RESUMEN
Accurate quantification of exosomal PD-L1 protein in tumors is closely linked to the response to immunotherapy, but robust methods to achieve high-precision quantitative detection of PD-L1 expression on the surface of circulating exosomes are still lacking. In this work, we developed a signal amplification approach based on aptamer recognition and DNA scaffold hybridization-triggered assembly of quantum dot nanospheres, which enables bicolor phenotyping of exosomes to accurately screen for cancers and predict PD-L1-guided immunotherapeutic effects through machine learning. Through DNA-mediated assembly, we utilized two aptamers for simultaneous ultrasensitive detection of exosomal antigens, which have synergistic roles in tumor diagnosis and treatment prediction, and thus, we achieved better sample classification and prediction through machine-learning algorithms. With a drop of blood, we can distinguish between different cancer patients and healthy individuals and predict the outcome of immunotherapy. This approach provides valuable insights into the development of personalized diagnostics and precision medicine.
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Nanosferas , Neoplasias , Puntos Cuánticos , Humanos , Detección Precoz del Cáncer , Antígeno B7-H1 , Inmunoterapia , Aprendizaje Automático , Oligonucleótidos , ADNRESUMEN
Quantum dots (QDs) exhibit superior brightness and photochemical stability, making them the preferred option for highly sensitive single-molecule detection compared with fluorescent dyes or proteins. Nevertheless, their high surface energy leads to nonspecific adsorption and poor colloidal stability. In the past decades, we have found that QD-based fluorescent nanoparticles (FNs) can not only address these limitations but also enhance detection sensitivity. However, the photoluminescence quantum yield (PLQY) of FNs is significantly lower compared with that of original QDs. It is urgent to develop a strategy to solve the issue, aiming to further enhance detection sensitivity. In this study, we found that the decrease of PLQY of FNs prepared by free radical polymerization was attributed to two factors: (1) generation of defects that can cause nonradiative transitions resulting from QD-ligands desorption and QD-shell oxidation induced by free radicals; (2) self-absorption resulting from aggregation caused by incompatibility of QDs with polymers. Based on these, we proposed a multihierarchical regulation strategy that includes: (1) regulating QD-ligands; (2) precisely controlling free radical concentration; and (3) constructing cross-linked structures of polymer to improve compatibility and to reduce the formation of surface defects. It is crucial to emphasize that the simultaneous coordination of multiple factors is essential. Consequently, a world-record PLQY of 97.6% for FNs was achieved, breaking through the current bottleneck at 65%. The flexible application of this regulatory concept paves the way for the large-scale production of high-brightness QD-polymer complexes, enhancing their potential applications in sensitive biomedical detection.
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The redox homeostasis in tumors enhances their antioxidant defense ability, limiting reactive oxygen species mediated tumor therapy efficacy. The development of strategies for specific and continuous disruption of the redox homeostasis in tumor cells facilitates the improvement of the cancer therapeutic effect by promoting the apoptosis of tumor cells. Herein, a responsively biodegradable targeting multifunctional integrated nanosphere (HDMn-QDs/PEG-FA) is designed to enhance the anti-tumor efficacy by triggering intratumoral cascade reactions to effectively disrupt intracellular redox homeostasis. Once HDMn-QDs/PEG-FA enters tumor cells, manganese dioxide (MnO2 ) shell on the surface of nanosphere consumes glutathione (GSH) to produce Mn2+ , enabling enhanced chemodynamic therapy (CDT) via a Fenton-like reaction and T1 -weighted magnetic resonance imaging. Meanwhile, the degradation of MnO2 can also cause the fluorescence recovery of quantum dots conjugated on the surface of the shell, realizing "turn-on" fluorescence imaging. In addition, the doxorubicin is released because of the cleavage of the embedded SS bond in the hybrid core framework by GSH. A superior synergistic therapeutic efficiency combined CDT and chemotherapy is shown by HDMn-QDs/PEG-FA in vivo. The tumor-inhibition rate reaches to 94.8% and does not cause normal tissue damage due to the good targeting and tumor microenvironment-specific response.
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Nanopartículas , Nanosferas , Neoplasias , Humanos , Línea Celular Tumoral , Glutatión/química , Peróxido de Hidrógeno/metabolismo , Compuestos de Manganeso/química , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Oxidación-Reducción , Óxidos/química , Microambiente TumoralRESUMEN
Bacterial infectious diseases are common clinical diseases that seriously threaten human health, especially in countries and regions with poor environmental hygiene. Due to the lack of characteristic clinical symptoms and signs, it is a challenge to distinguish a bacterial infection from other infections, leading to misdiagnosis and antibiotic overuse. Therefore, there is an urgent need to develop a specific method for detection of bacterial infections. Herein, utilizing ultrabright fluorescent nanospheres (FNs) as reporters, immunochromatographic dyad test strips are developed for the early detection of bacterial infections and distinction of different stages of bacterial infectious diseases in clinical samples. C-reactive protein (CRP) and heparin-binding protein (HBP) are quantified and assayed because their levels in plasma are varied dynamically and asynchronously during the progression of the disease. The detection limits of CRP and HBP can reach as low as 0.51 and 0.65 ng/mL, respectively, due to the superior fluorescence intensity of each FN, which is 570 times stronger than that of a single quantum dot. The assay procedure can be achieved in 22 min, fully meeting the needs of rapid and ultrasensitive detection in the field. This constructed strip has been successfully used to profile the stage and severity of bacterial infections by monitoring the levels of CRP and HBP in human plasma samples, showing great potential as a point-of-care biosensor for clinical diagnosis. In addition to bacterial infections, the developed ultrabright FN-based point-of-care testing can be readily expanded for rapid, quantitative, and ultrasensitive detection of other trace substances in complex systems.
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Infecciones Bacterianas , Técnicas Biosensibles , Enfermedades Transmisibles , Nanosferas , Puntos Cuánticos , Infecciones Bacterianas/diagnóstico , Técnicas Biosensibles/métodos , Proteína C-Reactiva/análisis , Humanos , Nanosferas/química , Puntos Cuánticos/químicaRESUMEN
Aim: To develop a H2O2/near-infrared (NIR) laser light-responsive nanoplatform (manganese-doped Prussian blue@polypyrrole [MnPB@PPy]) for synergistic chemo/photothermal cancer theranostics. Materials & methods: Doxorubicin (DOX) was loaded onto the surface of polypyrrole shells. The in vitro and in vivo MRI performance and anticancer effects of these nanoparticles (NPs) were evaluated. Results: The MnPB@PPy NPs could not only generate heat under NIR laser irradiation for cancer photothermal therapy but also act as an excellent MRI contrast agent. The loaded DOX could be triggered to release by both NIR light and H2O2 to enhance synergistic therapeutic efficacy. The antitumor effects were confirmed by in vitro cellular cytotoxicity assays and in vivo treatment in a xenograft tumor model. Conclusion: The designed H2O2/NIR light-responsive MnPB@PPy-DOX NPs hold great potential for future biomedical applications.
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Doxorrubicina/uso terapéutico , Peróxido de Hidrógeno/uso terapéutico , Imagen por Resonancia Magnética/métodos , Fototerapia/métodos , Animales , Línea Celular Tumoral , Doxorrubicina/química , Femenino , Humanos , Hipertermia Inducida/métodos , Rayos Láser , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Espectroscopía de Fotoelectrones , Polímeros/química , Pirroles/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In this paper, it is proposed the directional estimation model on the overcomplete dictionary, which bridges the compressed measurements of the image blocks and the directional structures of the dictionary. In the model, it is established the analytical method to estimate the structure type of a block as either smooth, single-oriented, or multioriented. Furthermore, the structures of each type of blocks are described by the structured subdictionaries. Then based on the obtained estimations and the constrains on the sparse dictionaries, the original image will be estimated. To verify the model, the nonconvex methods are designed for compressed sensing. Specifically, the greedy pursuit-based methods are established to search the subdictionaries obtained by the model, which achieve better local structural estimation than the methods without the directional estimation. More importantly, it is proposed the nonconvex image reconstruction method with direction-guided dictionaries and evolutionary searching strategies (NR_DG), where the evolutionary searching strategies are delicately designed for each type of the blocks based on the directional estimation. By the experimental results, it is shown that the NR_DG method performs better than the available two-stage evolutionary reconstruction method.
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Imaging-guided photodynamic/photothermal (PDT/PTT) synergetic therapy is important in more precise and efficient cancer treatment. Herein, gadolinium-chelated porphyrin-protein composite based on gold nanorods (GNRs@BPP-Gd) was synthesized through a straightforward and environmentally friendly method. Based on the high longitudinal relaxivity (9.544 mM-1 s-1), GNRs@BPP-Gd can serve as a decent T1-weighted magnetic resonance imaging (MRI) probe to steer treatment. A relevant cellular uptake assay showed that GNRs@BPP-Gd could be internalized into cancer cells effectively with negligible cytotoxicity. Furthermore, MRI-guided PDT/PTT studies in vivo indicated that GNRs@BPP-Gd could efficiently take effect after intravenous injection, leading to almost complete ablation at the tumor site. A single treatment was conducted for comparison with the combined treatment, indicating that synergetic therapy greatly enhanced the anti-tumor effect.
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Magnetic resonance imaging (MRI)-guided photothermal therapy (PTT) has recently attracted tremendous attention. In this study, a paramagnetic zwitterionic amphiphilic copolymer (PZAC) was successfully prepared and utilized as a multifunctional surfactant to form micelles in diethylene glycol to coordinate with a molybdenum disulfide precursor (MoS2). Uniform spherical MoS2 nanohybrids (MoS2@PZAC) were first prepared by a microwave-assisted solvothermal process, which is simpler, easier and more efficient than hydrothermal methods or exfoliation processes. In this nanoplatform, MoS2 serves as a phototherapeutic agent possessing a high photothermal conversion efficiency (33.8%), while PZAC acts as a T1-weighted MRI contrast agent. This nanoplatform has the advantages of ultralow toxicity, prolonged circulation time and bio-imaging guided capability. The cytotoxicity assessment showed the good cytocompatibility of MoS2@PZAC. Furthermore, MoS2@PZAC could effectively kill cancer cells upon 2 W cm-2 808 nm laser irradiation for 10 min in both in vitro and in vivo experiments. This work provides a novel and efficient solution to synthesize a multifunctional and uniform theranostic agent, and the results show that the as-prepared MoS2@PZAC can be used as a promising theranostic agent for T1-weighted MRI-guided PTT of cancer cells.
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Sorafenib (SF), as an irreplaceable first-line drug to help advanced hepatocellular carcinoma (HCC) patients to prolong their lives, has already been used in clinical practice for several years. However, this treatment causes several side effects, and few alternatives to SF treatment exist. Herein, we designed NIR fluorescence imaging-guided photothermally sensitive nanoliposomes based on co-encapsulation of SF and the clinical photothermal and photodynamic therapy agent Indocyanine Green (ICG) to solve the problems of SF-based treatment in advanced HCC. As expected, in vitro and in vivo drug release studies on SF-ICG liposomes (SILs) demonstrated SF release from SILs compared with free SF at the same concentration. In addition, in vivo NIR fluorescence imaging and anti-tumor treatment using SILs have been demonstrated by using Hep3B tumor-bearing xenograft nude mice. All detailed experimental evidence suggested that biocompatibility, biotoxicity, and anti-tumor effects were improved by using SILs instead of free SF. In conclusion, our designed SILs could present a novel and suitable SF-based treatment strategy for advanced HCC therapy in the future.
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Theranostic agents with perfect properties are needed urgently for the development of imaging guided photothermal therapy (PTT). In this work, Gd-integrated polypyrrole nanotheranostic agent (PPy@BSA-Gd) was successfully built through selecting bovine serum albumin (BSA) as both stabilizers for polymerization and biomimetic mineralization in "one pot". The obtained PPy@BSA-Gd possessed high stability and excellent photothermal property. Besides, relevant cellular assays indicated that PPy@BSA-Gd had fantastic cytocompatibility which could be further internalized by cancer cells. Due to their high longitudinal relaxivity value (r1â¯=â¯10.203â¯mM-1â¯s-1), PPy@BSA-Gd could serve as considerable probe for T1-weighted magnetic resonance imaging (MRI). After tail vein injection of PPy@BSA-Gd, the MR signal of tumor section exhibited a time-dependent increase, indicating effective tumor accumulation of PPy@BSA-Gd. Notably, when exposed to 808â¯nm laser, the tumor growth of PPy@BSA-Gd treated mice could be inhibited by photothermal ablation successfully. All the results demonstrated the well-designed PPy@BSA-Gd have the potential for tumor diagnose and photothermal therapy.
Asunto(s)
Albúminas/química , Gadolinio/química , Imagen por Resonancia Magnética/métodos , Fototerapia/métodos , Polímeros/química , Pirroles/química , Nanomedicina Teranóstica/métodos , Animales , Línea Celular Tumoral , Femenino , Ratones , Ratones Endogámicos BALB CRESUMEN
The l 0 regularized problem in compressed sensing reconstruction is nonconvex with NP-hard computational complexity. Methods available for such problems fall into one of two types: greedy pursuit methods and thresholding methods, which are characterized by suboptimal fast search strategies. Nature-inspired algorithms for combinatorial optimization are famous for their efficient global search strategies and superior performance for nonconvex and nonlinear problems. In this paper, we study and propose nonconvex compressed sensing for natural images by nature-inspired optimization algorithms. We get measurements by the block-based compressed sampling and introduce an overcomplete dictionary of Ridgelet for image blocks. An atom of this dictionary is identified by the parameters of direction, scale and shift. Of them, direction parameter is important for adapting to directional regularity. So we propose a two-stage reconstruction scheme (TS_RS) of nature-inspired optimization algorithms. In the first reconstruction stage, we design a genetic algorithm for a class of image blocks to acquire the estimation of atomic combinations in all directions; and in the second reconstruction stage, we adopt clonal selection algorithm to search better atomic combinations in the sub-dictionary resulted by the first stage for each image block further on scale and shift parameters. In TS_RS, to reduce the uncertainty and instability of the reconstruction problems, we adopt novel and flexible heuristic searching strategies, which include delicately designing the initialization, operators, evaluating methods, and so on. The experimental results show the efficiency and stability of the proposed TS_RS of nature-inspired algorithms, which outperforms classic greedy and thresholding methods.