PD-L1/PD-1 blockade therapy shows durable responses to triple-negative breast cancer (TNBC), but the response rate is low. CD155 promotes tumor metastasis intrinsically and modulates the immune ...response extrinsically as the ligand of DNAM-1 (costimulatory receptor) and TIGIT/CD96 (coinhibitory receptors). Herein, we verified that TNBC cells coexpressed PD-L1 and CD155. By examining the receptors of PD-L1 and CD155 on TNBC tumor-infiltrating lymphocytes (TILs) over time, we observed that PD-1 and DNAM-1 were upregulated early, whereas CD96 and TIGIT were upregulated late in CD8+ TILs. Based on these findings, we developed CD155 siRNA (siCD155)-loaded mPEG-PLGA-PLL (PEAL) nanoparticles (NPs) coated with PD-L1 blocking antibodies (P/PEALsiCD155) to asynchronously block PD-L1 and CD155 in a spatiotemporal manner. P/PEALsiCD155 maximized early-stage CD8+ T cell immune surveillance against 4T1 tumor, whereas reversed inhibition status of the late stage CD8+ T cells to prevent 4T1 tumor immune escape. In addition, the combination of P/PEALsiCD155 and tumor-specific CD8 T cells induced immunogenic cell death (ICD) of 4T1 cells to further boost immune checkpoint therapy. Most importantly, P/PEALsiCD155 displayed excellent TNBC targeting and induced CD8+ TILs-dominant intratumor antitumor immunity to efficiently inhibit TNBC progression and metastasis with excellent safety in a syngeneic 4T1 orthotopic TNBC tumor model.
The manuscript proposes a synergetic fluorescence enhancement strategy based on the micro/nanostructure optimization of ZnO nanorod and in situ ZIF-8 coating for highly sensitive microfluidic ...detection of carcinoembryonic antigen.
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•Structure optimization of ZnO NR in capillary-like fluorescence assays was studied.•The enhancement property of ZIF-8 towards organic fluorescence dyes was verified.•In situ ZIF-8 coating effectively enhanced the signal of organic fluorescence label.•In CEA detection based on ZnO NR array/ZIF-8 coating, the LOD reached 0.01 pg mL−1.
In this work, a synergetic fluorescence enhancement strategy based on micro/nanostructure optimization of ZnO nanorod arrays and in situ ZIF-8 coating was proposed for the highly sensitive microfluidic detection of carcinoembryonic antigen (CEA). The glass capillary was chosen as the microfluidic channel, and controllable construction of ZnO nanorod arrays on the inner wall of the microchannel was conducted via the intermittent reaction method. Additionally, the application of the optimal ZnO nanorod array to glass capillary-based microfluidic fluorescence detection was demonstrated. The fluorescence enhancement characteristic of the zeolitic imidazolate framework-8 (ZIF-8) towards organic fluorescence labels were investigated and successfully applied to protein marker detection. After formation of sandwich immunoassay on the ZnO/PAA nanorod arrays, the in situ ZIF-8 coating via a moderate chemical method could significantly improve the fluorescence intensity of fluorescent labels via direct contact. In CEA detection, the limit of detection (LOD) reached as low as 0.01 pg mL−1, and the dynamic range was 0.01 pg mL−1 to 100 pg mL−1. Hence, the microfluidic fluorescence detection strategy based on the ZnO nanorod arrays/PAA layers/ZIF-8 coating with a synergetic fluorescence enhancement effect provides a superior, promising, and highly sensitive approach for the detection of protein markers, including CEA.
Although cisplatin-based chemotherapy has been used as the first-line treatment for ovarian cancer (OC), tumor cells develop resistance to cisplatin during treatment, causing poor prognosis in OC ...patients. Studies have demonstrated that overactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is involved in tumor chemoresistance and that overexpression of microRNA-497 (miR497) may overcome OC chemotherapy resistance by inhibiting the mTOR pathway. However, the low transcriptional efficiency and unstable chemical properties of miR497 limit its clinical application. Additionally, triptolide (TP) was confirmed to possess a superior killing effect on cisplatin-resistant cell lines, partially through inhibiting the mTOR pathway. Even so, the clinical applications of TP are restricted by serious systemic toxicity and weak water solubility.
Herein, whether the combined application of miR497 and TP could further overcome OC chemoresistance by synergically suppressing the mTOR signaling pathway was investigated. Bioinspired hybrid nanoparticles formed by the fusion of CD47-expressing tumor exosomes and cRGD-modified liposomes (miR497/TP-HENPs) were prepared to codeliver miR497 and TP. In vitro results indicated that the nanoparticles were efficiently taken up by tumor cells, thus significantly enhancing tumor cell apoptosis. Similarly, the hybrid nanoparticles were effectively enriched in the tumor areas and exerted significant anticancer activity without any negative effects in vivo. Mechanistically, they promoted dephosphorylation of the overactivated PI3K/AKT/mTOR signaling pathway, boosted reactive oxygen species (ROS) generation and upregulated the polarization of macrophages from M2 to M1 macrophages.
Overall, our findings may provide a translational strategy to overcome cisplatin-resistant OC and offer a potential solution for the treatment of other cisplatin-resistant tumors.
Efficient monitoring of glucose concentration in the human body necessitates the utilization of electrochemically active sensing materials in nonenzymatic glucose sensors. However, prevailing ...limitations such as intricate fabrication processes, lower sensitivity, and instability impede their practical application. Herein, ternary Cu-Co-Ni-S sulfides nanoporous network structure was synthesized on carbon fiber paper (CP) by an ultrafast, facile, and controllable technique through on-step cyclic voltammetry, serving as a superior self-supporting catalytic electrode for the high-performance glucose sensor. The direct growth of free-standing Cu-Co-Ni-S on the interconnected three-dimensional (3D) network of CP boosted the active site of the composites, improved ion diffusion kinetics, and significantly promoted the electron transfer rate. The multiple oxidation states and synergistic effects among Co, Ni, Cu, and S further promoted glucose electrooxidation. The well-architected Cu-Co-Ni-S/CP presented exceptional electrocatalytic properties for glucose with satisfied linearity of a broad range from 0.3 to 16,000 muM and high sensitivity of 6829 muA mM.sup.- 1 cm.sup.- 2. Furthermore, the novel sensor demonstrated excellent selectivity and storage stability, which could successfully evaluate the glucose levels in human serum. Notably, the novel Cu-Co-Ni-S/CP showed favorable biocompatibility, proving its potential for in vivo glucose monitoring. The proposed 3D hierarchical morphology self-supported electrode sensor, which demonstrates appealing analysis behavior for glucose electrooxidation, holds great promise for the next generation of high-performance glucose sensors.
Polyampholyte-coated (poly(acrylic acid) (PAA)-co-3-(diethylamino)-propylamine (DEAPA)) magnetite nanoparticles (PAMNPs) have been prepared as contrasting agent used in magnetic resonance imaging ...(MRI). Excellent biocompatibility is required for contrasting agents used in high-resolution magnetic resonance angiography. To evaluate the biocompatibility of PAMNPs, some experiments have been conducted. The hemolysis, plasma recalcification, dynamic blood clotting, prothrombin time, inflammatory cytokine release and complement system activation assays were carried out to investigate the hemocompatibility. To evaluate the toxicity to vessel, MTT test and vascular irritation tests were conducted. Tissue toxicity test was also performed to investigate the biocompability in vivo. We also looked into the biodistribution. The results showed that PAMNPs at the working concentration (0.138 mM) present similar hemocompatibility with negative control, thus have no significant effect to vessels. PAMNPs were mainly distributed in the liver and the blood. The circulation time in blood was considerably long, with the half-time of 3.77 h in plasma. This property is advantageous for PAMNPs' use in angiography. PAMNPs could be metabolized rapidly in mice and were not observed to cause any toxic or adverse effect. In short, these results suggest that the PAMNPs have great potential to serve as safe contrast agents in magnetic resonance imaging (MRI).
The purpose of this work was to investigate the synthetic phospholipid dependence of permeability measured by parallel artificial membrane permeability assay (PAMPA) method. Three phospholipids with ...hydrophobic groups of different lengths and phosphorylcholine as the hydrophilic group were concisely synthesized. Ten model drug molecules were selected because of their distinct human fraction absorbed (%FA) values and various pKa characteristics. In vitro drug permeation experiments were designed to determine the effect of the incubation time (4-20 h), pH gradient (4.6-9.32) and carbon chain length (8, 10, 12) on the drug permeability through the synthetic phospholipid membrane in the PAMPA system. The results showed that intensive and significant synthetic phospholipids dependence of permeability influenced by the length of lipid's hydrophobic carbon chain. The effective permeability constant (Pe) of each drug increased rapidly with time, then decreased slightly after reaching the maximum; the pH gradient changed the drug permeability according to the pH-partition hypothesis for drugs with diverse pKa values; and longer hydrophobic chains in the synthetic phospholipid membrane improved the drug permeability, as observed for all test drugs at almost all incubation time points. This newly proposed PAMPA model considered the synthetic phospholipid membrane and showed good Pe-%FA correlation for the passive transport of drugs, making it a helpful supplementary method for PAMPA systems.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To get better chemotherapy efficacy, the optimal synergic effect of Paclitaxel (PTX) and Temozolomide (TMZ) on glioblastoma cells lines was investigated. A dual drug-loaded delivery system based on ...mPEG-PLGA nanoparticles (NPs) was developed to potentiate chemotherapy efficacy for glioblastoma. PTX/TMZ-NPs were prepared with double emulsification solvent evaporation method and exhibited a relatively uniform diameter of 206.3 ± 14.7 nm. The NPs showed sustained release character. Cytotoxicity assays showed the best synergistic effects were achieved when the weight ratios of PTX to TMZ were 1:5 and 1:100 on U87 and C6 cells, respectively. PTX/TMZ-NPs showed better inhibition effect to U87 and C6 cells than single drug NPs or free drugs mixture. PTX/TMZ-NPs (PTX: TMZ was 1:5(w/w)) significantly inhibited the tumor growth in the subcutaneous U87 mice model. These results indicate that coordinate administration of PTX and TMZ combined with NPs is an efficient method for glioblastoma.
Superhydrophobic substrate modifications are an effective way to improve SERS sensitivity by concentrating analyte molecules into a small surface area. However, it is difficult to manipulate ...low-volume liquid droplets on superhydrophobic substrates. To overcome this limitation, we deposited a hydrophilic Ti.sub.3C.sub.2T.sub.x film on a superhydrophobic ZnO nanorod array to create a SERS substrate with improved analyte affinity. Combined with its interfacial charge transfer properties, this enabled a rhodamine 6G detection limit of 10.sup.-11 M to be achieved. In addition, the new SERS substrate showed potential for detection of biological macromolecules, such as microRNA. Combined with its facile preparation, the SERS activity of ZnO/Ti.sub.3C.sub.2T.sub.x suggests it may provide an ultrasensitive environmental pollutant-monitoring and effective substrate for biological analyte detection.
Zinc oxide (ZnO) often serves as protein microarray substrates owing to its outstanding fluorescence enhancement effect. However, the integration of functional substrates with microfluidic technology ...to detect cancer biomarkers still needs to be optimized and promoted, for example, the optimization of micro/nanostructure and hydrophilic modification strategies for fluorescence immunoassays. Here, ZnO nanorod arrays were constructed on the inner wall of glass capillaries through a microfluidic chemical method, and the electrostatic layer by layer self-assembly was applied to modify the nanorod array with hydrophilic polyelectrolyte-polyacrylic acid (PAA). The effects of the flow rate and the reagent concentration on the morphology of the ZnO nanorod array were investigated. The ZnO nanorod array-based glass capillary, prepared at 25 μL min-1 for 4 min with 50 mM Zn2+ in solution, showed a remarkable enhancement in fluorescence performance. In addition, the introduction of PAA suppressed the interference of nonspecific protein and improved the antibody loading capacity effectively. In the detection of carcinoembryonic antigen, the limit of detection reached 100 fg mL-1, which indicated that the ZnO@PAA nanorod array-based microfluidic device exhibits remarkable fluorescence detection performance towards protein markers and possesses potential to be applied to point-of-care diagnostics and high throughput cancer biomarker detection.
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