RESUMO
This work explored the changes in production decision-making trends of Chinese steel enterprises under the influence of the carbon border adjustment mechanism. First, using evolutionary game theory, the interactive mechanism of complex production strategies among steel enterprises considering the carbon border adjustment mechanism was studied, including the impact of government subsidy coefficients, additional profits and carbon tax prices on enterprise decision-making. Second, the influence of key parameters on the dynamic evolutionary process was analysed. On this basis, the empirical simulation method was used to verify the game model and the main conclusions. Finally, the sensitivity analysis of the selected parameters was determined using Matlab software. The results showed that additional profits from green investment, government subsidy coefficients, input-output values and carbon tax prices had a higher impact on the evolution of enterprise production strategies. The results of this study provide a decision-making basis for the selection of future production methods for steel enterprises.
RESUMO
Haematologic malignancies commonly arise from the bone marrow lesion, yet there are currently no effective targeted therapies against tumour cells in this location. Here we constructed a bone-marrow-targeting nanosystem, CSF@E-Hn, which is based on haematopoietic-stem-cell-derived nanovesicles adorned with gripper ligands (aPD-L1 and aNKG2D) and encapsulated with colony-stimulating factor (CSF) for the treatment of haematologic malignancies. CSF@E-Hn targets the bone marrow and, thanks to the gripper ligands, pulls together tumour cells and natural killer cells, activating the latter for specific tumour cell targeting and elimination. The therapeutic efficacy was validated in mice bearing acute myeloid leukaemia and multiple myeloma. The comprehensive assessment of the post-treatment bone marrow microenvironment revealed that the integration of CSF into a bone-marrow-targeted nanosystem promoted haematopoietic stem cell differentiation, boosted memory T cell generation and maintained bone homoeostasis, with long-term prevention of relapse. Our nanosystem represents a promising strategy for the treatment of haematologic malignancies.
RESUMO
Breast cancer, globally the most common cancer in women, presents significant challenges in treatment. Breast-conserving surgery (BCS), a less traumatic and painful alternative to radical mastectomy, not only preserves the breast's appearance but also supports postsurgical functional recovery. However, accurately identifying tumors, precisely delineating margins, and thoroughly removing metastases remain complex surgical challenges, exacerbated by the limitations of current imaging techniques, including poor tumor uptake and low signal contrast. Addressing these challenges, our study developed a series of GnRHR-targeted probes (YQGN-n) for fluorescence imaging and surgical navigation of breast cancer through a drug repositioning strategy. Notably, YQGN-7, with its high cellular affinity (Kd of 217.8 nM), demonstrates exceptional selectivity and specificity for breast cancer tumors, surpassing traditional imaging agents like ICG in tumor uptake and pharmacokinetic properties. Furthermore, YQGN-7's effectiveness in surgical navigation, both for primary breast tumors and metastases, highlights its potential as a revolutionary tool in BCS.
Assuntos
Neoplasias da Mama , Corantes Fluorescentes , Hormônio Liberador de Gonadotropina , Feminino , Humanos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Corantes Fluorescentes/química , Animais , Hormônio Liberador de Gonadotropina/química , Camundongos , Imagem Óptica , Reposicionamento de Medicamentos , Linhagem Celular Tumoral , Camundongos Nus , Receptores LHRH/metabolismo , Metástase Neoplásica , Camundongos Endogâmicos BALB CRESUMO
Colorectal cancer (CRC) is the third most prevalent malignancy and the second leading cause of cancer-related mortality worldwide. Currently, CRC staging heavily relies on invasive surgical procedures for in vitro pathological analysis, which entails long detection cycles and increases the risk of metastasis. There is an urgent need for specific biomarkers to classify adenomas and cancers, while early in vivo staging detection could potentially reduce mortality and morbidity rates. This study focused on Type IV histamine receptor (H4R), which is highly expressed only in the inflammatory stage, and Dopamine receptor D4 (DRD4), which is highly expressed in colorectal adenoma and carcinoma stages. Fluorescent targeted molecular probes H4R-Cy5 and DRD4-M were constructed respectively. The in vitro cell level proves that H4R-Cy5 only has high specificity for RAW264.7 cells, and DRD4-M only has good affinity for HT29 cells. In inflammation-HT29 subcutaneous tumors, H4R-Cy5 and DRD4-M can target inflammation and tumor lesions respectively. In addition, this study is the first to combine the two probes to explore the feasibility of in vivo non-invasive staging on CRC mouse models. The results show that H4R-Cy5 can distinguish and identify the stages of inflammation in vivo, and the DRD4-M probe can accurately identify the stages of colorectal adenoma and carcinoma in vivo. The combination of these two probes can achieve precise non-invasive staging of colitis, adenoma and carcinoma, which is a major advance in the development of accurate diagnostic methods for colorectal precancerous lesions and has important implications for the selection of treatment strategies.
Assuntos
Adenoma , Colite , Neoplasias Colorretais , Corantes Fluorescentes , Receptores de Dopamina D4 , Receptores Histamínicos H4 , Animais , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/diagnóstico , Camundongos , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Adenoma/patologia , Colite/patologia , Receptores de Dopamina D4/metabolismo , Receptores Histamínicos H4/metabolismo , Receptores Histamínicos H4/antagonistas & inibidores , Células RAW 264.7 , Progressão da Doença , Estrutura Molecular , Estadiamento de Neoplasias , Células HT29 , Imagem Óptica , Carcinoma/patologiaRESUMO
The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase linked to the proliferation, survival, invasion, and metastasis of several types of cancers, including colorectal cancer (CRC), particularly when aberrantly activated. Our study strategically designs peptides derived from interactions between c-Met and the antibody Onartuzumab. By utilizing a cyclic strategy, we achieved significantly enhanced peptide stability and affinity. Our in vitro assessments confirmed that the cyclic peptide HYNIC-cycOn exhibited a higher affinity (KD = 83.5 nM) and greater specificity compared with its linear counterpart. Through in vivo experiments, [99mTc]Tc-HYNIC-cycOn displayed exceptional tumor-targeting capabilities and minimal absorption in nontumor cells, as confirmed by single-photon emission computed tomography. Notably, the ratios of tumor to muscle and tumor to intestine, 1 h postinjection, were 4.78 ± 0.86 and 3.24 ± 0.47, respectively. Comparable ratios were observed in orthotopic CRC models, recording 4.94 ± 0.32 and 3.88 ± 0.41, respectively. In summary, [99mTc]Tc-HYNIC-cycOn shows substantial promise as a candidate for clinical applications. We show that [99mTc]Tc-HYNIC-cycOn can effectively target and visualize c-Met-expressing tumors in vivo, providing a promising approach for enhancing diagnostic accuracy when detecting c-Met in CRC.
Assuntos
Neoplasias Colorretais , Peptídeos Cíclicos , Proteínas Proto-Oncogênicas c-met , Neoplasias Colorretais/diagnóstico por imagem , Proteínas Proto-Oncogênicas c-met/metabolismo , Peptídeos Cíclicos/química , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Camundongos Nus , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Camundongos Endogâmicos BALB C , Feminino , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This paper presents the development of a fiber-optic-based fluorescence detection system for multi-scale monitoring of drug distribution in living animals. The integrated system utilized dual laser sources at the wavelengths of 488 nm and 650 nm and three photomultiplier channels for multi-color fluorescence detection. The emission spectra of fluorescent substances were tracked using the time-resolved fluorescence spectroscopy module to continuously monitor their blood kinetics. The fiber bundle, consisting of 30,000 optic filaments, was designed for wide-field mesoscopic imaging of the drug's interactions within organs. The inclusion of a gradient refractive index (GRIN) lens within the setup enabled fluorescence confocal laser scanning microscopy to visualize the drug distribution at the cellular level. The system performance was verified by imaging hepatic and renal tissues in mice using cadmium telluride quantum dots (CdTe QDs) and R3. By acquiring multi-level images and real-time data, our integrated system underscores its potential as a potent tool for drug assessment, specifically within the realms of pharmacokinetic and pharmacodynamic investigations.
RESUMO
Near-infrared (NIR) fluorescence imaging has attracted much attention in image-guided interventions with unique advantages. However, the clinical translation rate of fluorescence probes is extremely low, primarily due to weak lesion signal contrast and poor specificity. To address this dilemma, a series of small-molecule near-infrared fluorescence probes have been designed for tumor imaging. Among them, YQ-04-03 showed notable optical stability and remarkable sensitivity toward tumor targeting. Moreover, within a specific concentration and time range against oxidizing reducing agents and laser, it demonstrated better stability than ICG. The retention time of YQ-04-03 in tumors was significantly longer compared to other nonspecific uptake sites in the subjects, and its tumor-to-normal tissue ratio (TNR) outperformed ICG. Successful resection of in situ hepatocarcinoma and peritoneal carcinoma was achieved using probe imaging guidance, with the smallest visual lesion resected measuring approximately 1 mm3. Ultimately, this probe holds great potential for advancing tumor tracer.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Cirurgia Assistida por Computador , Humanos , Corantes Fluorescentes , Imagem Óptica/métodos , Cirurgia Assistida por Computador/métodosRESUMO
Despite advancements in colorectal cancer (CRC) treatment, the prognosis remains unfavorable for patients with distant liver metastasis. Fluorescence molecular imaging with specific probes is increasingly used to guide CRC surgical resection in real-time and treatment planning. Here, we demonstrate the targeted imaging capacity of an MPA-PEG4-N3-Ang II probe labeled with near-infrared (NIR) fluorescent dye targeting the angiotensin II (Ang II) type 1 receptor (AGTR1) that is significantly upregulated in CRC. MPA-PEG4-N3-Ang II was highly selective and specific to in vitro tumor cells and in vivo tumors in a mouse CRC xenograft model. The favorable ex vivo imaging and in vivo biodistribution of MPA-PEG4-N3-Ang II afforded tumor-specific accumulation with low background and >10 contrast tumor-to-colorectal values in multiple subcutaneous CRC models at 8 h following injection. Biodistribution analysis confirmed the probe's high uptake in HT29 and HCT116 orthotopic and liver metastatic models of CRC with signal-to-noise ratio (SNR) values of tumor-to-colorectal and -liver fluorescence of 5.8 ± 0.6, 5.3 ± 0.7, and 2.7 ± 0.5, 2.6 ± 0.5, respectively, enabling high-contrast intraoperative tumor visualization for surgical navigation. Given its rapid tumor targeting, precise tumor boundary delineation, durable tumor retention and docking study, MPA-PEG4-N3-Ang II is a promising high-contrast imaging agent for the clinical detection of CRC.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Sondas Moleculares , Imagem Óptica , Receptor Tipo 1 de Angiotensina , Animais , Neoplasias Colorretais/patologia , Humanos , Camundongos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Sondas Moleculares/química , Sondas Moleculares/síntese química , Sondas Moleculares/farmacocinética , Receptor Tipo 1 de Angiotensina/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Estrutura Molecular , Distribuição Tecidual , Camundongos NusRESUMO
Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs. To address this challenge, we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug, specifically 6-diazo-5-oxo-l-norleucine (DON), using a thioketal linkage (TK). This system enables imaging, chemotherapy, photodynamic therapy, and on-demand drug release upon radiation exposure. The optimized prodrug, DON-TK-BM3, incorporating cyanine dyes as the fluorophore, displayed potent reactive oxygen species release and efficient tumor cell killing. Unlike the parent drug DON, DON-TK-BM3 exhibited no toxicity toward normal cells. Moreover, DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects, including gastrointestinal toxicity, in mice. This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.
RESUMO
Hepatocellular carcinoma (HCC) is a frequent malignancy that has a high death rate and a high rate of recurrence following surgery, owing to insufficient surgical resection. Furthermore, HCC is prone to peritoneal metastasis (HCC-PM), resulting in a significant number of tiny cancer lesions, making surgical removal more challenging. As a potential imaging target, FGFR4 is highly expressed in tumors, especially in HCC, but is less expressed in the normal liver. In this study, we used computational simulation approaches to develop peptide I0 derived from FGF19, a particular ligand of FGFR4, and labeled it with the NIRF dye, MPA, for HCC detection. In surgical navigation, the TBR was 9.31 ± 1.36 and 8.57 ± 1.15 in HepG2 in situ tumor and HCC-PM models, respectively, indicating considerable tumor uptake. As a result, peptide I0 is an excellent clinical diagnostic reagent for HCC, as well as a tool for surgically resecting HCC peritoneal metastases.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Cirurgia Assistida por Computador , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos , Linhagem Celular TumoralRESUMO
PURPOSE: The data acquisition of drug metabolism analysis requires a lot of time and animal resources. However, there are often many deviations in the results of pharmacokinetic analysis. Conventional methods cannot measure the blood drug concentration data in multiple tissues at the same time, and the data is obtained by in vitro measurement, which produces time errors, in vitro data errors, and individual differences between animals. In the analysis of pharmacokinetic parameters, it will seriously affect the pass rate of clinical trials of R&D drugs and the accuracy of the dosing schedule. To the best of our knowledge, we have not found the study of in vivo blood drug concentration using multi-channel equipment. Therefore, the purpose of this paper is to build a set of multi-organ monitoring and analysis instruments for synchronously monitoring the metabolism of drugs in various tissues of small animals, so as to obtain real in vivo data of blood drug concentration in real time. PROCEDURES: Using the fluorescence properties and laser-induced fluorescence principle of drugs, we designed six channels to monitor the changes of fluorescence-labeled drugs in their main metabolic organs, a multi-channel calibration method was proposed to improve the accuracy of the time-division multiplexing, the real-time collection of drug concentration in vivo is realized, and the drug metabolism curve in vivo can be observed. RESULTS: The instrument satisfies the collection of small doses of drugs such as microgram; the detection sensitivity can reach 10 ng/ml, and can monitor and collect the drug metabolism of multiple small animal tissues at the same time, which greatly reduces the use of animals, reduces the differences between individuals, and reduces consumption cost and improve the detection efficiency of parameters, and obtain data information that is closer to the real biology. CONCLUSION: The real-time continuous monitoring and data collection of the drug metabolism in the plasma of living small animals and the important organs such as kidney, liver, and spleen were realized. The research and development of new drugs and clinical research have higher practical value.
Assuntos
Fígado , Humanos , Animais , FluorescênciaRESUMO
The erythropoietin-producing hepatoma A2 receptor (EphA2) is a tyrosine kinase, which is overexpressed in tumors while having lower expression in normal tissues, making it an excellent target for tumor diagnosis and treatment. Peptide radiotracers offer unique advantages in tumor diagnosis and therapy and have been approved for clinical use. In this study, a high-affinity EPHA2-targeted radiotracer, 99mTc-HYNIC-PEG4-EPH-3, was developed and designed based on linear peptides. 99mTc-HYNIC-PEG4-EPH-3 exhibited superior water solubility and stability. And 99mTc-HYNIC-PEG4-EPH-3 could specifically target EphA2-expressing tumors, particularly with a tumor-to-non-target (T/NT) ratio >4.7 excluding kidneys. As a result of excellent biodistribution and tumor targeting capability of 99mTc-HYNIC-PEG4-EPH-3, it might be a promising candidate drug for clinical diagnosis of EphA2-overexpressing tumors.
Assuntos
Peptídeos , Tomografia Computadorizada de Emissão de Fóton Único , Linhagem Celular Tumoral , Peptídeos/metabolismo , Proteínas Tirosina Quinases/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
Histone deacetylases (HDACs) are a class of epigenetic enzymes that are closely related to tumorigenesis and suppress the expression of tumor suppressor genes. Whereas the HDACs inhibitors can release DNA into the cytoplasm and trigger innate immunity. However, the high density of chromatin limits DNA damage and release. In this study, suitable nanosized CycNHOH NPs (150 nm) and CypNHOH NPs (85 nm) efficiently accumulate at the tumor site due to the enhanced permeability and retention (EPR) effect. In addition, robust single-linear oxygen generation and good photothermal conversion efficiency under NIR laser irradiation accelerated the DNA damage process. By effectively initiating immune cell death, CypNHOH NPs activated both innate and adaptive immunity by maturing dendritic cells, infiltrating tumors with natural killer cells, and activating cytotoxic T lymphocytes, which offer a fresh perspective for the development of photo-immunotherapy.
Assuntos
Epigênese Genética , Imunoterapia , Raios Infravermelhos , Nanopartículas , Neoplasias , Imunoterapia/métodos , Epigênese Genética/efeitos dos fármacos , Nanopartículas/química , Animais , Neoplasias/terapia , Fototerapia/métodos , Humanos , Morte Celular/efeitos dos fármacos , Camundongos , Linhagem Celular TumoralRESUMO
Glycosylation of proteins is an essential feature of extracellular vesicles (EVs). However, while the glycosylation heterogeneity focusing on specific EV subtypes and proteins will better reveal the functions of EVs, the determination of their specific glycans remains highly challenging. Herein, we report a method of protein-specific glycan recognition using DNA-encoded affinity ligands to label proteins and glycans. Manipulating the sequences of DNA tags and employing a DNA logic gate to trigger a spatial proximity-induced DNA replacement reaction enabled the release of glycan-representative DNA strands for the quantitative detection of multiple glycoforms. After size-dependent isolation of EV subgroups and decoding of three typical glycoforms on the epithelial growth factor receptor (EGFR), we found that the different EV subgroups of the EGFR glycoprotein varied with respect to glycan types and abundance. The distinctive glycoforms of the EV subgroups could interfere with the EGFR-related EV functions. Furthermore, the sialylation of small EVs possessed the potential as a cancer biomarker. This method provides new insights into the role of protein-specific glycoforms in EV functions.
Assuntos
Vesículas Extracelulares , Glicoproteínas , Glicosilação , Glicoproteínas/metabolismo , Polissacarídeos/metabolismo , Vesículas Extracelulares/metabolismo , Receptores ErbB/metabolismoRESUMO
This paper develops a process-level carbon emission calculation model for iron and steel enterprises through the carbon emission mechanism of the whole production process. The relationship between material, energy and carbon flows is considered and combined. The carbon emissions of enterprises are divided into industrial emissions and combustion emissions, and the indirect emissions of purchased intermediate products and electricity purchased from the grid are also considered. Carbon emission targets and corresponding emission reduction strategies are formulated at the enterprise and process levels. For example, consider an iron and steel enterprise. The different types of carbon emissions are accounted for, with their reduction potential analysed based on the carbon material flow analysis method. The results show that the carbon emission of this enterprise is 1930.87 kgCO2/t (CS), and the combustion emission caused by energy flow is the main contributor to the enterprise's carbon emission, accounting for 57.02% of the total emission. The carbon emission during iron-making accounts for 69.06% of the entire process and is critical in any carbon emission reduction of the enterprise. Among them, process emissions from the blast furnace process account for 81.79% of industrial emissions of the whole process, which is 356.51 kgCO2/t (CS), and is the main challenge of low carbon transformation in this extensive process. This study highlights that increasing the integrated steel-making scrap ratio and electric furnace steel production can break through the existing emission reduction limits. A 65.02% carbon emission reduction can be achieved, and using green electricity can reduce emissions by 24.15%. Reasonably determining the amount of purchased coke and paying attention to the high-value recycling of byproduct gas resources in the plant are essential to achieve low-carbon economic development of steel.
Assuntos
Dióxido de Carbono , Aço , Dióxido de Carbono/análise , Aço/análise , Carbono/análise , Ferro/análise , Reciclagem , ChinaRESUMO
Despite advancements in pancreatic cancer treatment, it remains one of the most lethal malignancies with extremely poor diagnosis and prognosis. Herein, we demonstrated the efficiency of a novel peptide GB-6 labeled with a near-infrared (NIR) fluorescent dye 3H-indolium, 2-[2-[2-[(2-carboxyethyl)thio]-3-[2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)-2H-indol-2-ylidene]ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)-, inner salt (MPA) and radionuclide technetium-99m (99mTc) as targeting probes using the gastrin-releasing peptide receptor (GRPR) that is overexpressed in pancreatic cancer as the target. A short linear peptide with excellent in vivo stability was identified, and its radiotracer [99mTc]Tc-HYNIC-PEG4-GB-6 and the NIR probe MPA-PEG4-GB-6 exhibited selective and specific uptake by tumors in an SW1990 pancreatic cancer xenograft mouse model. The favorable biodistribution of the tracer [99mTc]Tc-HYNIC-PEG4-GB-6 in vivo afforded tumor-specific accumulation with high tumor-to-muscle and -bone contrasts and renal body clearance at 1 h after injection. The biodistribution analysis revealed that the tumor-to-pancreas and -intestine fluorescence signal ratios were 5.2 ± 0.3 and 6.3 ± 1.5, respectively, in the SW1990 subcutaneous xenograft model. Furthermore, the high signal accumulation in the orthotopic pancreatic and liver metastasis tumor models with tumor-to-pancreas and -liver fluorescence signal ratios of 7.66 ± 0.48 and 3.94 ± 0.47, respectively, enabled clear tumor visualization for intraoperative navigation. The rapid tumor targeting, precise tumor boundary delineation, chemical versatility, and high potency of the novel GB-6 peptide established it as a high-contrast imaging probe for the clinical detection of GRPR, with compelling additional potential in molecular-targeted therapy.
Assuntos
Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Receptores da Bombesina , Distribuição Tecidual , Linhagem Celular Tumoral , Peptídeos/química , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Modelos Animais de Doenças , Imagem Molecular , Neoplasias PancreáticasRESUMO
A challenge in developing proteolysis targeting chimeras (PROTACs) is the establishment of a universal platform applicable in multiple scenarios for precise degradation of proteins of interest (POIs). Inspired by the addressability, programmability, and rigidity of DNA frameworks, we develop covalent DNA framework-based PROTACs (DbTACs), which can be synthesized in high-throughput via facile bioorthogonal chemistry and self-assembly. DNA tetrahedra are employed as templates and the spatial position of each atom is defined. Thus, by precisely locating ligands of POI and E3 ligase on the templates, ligand spacings can be controllably manipulated from 8 Å to 57 Å. We show that DbTACs with the optimal linker length between ligands achieve higher degradation rates and enhanced binding affinity. Bispecific DbTACs (bis-DbTACs) with trivalent ligand assembly enable multi-target depletion while maintaining highly selective degradation of protein subtypes. When employing various types of warheads (small molecules, antibodies, and DNA motifs), DbTACs exhibit robust efficacy in degrading diverse targets, including protein kinases and transcription factors located in different cellular compartments. Overall, utilizing modular DNA frameworks to conjugate substrates offers a universal platform that not only provides insight into general degrader design principles but also presents a promising strategy for guiding drug discovery.
Assuntos
Fatores de Transcrição , Ubiquitina-Proteína Ligases , Proteólise , Ligantes , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Fatores de Transcrição/metabolismoRESUMO
Currently colorectal cancer (CRC) staging (colitis, adenoma, and carcinoma) mainly relies on ex vivo pathologic analysis requiring an invasive surgical process with limited sample collection and increased metastatic risk. Thus, in vivo noninvasive pathological diagnosis is extremely demanded. By verifying the samples of clinical patients and CRC mouse models, it was found that vascular endothelial growth factor receptor 2 (VEGFR2) was barely expressed in the colitis stage and only appeared in adenoma and carcinoma stages with obvious elevation, while prostaglandin E receptor 4 (PTGER4) could be observed from colitis to adenoma and carcinoma stages with a gradient increase of expression. VEGFR2 and PTGER4 were further chosen as key biomarkers for molecular pathological diagnosis in vivo and corresponding molecular probes were constructed. The feasibility of in vivo noninvasive CRC staging by concurrent microimaging of dual biomarkers using confocal laser endoscopy (CLE) was verified in CRC mouse models and further confirmed by ex vivo pathological analysis. In vivo CLE imaging exhibited the correlation of severe colonic crypt structural alteration with a higher biomarker expression in adenoma and carcinoma stages. This strategy shows promise in benefiting patients undergoing CRC progression with in-time, noninvasive, and precise pathological staging, thus providing valuable guidance for selecting therapeutic strategies.
Assuntos
Adenoma , Carcinoma , Colite , Neoplasias Colorretais , Animais , Camundongos , Fator A de Crescimento do Endotélio Vascular , Neoplasias Colorretais/diagnóstico , Colite/complicações , Colite/diagnóstico por imagem , Colite/patologia , Carcinoma/patologia , Biomarcadores Tumorais , Estadiamento de Neoplasias , Adenoma/complicações , Adenoma/diagnóstico por imagem , Adenoma/metabolismoRESUMO
The 5-year survival rate for pancreatic adenocarcinoma (PA) is less than 10%, making it one of the most lethal forms of cancer. Early-stage diagnosis and resection of the incipient lesions could increase the 4-year survival rate of PA up to 78%. Platelet-derived growth factor receptor ß (PDGFRß), an oncogenic key regulator for migration, proliferation and angiogenesis of cancer cells, has been proved to be aberrantly expressed in the majority of PA. Herein, by amino acid substitution strategy and surface plasmon resonance (SPR) analysis, we designed a novel PDGFRß-targeting peptide (YQGX-10) with high affinity (Kd = 227.7 nM) and coupled it with a near-infrared fluorescent (NIRF) dye MPA for precisely detection of PA. Great binding affinity and specificity were displayed in a series of in vitro assays. NIRF imaging experiments demonstrated that the synthesized probe could be highly accumulated in xenograft and orthotopic BxPC-3 tumors and provide favorable tumor contrast in the mice, offering a potential novel approach for the early diagnosis of PA. Moreover, YQGX-10 could visualize tumor boundaries and minor lesions in BxPC-3 xenograft mice, shedding a new light on NIRF-guided tumor resection of PA. In addition, we successfully constructed the radioactive probe 99mTc-HYNIC-YQGX-10 for the diagnosis of PA with high specificity and sensitivity. In summary, the probe warrants further exploration for clinical translation in the early diagnosis and NIRF-guided surgery of PA.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Adenocarcinoma/diagnóstico por imagem , Linhagem Celular Tumoral , Diagnóstico por Imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Neoplasias PancreáticasRESUMO
The in situ lactate oxidase (LOx) catalysis is highly efficient in reducing oxygen to H2O2 due to the abundant lactate substrate in the hypoxia tumor microenvironment. Dynamic therapy, including chemodynamic therapy (CDT), photodynamic therapy (PDT), and enzyme dynamic therapy (EDT), could generate reactive oxygen species (ROS) including ·OH and 1O2 through the disproportionate or cascade biocatalytic reaction of H2O2 in the tumor region. Here, we demonstrate a ROS-based tumor therapy by integrating LOx and the antiglycolytic drug Mito-LND into Fe3O4/g-C3N4 nanoparticles coated with CaCO3 (denoted as FGLMC). The LOx can catalyze endogenous lactate to produce H2O2, which decomposes cascades into ·OH and 1O2 through Fenton reaction-induced CDT and photo-triggered PDT. Meanwhile, the released Mito-LND contributes to metabolic therapy by cutting off the source of lactate and increasing ROS generation in mitochondria for further improvement in CDT and PDT. The results showed that the FGLMC nanoplatform can multifacetedly elevate ROS generation and cause fatal damage to cancer cells, leading to effective cancer suppression. This multidirectional ROS regulation strategy has therapeutic potential for different types of tumors.