Novel theranostics based on photosensitizer‐conjugated carbon dots is reported. The prepared C‐dots–Ce6 has good stability and high water dispersibility and solubility, non‐cytotoxicity, good ...biocompatibility, enhanced photosensitizer fluorescence detection and remarkable photodynamic efficacy upon irradiation. The C‐dots–Ce6 conjugate is a good candidate with excellent imaging and tumor‐homing ability for NIR fluorescence imaging monitored PDT treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Fluorescent carbon dots (Cdots) have attracted increasing attention due to their potential applications in sensing, catalysis, and biomedicine. Currently, intensive research has been concentrated on ...the synthesis and imaging-guided therapy of these benign photoluminescent materials. Meanwhile, Cdots have been explored as nonviral vector for nucleic acid or drug delivery by chemical modification on purpose.
We have developed a microwave assisted one-step synthesis of Cdots with citric acid as carbon source and tryptophan (Trp) as both nitrogen source and passivation agent. The Cdots with uniform size show superior water solubility, excellent biocompatibility, and high quantum yield. Afterwards, the PEI (polyethylenimine)-adsorbed Cdots nanoparticles (Cdots@PEI) were applied to deliver Survivin siRNA into human gastric cancer cell line MGC-803. The results have confirmed the nanocarrier exhibited excellent biocompatibility and a significant increase in cellular delivery of siRNA, inducing efficient knockdown for Survivin protein to 6.1%. In addition, PEI@Cdots complexes mediated Survivin silencing, the arrested cell cycle progression in G1 phase as well as cell apoptosis was observed.
The Cdots-based and PEI-adsorbed complexes both as imaging agents and siRNA nanocarriers have been developed for Survivin siRNA delivery. And the results indicate that Cdots-based nanocarriers could be utilized in a broad range of siRNA delivery systems for cancer therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pancreatic cancer, at unresectable advanced stages, presents poor prognoses, which could be prevented by early pancreatic cancer diagnosis methods. Recently, a promising early-stage pancreatic cancer ...biomarker, extracellular vesicles (EVs) related glypican-1 (GPC1) mRNA, is found to overexpress in pancreatic cancer cells. Current mRNA detection methods usually require expensive machinery, strict preservation environments, and time-consuming processes to guarantee detection sensitivity, specificity, and stability. Herein, we propose a novel two-step amplification method (CHAGE) via the target triggered Catalytic Hairpin Assembly strategy combined with Gold-Enhanced point-of-care-testing (POCT) technology for sensitive visual detection of pancreatic cancer biomarker. First, utilizing the catalyzed hairpin DNA circuit, low expression of the GPC1 mRNA was changed into amplification product 1 (AP1, a DNA duplex) as the next detection targets of the paper strips. Second, the AP1 was loaded onto a lateral flow assay and captured with the gold signal nanoparticles to visualize results. Finally, the detected results can be further enhanced by depositing gold to re-enlarge the sizes of gold nanoparticles in detection zones. As a result, the CHAGE methodology lowers the detection limit of mRNA to 100 fM and provides results within 2 h at 37 °C. Furthermore, we demonstrate the successful application in discriminating pancreatic cancer cells by analyzing EVs' GPC1 mRNA expression levels. Hence, the CHAGE methodology proposed here provides a rapid and convenient POCT platform for sensitive detection of mRNAs through unique probes designs (COVID, HPV, etc.).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Electrogenerated microscale bubbles that are confined at the electrode surface have already been extensively studied because of their significant influence on electrochemistry. In contrast, as far as ...we know, whether nanoscale bubbles exist on the electrode surface has not been experimentally confirmed yet. Here, we report the observation of electrochemically controlled formation and growth of hydrogen nanobubbles on bare highly oriented pyrolytic graphite (HOPG) surface via in-situ tapping mode atomic force microscopy (TMAFM). By using TMAFM imaging, we observed that electrochemically generated hydrogen gas led to the formation of nanobubbles at the HOPG surface. We then employed a combination of techniques, including phase imaging, ex-situ degassing, and tip perturbation, to confirm the gas origin of such observed nanobubbles. We further demonstrated that the formation and growth of nanobubbles could be well controlled by tuning either the applied voltage or the reaction time. Remarkably, we could also monitor the evolution process of nanobubbles, that is, formation, growth, coalescence, as well as the eventual release of merged microbubbles from the HOPG surface.
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IJS, KILJ, NUK, PNG, UL, UM
Co‐detection of multiplex cancer subtypes and bacteria subtypes in situ is crucial for understanding tumor microbiome interactions in tumor microenvironment. Current standard techniques such as ...immunohistochemical staining and immunofluorescence staining are limited for their multiplicity. Simultaneously visualizing detailed cell subtypes and bacteria distribution across the same pathological section remains a major technical challenge. Herein, we developed a rapid semi‐quantitative method for in situ imaging of bacteria and multiplex cell phenotypes on the same solid tumor tissue sections. We designed a panel of antibody probes labeled with mass tags, namely prokaryotic and eukaryotic cell hybrid probes for in situ imaging (PEHPSI). For application demonstration, PEHPSI stained two bacteria subtypes (lipopolysaccharides (LPS) for Gram‐negative bacteria and lipoteichoic acid (LTA) for Gram‐positive bacteria) simultaneously with four types of immune cells (leukocytes, CD8 + T‐cells, B‐cells and macrophages) and four breast cancer subtypes (classified by a panel of 12 human proteins) on the same tissue section. We unveiled that breast cancer cells are commonly enriched with Gram‐negative bacteria and almost absent of Gram‐positive bacteria, regardless of the cancer subtypes (triple‐negative breast cancer TNBC, HER2+, Luminal A and Luminal B). Further analysis revealed that on the single‐cell level, Gram‐negative bacteria have a significant correlation with CD8 + T‐cells only in HER2+ breast cancer, while PKCD, ER, PR and Ki67 are correlated with Gram‐negative bacteria in the other three subtypes of breast cancers. On the cell population level, in TNBC, CD19 expression intensity is up‐regulated by approximately 25% in bacteria‐enriched cells, while for HER2+, Luminal A and Luminal B breast cancers, the intensity of biomarkers associated with the malignancy, metastasis and proliferation of cancer cells (PKCD, ISG15 and IFI6) is down‐regulated by 29%–38%. The flexible and expandable PEHPSI system permits intuitive multiplex co‐visualization of bacteria and mammalian cells, which facilitates future research on tumor microbiome and tumor pathogenesis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Uveal melanoma (UM) is the most common intraocular malignant tumor in adults and has a low survival rate following metastasis; it is derived from melanocytes susceptible to reactive oxygen species ...(ROS). Carbon dot (Cdot) nanoparticles are a promising tool in cancer detection and therapy due to their unique photophysical properties, low cytotoxicity, and efficient ROS productivity. However, the effects of Cdots on tumor metabolism and growth are not well characterized. Here, the effects of Cdots on UM cell metabolomics, growth, invasiveness, and tumorigenicity are investigated in vitro and in vivo zebrafish and nude mouse xenograft model. Cdots dose‐dependently increase ROS levels in UM cells. At Cdots concentrations below 100 µg mL−1, Cdot‐induced ROS promote UM cell growth, invasiveness, and tumorigenicity; at 200 µg mL−1, UM cells undergo apoptosis. The addition of antioxidants reverses the protumorigenic effects of Cdots. Cdots at 25–100 µg mL−1 activate Akt/mammalian target of rapamycin (mTOR) signaling and enhance glutamine metabolism, generating a cascade that promotes UM cell growth. These results demonstrate that moderate, subapoptotic doses of Cdots can promote UM cell tumorigenicity. This study lays the foundation for the rational application of ROS‐producing nanoparticles in tumor imaging and therapy.
Uveal melanoma (UM) originates from melanocytes that are susceptible to malignant transformation by reactive oxygen species (ROS). Carbon dots (Cdots) with efficient ROS productivity dose‐dependently promote UM cell growth, invasiveness, and tumorigenicity at concentrations below 100 µg mL−1. Cdot‐induced ROS act as stimulatory signaling molecules to activate Akt/mammalian target of rapamycin signaling, accelerate glutamine metabolism, thus promoting UM cell growth.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Phosphomolybdate-based nanoparticles (PMo
-based NPs) have been commonly applied in nanomedicine. However, upon contact with biofluids, proteins are quickly adsorbed onto the NPs surface to form a ...protein corona, which induces the opsonization and facilitates the rapid clearance of the NPs by macrophage uptake. Herein, we introduce a family of structurally homologous PMo
-based NPs (CDS-PMo
@PVP
(x = 0 ~ 1) NPs) capping diverse content of zwitterionic polymer poly (N-vinylpyrrolidone) (PVP) to regulate the protein corona formation on PMo
-based NPs. The fluorescence quenching data indicate that the introduction of PVP effectively reduces the number of binding sites of proteins on PMo
-based NPs. Molecular docking simulations results show that the contact surface area and binding energy of proteins to CDS-PMo
@PVP
NPs are smaller than the CDS-PMo
@PVP
NPs. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) is further applied to analyze and quantify the compositions of the human plasma corona formation on CDS-PMo
@PVP
(x = 0 ~ 1) NPs. The number of plasma protein groups adsorption on CDS-PMo
@PVP
NPs, compared to CDS-PMo
@PVP
NPs, decreases from 372 to 271. In addition, 76 differentially adsorption proteins are identified between CDS-PMo
@PVP
and CDS-PMo
@PVP
NPs, in which apolipoprotein is up-regulated in CDS-PMo
@PVP
NPs. The apolipoprotein adsorption onto the NPs is proposed to have dysoponic activity and enhance the circulation time of NPs. Our findings demonstrate that PVP grafting on PMo
-based NPs is a promising strategy to improve the anti-biofouling property for PMo
-based nanodrug design.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The bandgap engineering of graphene is a challenging task for its potential application. Forming unique structures such as nanoribbons or nanomeshes is an effective way to open up a bandgap in ...graphene. In this work, a graphene nanomesh (GNM) was prepared through UV-mediated oxidation of a graphene oxide (GO) film at atmosphere. Atomic force microscopy (AFM) was used to track the evolution of the surface morphology of GO during the irradiation. It was observed that a nanoporous network structure was progressively produced in the basal plane, which can be attributed to the fact that highly reactive oxygen species preferentially attack sp3 carbon-rich regions of the GO. In particular, the as-prepared GNM shows interesting semiconducting characteristics and photoluminescence (PL) phenomenon, which make it become a promising candidate for the use of electronics, optoelectronics, and biomedical engineering. Finally, the field-effect transistors (FETs) were fabricated using the as-prepared GNM as the active channel. The measured electrical characteristics indicate that the use of UV/O3 is an available choice to open the bandgap of graphene and tune its properties for optoelectronics or biomedical applications.
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IJS, KILJ, NUK, PNG, UL, UM
High‐dimensional imaging mass cytometry (IMC) enables simultaneous quantification of over 35 biomarkers on one tissue section. However, its limited resolution and ultralow acquisition speed remain ...major issues for general clinical application. Meanwhile, conventional immunofluorescence microscopy (IFM) allows sub‐micrometer resolution and rapid identification of the region of interest (ROI), but only operates with low multiplicity. Herein, a series of lanthanide‐doped blue‐, green‐, and red‐fluorescent carbon nanodots (namely, B‐Cdots(Ln1), G‐Cdots(Ln2), and R‐Cdots(Ln3)) as fluorescence and mass dual‐modal tags are developed. Coupled with aptamers, B‐Cdots(159Tb)‐A10‐3.2, G‐Cdots(165Ho)‐AS1411, and R‐Cdots(169Tm)‐SYL3C dual‐functional aptamer probes, which are then multiplexed with commercially available Maxpar metal‐tagged antibodies for analyzing clinical formalin‐fixed, paraffin‐embedded (FFPE) prostatic adenocarcinoma (PaC) tissue, are further synthesized. The rapid identification of ROI with IFM using fluorescence signals and subsequent multiplexed detection of in situ ROI with IMC using the same tissue section is demonstrated. Dual‐modal probes save up to 90% IMC blind scanning time for a standard 3.5 mm × 3.5 mm overall image. Meanwhile, the IFM provides refined details and topological spatial distributions for the functional proteins at optical resolution, which compensates for the low resolution of the IMC imaging.
The MC‐Cdots(Ln)‐aptamers serve as dual‐modal probes that realize the rapid identification of region of interest (ROI) with immunofluorescence microscopy using fluorescence signal, and then multiplexed detection of in situ ROI with imaging mass cytometry on the same tissue section.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Extracellular vesicle (EV) surface proteins, expressed by primary tumours, are important biomarkers for early cancer diagnosis. However, the detection of these EV proteins is complicated by ...their low abundance and interference from non‐EV components in clinical samples. Herein, we present a MEmbrane‐Specific Separation and two‐step Cascade AmpLificatioN (MESS2CAN) strategy for direct detection of EV surface proteins within 4 h. MESS2CAN utilises novel lipid probes (long chains linked by PEG2K with biotin at one end, and DSPE at the other end) and streptavidin‐coated magnetic beads, permitting a 49.6% EV recovery rate within 1 h. A dual amplification strategy with a primer exchange reaction (PER) cascaded by the Cas12a system then allows sensitive detection of the target protein at 10 EV particles per microliter. Using 4 cell lines and 90 clinical test samples, we demonstrate MESS2CAN for analysing HER2, EpCAM and EGFR expression on EVs derived from cells and patient plasma. MESS2CAN reports the desired specificity and sensitivity of EGFR (AUC = 0.98) and of HER2 (AUC = 1) for discriminating between HER2‐positive breast cancer, triple‐negative breast cancer and healthy donors. MESS2CAN is a pioneering method for highly sensitive in vitro EV diagnostics, applicable to clinical samples with trace amounts of EVs.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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