring approach based on the expression levels of 9 prognosis­associated lncRNAs using Cox's regression analysis. Moreover, the prognostic capacity of the 9­lncRNA signature was independent of known clinical prognostic factors. These results provide novel insight into the potential of lncRNA ceRNAs to be candidate biomarkers associated with LUAC overall survival.

Tumor Oxygenation and Hypoxia Inducible Factor-1 Functional Inhibition via a Reactive Oxygen Species Responsive Nanoplatform for Enhancing Radiation Therapy and Abscopal Effects.

Hypoxia, and hypoxia inducible factor-1 (HIF-1), can induce tumor resistance to radiation therapy. To overcome hypoxia-induced radiation resistance, recent studies have described nanosystems to improve tumor oxygenation for immobilizing DNA damage and simultaneously initiate oxygen-dependent HIF-1α degradation. However, HIF-1α degradation is incomplete during tumor oxygenation treatment alone. Therefore, tumor oxygenation combined with residual HIF-1 functional inhibition is crucial to optimizing therapeutic outcomes of radiotherapy. Here, a reactive oxygen species (ROS) responsive nanoplatform is reported to successfully add up tumor oxygenation and HIF-1 functional inhibition. This ROS responsive nanoplatform, based on manganese dioxide (MnO2) nanoparticles, delivers the HIF-1 inhibitor acriflavine and other hydrophilic cationic drugs to tumor tissues. After reacting with overexpressed hydrogen peroxide (H2O2) within tumor tissues, Mn2+ and oxygen molecules are released for magnetic resonance imaging and tumor oxygenation, respectively. Cooperating with the HIF-1 functional inhibition, the expression of tumor invasion-related signaling molecules (VEGF, MMP-9) is obviously decreased to reduce the risk of metastasis. Furthermore, the nanoplatform could relieve T-cell exhaustion via downregulation of PD-L1, whose effects are similar to the checkpoint inhibitor PD-L1 antibody, and subsequently activates tumor-specific immune responses against abscopal tumors. These therapeutic benefits including increased X-ray-induced damage, downregulated resistance, and T-cell exhaustion related proteins expression achieved synergistically the optimal inhibition of tumor growth. Overall, this designed ROS responsive nanoplatform is of great potential in the sensitization of radiation for combating primary and metastatic tumors.