RESUMEN
Background: Mangiferin (MA), a bioactive C-glucosyl xanthone with a wide range of interesting therapeutic properties, has recently attracted considerable attention. However, its application in biomedicine is limited by poor solubility and bioavailability. Carbon dots (CDs), novel nanomaterials, have immense promise as carriers for improving the biopharmaceutical properties of active components because of their outstanding characteristics. Methods: In this study, a novel water-soluble carbon dot (MC-CDs) was prepared for the first time from an aqueous extract of Moutan Cortex Carbonisata, and characterized by various spectroscopies, zeta potential and high-resolution transmission electron microscopy (HRTEM). The toxicity effect was investigated using the CCK-8 assay in vitro. In addition, the potential of MC-CDs as carriers for improving the pharmacokinetic parameters was evaluated in vivo. Results: The results indicated that MC-CDs with a uniform spherical particle size of 1-5 nm were successfully prepared, which significantly increased the solubility of MA in water. The MC-CDs exhibited low toxicity in HT-22 cells. Most importantly, the MC-CDs effectively affected the pharmacokinetic parameters of MA in normal rats. UPLC-MS analysis indicated that the area under the maximum blood concentration of MA from mangiferin-MC-CDs (MA-MC-CDs) was 1.6-fold higher than that from the MA suspension liquid (MA control) after oral administration at a dose of 20 mg/kg. Conclusion: Moutan Cortex-derived novel CDs exhibited superior performance in improving the solubility and bioavailability of MA. This study not only opens new possibilities for the future clinical application of MA but also provides evidence for the development of green biological carbon dots as a drug delivery system to improve the biopharmaceutical properties of insoluble drugs.
Asunto(s)
Disponibilidad Biológica , Carbono , Paeonia , Tamaño de la Partícula , Ratas Sprague-Dawley , Solubilidad , Xantonas , Xantonas/farmacocinética , Xantonas/química , Xantonas/administración & dosificación , Animales , Carbono/química , Carbono/farmacocinética , Masculino , Ratas , Paeonia/química , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/administración & dosificación , Puntos Cuánticos/química , Puntos Cuánticos/toxicidad , Línea Celular , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Supervivencia Celular/efectos de los fármacosRESUMEN
Fluorescent carbon dots (CDs) are potential tools for the labeling of cells with many advantages such as photostability, multicolor emission, small size, rapid uptake, biocompatibility, and easy preparation. Affinity towards organelles can be influenced by the surface properties of CDs which affect the interaction with the cell and cytoplasmic distribution. Organelle targeting by carbon dots is promising for anticancer treatment; thus, intracellular trafficking and cytotoxicity of cationic CDs was investigated. Based on our previous study, we used quaternized carbon dots (QCDs) for treatment and monitoring the behavior of two human cancer cell MCF-7 and HeLa lines. We found similarities between human cancer cells and mouse fibroblasts in the case of QCDs uptake. Time lapse microscopy of QCDs-labeled MCF-7 cells showed that cells are dying during the first two hours, faster at lower doses than at higher ones. QCDs at a concentration of 100 µg/mL entered into the nucleus before cellular death; however, at a dose of 200 µg/mL, blebbing of the cellular membrane occurred, with a subsequent penetration of QCDs into the nuclear area. In the case of HeLa cells, the dose-depended effect did not happen; however, the labeled cells were also dying in mitosis and genotoxicity occurred nearly at all doses. Moreover, contrasted intracellular compartments, probably mitochondria, were obvious after 24 h incubation with 100 µg/mL of QCDs. The levels of reactive oxygen species (ROS) slightly increased after 24 h, depending on the concentration, thus the genotoxicity was likely evoked by the nanomaterial. A decrease in viability did not reach IC 50 as the DNA damage was probably partly repaired in the prolonged G0/G1 phase of the cell cycle. Thus, the defects in the G2/M phase may have allowed a damaged cell to enter mitosis and undergo apoptosis. The anticancer effect in both cell lines was manifested mainly through genotoxicity.
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Carbono/farmacocinética , Fibroblastos/citología , Neoplasias/metabolismo , Puntos Cuánticos/química , Especies Reactivas de Oxígeno/metabolismo , Imagen de Lapso de Tiempo/métodos , Animales , Transporte Biológico , Carbono/química , Carbono/farmacología , Línea Celular , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HeLa , Humanos , Células MCF-7 , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Imagen ÓpticaRESUMEN
We disclose for the first time a facile synthetic methodology for the preparation of multicolor carbon dots (CDs) from a single source barring any chromatographic separations. This was achieved via sequential intraparticle cross-linking of surface abundant carboxylic acid groups on the CDs synthesized from a precursor to control their photoluminescence (PL) spectra as well as affect their degree of cellular internalization in cancer cells. The change in PL spectra with sequential cross-linking was projected by theoretical density functional theory (DFT) studies and validated by multiple characterization tools such as X-ray photoelectron spectroscopy (XPS), PL spectroscopy, ninhydrin assay, etc. The variation in cellular internalization of these cross-linked CDs was demonstrated using inhibitor assays, confocal microscopy, and flow cytometry. We supplemented our findings with high-resolution dark-field imaging to visualize and confirm the colocalization of these CDs into distinct intracellular compartments. Finally, to prove the surface-state controlled PL mechanisms of these cross-linked CDs, we fabricated a triple-channel sensor array for the identification of different analytes including metal ions and biologically relevant proteins.
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Materiales Biocompatibles/farmacocinética , Carbono/farmacocinética , Reactivos de Enlaces Cruzados/farmacocinética , Colorantes Fluorescentes/farmacocinética , Luminiscencia , Puntos Cuánticos/química , Materiales Biocompatibles/química , Carbono/química , Línea Celular Tumoral , Reactivos de Enlaces Cruzados/química , Teoría Funcional de la Densidad , Colorantes Fluorescentes/química , Humanos , Ensayo de Materiales , Estructura Molecular , Imagen Óptica , Procesos Fotoquímicos , Espectroscopía de Fotoelectrones , Propiedades de SuperficieRESUMEN
Current treatments for osteoporosis and other bone degenerative diseases predominately rely on preventing further bone erosion rather than restoring bone mass, as the latter treatments can unintentionally trigger cancer development by undiscriminatingly promoting cell proliferation. One approach to circumvent this problem is through the development of novel chemical carriers to deliver drug agents specifically to bones. We have recently shown that carbon nanodots (C-dots) synthesized from carbon nanopowder can bind with high affinity and specificity to developing bones in the larval zebrafish. Larval bones, however, are physiologically different from adult bones in their growth, repair, and regeneration properties. Here we report that C-dots can bind to adult zebrafish bones and that this binding is highly specific to areas of appositional growth. C-dots deposition occurred within 30 minutes after delivery and was highly selective, with bones undergoing regeneration and repair showing higher levels of C-dots deposition than bones undergoing normal homeostatic turnover. Importantly, C-dots deposition did not interfere with bone regeneration or the animal's health. Together, our results establish C-dots as a potential novel vehicle for the targeted delivery of drugs to treat adult bone disease.
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Carbono/farmacocinética , Portadores de Fármacos/farmacocinética , Nanopartículas/química , Animales , Regeneración Ósea/fisiología , Huesos/metabolismo , Carbono/química , Portadores de Fármacos/química , Pez CebraRESUMEN
Ulcerative colitis (UC) is a modern refractory disease with steadily increasing incidence worldwide that urgently requires effective and safe therapies. Therapeutic peptides delivered using nanocarriers have shown promising developments for the treatment of UC. We developed a novel colon-accumulating oral drug delivery nanoplatform consisting of Musca domestica cecropin (MDC) and mesoporous carbon nanoparticles (MCNs) and investigated its effects and mechanism of action for the treatment of UC. Methods: An optimized one-step soft templating method was developed to synthesize MCNs, into which MDC was loaded to fabricate MDC@MCNs. MCNs and MDC@MCNs were characterized by BET, XRD, and TEM. MDC and MDC@MCNs resistance to trypsin degradation was measured through Oxford cup antibacterial experiments using Salmonella typhimurium as the indicator. Uptake of MDC and MDC@MCNs by NCM460 cells was observed by fluorescence microscopy. The biocompatibility of MDC, MCNs, and MDC@MCNs was evaluated in three cell lines (NCM460, L02, and NIH3T3) and C57BL/6 mice. Dextran sulphate sodium was used to establish models of NCM460 cell injury and UC in mice. MTT assay, flow cytometry, and mitochondrial membrane potential assay were applied to determine the effects of MDC@MCNs on NCM460 cells injury. Additionally, a variety of biological methods such as H&E staining, TEM, ELISA, qPCR, Western blotting, and 16s rDNA sequencing were performed to explore the effects and underlying mechanism of MDC@MCN on UC in vivo. Colonic adhesion of MCNs was compared in normal and UC mice. The oral biodistributions of MDC and MDC@MCNs in the gastrointestinal tract of mice were also determined. Results: MDC@MCNs were successfully developed and exhibited excellent ability to resist destruction by trypsin and were taken up by NCM460 cells more readily than MDC. In vitro studies showed that MDC@MCNs better inhibited DSS-induced NCM460 cells damage with lower toxicity to L02 and NIH3T3 cells compared with MDC. In vivo results indicated that MDC@MCNs have good biocompatibility and significantly improved colonic injury in UC mice by effectively inhibiting inflammation and oxidative stress, maintaining colonic tight junctions, and regulating intestinal flora. Moreover, MDC@MCNs were strongly retained in the intestines, which was attributed to intestinal adhesion and aggregation of MCNs, serving as one of the important reasons for its enhanced efficacy after oral administration compared with MDC. Conclusion: MDC@MCNs alleviated DSS-induced UC by ameliorating colonic epithelial cells damage, inhibiting inflammation and oxidative stress, enhancing colonic tight junctions, and regulating intestinal flora. This colon-accumulating oral drug delivery nanoplatform may provide a novel and precise therapeutic strategy for UC.
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Antiinflamatorios/farmacología , Cecropinas/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/administración & dosificación , Administración Oral , Animales , Antiinflamatorios/farmacocinética , Carbono/química , Carbono/farmacocinética , Cecropinas/farmacocinética , Línea Celular , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Modelos Animales de Enfermedad , Femenino , Moscas Domésticas/química , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Nanopartículas/metabolismo , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/crecimiento & desarrollo , Dodecil Sulfato de Sodio/administración & dosificaciónRESUMEN
Boronic acids have been successfully employed as inhibitors of hydrolytic enzymes. Typically, an enzymatic nucleophile catalyzing hydrolysis adds to the electrophilic boron atom forming a tetrahedral species that mimics the intermediate(s)/transition state(s) for the hydrolysis reaction. We show that para-substituted phenylboronic acids (PBAs) are potent competitive inhibitors of mandelate racemase (MR), an enzyme that catalyzes a 1,1-proton transfer rather than a hydrolysis reaction. The Ki value for PBA was 1.8 ± 0.1 µM, and p-Cl-PBA exhibited the most potent inhibition (Ki = 81 ± 4 nM), exceeding the binding affinity of the substrate by â¼4 orders of magnitude. Isothermal titration calorimetric studies with the wild-type, K166M, and H297N MR variants indicated that, of the two Brønsted acid-base catalysts Lys 166 and His 297, the former made the greater contribution to inhibitor binding. The X-ray crystal structure of the MR·PBA complex revealed the presence of multiple H-bonds between the boronic acid hydroxyl groups and the side chains of active site residues, as well as formation of a His 297 Nε2-B dative bond. The dramatic upfield change in chemical shift of 27.2 ppm in the solution-phase 11B nuclear magnetic resonance spectrum accompanying binding of PBA by MR was consistent with an sp3-hybridized boron, which was also supported by density-functional theory calculations. These unprecedented findings suggest that, beyond substituting boron at carbon centers participating in hydrolysis reactions, substitution of boron at the acidic carbon center of a substrate furnishes a new approach for generating inhibitors of enzymes catalyzing the deprotonation of carbon acid substrates.
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Boro/farmacología , Ácidos Borónicos/farmacología , Racemasas y Epimerasas/antagonistas & inhibidores , Sustitución de Aminoácidos , Sitios de Unión/efectos de los fármacos , Boro/química , Ácidos Borónicos/farmacocinética , Carbono/química , Carbono/farmacocinética , Carbono/farmacología , Ácido Carbónico/química , Ácido Carbónico/farmacología , Catálisis/efectos de los fármacos , Dominio Catalítico/efectos de los fármacos , Cinética , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Racemasas y Epimerasas/genética , Racemasas y Epimerasas/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The alpine meadow is highly sensitive to global climate change due to its high elevation and cold environment. To understand the dynamics of ecosystem carbon cycling, CO2 fluxes were measured over the Suli alpine meadow, which is located at the upper reach of the Shule River basin at the northeastern edge of the Qinghai-Tibet Plateau (QTP), China. The measurements were taken from October 2008 to September 2012 using the eddy covariance technique. Obvious seasonal and inter-annual variations were observed in the CO2 flux. The annual net carbon exchange ranged from -195.28 g·CO2·m-2 to -118.49 g·CO2·m-2, indicating that the alpine meadow ecosystem in this area played a role as a carbon sink. The inter-annual variability in the net carbon exchange was significantly related to the length of the growing season for the alpine meadow. The results showed that the months of June, July and August were the strongest CO2 absorption periods, while April, May and October were the strongest CO2 release periods. The annual net exchanges of CO2 in the four years were -118.49 g·CO2·m-2, -130.75 g·CO2·m-2, -195.83 g·CO2·m-2 and -160.65 g·CO2·m-2, and the average value was -151.43 g·CO2·m-2. On a seasonal scale, the monthly CO2 fluxes were largely controlled by temperature. At the annual scale, there was no dominant factor that influenced the interannual variations in the CO2 flux.
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Ciclo del Carbono/fisiología , Carbono/farmacocinética , Cambio Climático , Pradera , Dióxido de Carbono/análisis , Secuestro de Carbono/fisiología , China , Ecosistema , Humanos , Ríos/química , Estaciones del Año , Suelo/química , Temperatura , Tibet , Factores de TiempoRESUMEN
OBJECTIVES: Carbon dots (CDs), as a fascinating class of fluorescent carbon nanomaterials, have been proven to be powerful tools in the field of bioimaging and biosensing due to their small size, suitable photostability and favourable biocompatibility. However, the cellular uptake of free CDs lacks selectivity and the same negative charges as cell membranes may cause inefficient cell internalization. In this study, an efficient detecting and targeting nanosystem was developed based on the DNA aptamer AS1411 modified CDs with polyethyleneimine (PEI) as connecting bridge. MATERIALS AND METHODS: Hydrothermally prepared CDs were assembled with positive-charged PEI, followed by conjugation with AS1411 through electrostatic interaction to form CDs-PEI-AS1411 nanocomplexes. The CDs, CDs-PEI and CDs-PEI-AS1411 were characterized by transmission electron microscopy (TEM), fourier transform infrared (FTIR) spectra, UV-vis spectra, zeta potential measurements and capillary electrophoresis characterizations. The cytotoxicity investigation of the CDs-PEI-AS1411 and CDs-PEI in both MCF-7 and L929 cells was carried out by the CCK-8 assay. The cellular uptake of the CDs-PEI-AS1411 was studied with confocal microscopy and flow cytometry. RESULTS: The as-prepared nanosystem possessed good photostability and no obvious cytotoxicity. On the basis of the confocal laser scanning microscope observation and the flow cytometry studies, the cellular uptake of CDs-PEI-AS1411 nanosystem in MCF-7 cells was significantly higher than that of L929 cells, which revealed the highly selective detection ability of nucleolin-positive cells. CONCLUSIONS: The results of this study indicated that the CDs-PEI-AS1411 nanosystem had a potential value in cancer cell targeted imaging.
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Aptámeros de Nucleótidos , Sistemas de Liberación de Medicamentos , Citometría de Flujo , Neoplasias , Oligodesoxirribonucleótidos , Puntos Cuánticos/química , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/farmacocinética , Aptámeros de Nucleótidos/farmacología , Carbono/química , Carbono/farmacocinética , Carbono/farmacología , Humanos , Células MCF-7 , Microscopía Confocal , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/farmacocinética , Oligodesoxirribonucleótidos/farmacología , Polietileneimina/química , Polietileneimina/farmacocinética , Polietileneimina/farmacologíaRESUMEN
p-Nitrophenol (p-NP) pollutants are widely present in soil and aquatic environments and can seriously impair the health of living beings. Hence, a rapid, sensitive, and selective method for p-NP detection is urgently needed. Herein, for the first time, we successfully synthesized fluorescent carbon dots (CDs) from Bacillus cereus (BC) via a one-step hydrothermal process. The obtained CDs-BC can be applied as a rapid, highly selective, and sensitive sensor for p-NP detection. The fluorescence quenching efficiency of the CD-BC sensor exhibited excellent linear responses with p-NP concentrations at both 0.3-6.5 µM and 6.5-30 µM, with a detection limit of 0.11 µM. The mechanism of p-NP detection is based on the inner filter effect (IFE). Preliminary bacteria, cell, and animal studies showed that the as-prepared CDs-BC possess high photostability, excellent biocompatibility, low or no biotoxicity, and multicolor fluorescence emission properties; furthermore, they can be rapidly excreted from the body of mice, which suggests their potential for applications in the biomedical field.
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Bacillus cereus/metabolismo , Carbono/química , Carbono/metabolismo , Límite de Detección , Microscopía Confocal/métodos , Nitrofenoles/análisis , Puntos Cuánticos/química , Animales , Carbono/farmacocinética , Colorantes Fluorescentes/química , Colorantes Fluorescentes/metabolismo , Colorantes Fluorescentes/farmacocinética , Células HeLa , Humanos , Ratones , Nitrofenoles/química , Serratia marcescens/metabolismo , Distribución TisularRESUMEN
Carbon dots (CDots) for their excellent optical and other properties have been widely pursued for potential biomedical applications, in which a more comprehensive understanding on the cellular behaviors and mechanisms of CDots is required. For such a purpose, two kinds of CDots with surface passivation by 3-ethoxypropylamine (EPA-CDots) and oligomeric polyethylenimine (PEI-CDots) were selected for evaluations on their uptakes by human cervical carcinoma HeLa cells at three cell cycle phases (G0/G1, S and G2/M), and on their different internalization pathways and translocations in cells. The results show that HeLa cells could internalize both CDots by different pathways, with an overall slightly higher internalization efficiency for PEI-CDots. The presence of serum in culture media could have major effects, significantly enhancing the cellular uptake of EPA-CDots, yet markedly inhibiting that of PEI-CDots. The HeLa cells at different cell cycle phases have different behaviors in taking up the CDots, which are also affected by the different dot surface moieties and serum in culture media. Mechanistic implications of the results and the opportunities associated with an improved understanding on the cellular behaviors of CDots for potentially the manipulation and control of their cellular uptakes and translocations are discussed.
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Carbono/farmacocinética , Puntos Cuánticos/química , Carbono/química , Supervivencia Celular/efectos de los fármacos , Células HeLa , Humanos , Tamaño de la Partícula , Polietileneimina/química , Polietileneimina/farmacocinética , Propilaminas/química , Propilaminas/farmacocinética , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
A green and simple process for preparing the polyethylene glycol passivated fluorescent carbon dots (CDs-PEG) have been studied by a microwave pyrolysis method, using gelatin and PEG as starting materials. This method is very effective for development of carbon-based quantum dots from gelatin with high quantum yield (QY). The synthesized CDs-PEG were found to emit blue photoluminescence (PL) with a maximum QY of 34%. At the following research, we investigated the effect of the presence of PEG on PL intensity, and the result showed that CDs-PEG becomes stronger PL properties than pure CDs from gelatin. The synthesized CDs-PEG were characterized by FTIR, TEM, UV-vis, PL, zeta potential and XRD analyses. The anticancer performance of developed CDs-PEG was evaluated by in vitro tests such as MTT assay and fluorescence microscopy analyses. The examination of CDs-PEG as an anti-cancer drug nanocarrier for methotrexate (MTX) illustrated a better antitumor efficacy than free MTX due to its enhanced nuclear delivery in vitro, which resulting in highly effective tumour growth inhibition and improving targeted cancer therapy in clinical medicine.
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Carbono , Portadores de Fármacos , Gelatina/química , Metotrexato , Microondas , Polietilenglicoles/química , Puntos Cuánticos , Carbono/química , Carbono/farmacocinética , Carbono/farmacología , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Metotrexato/química , Metotrexato/farmacocinética , Metotrexato/farmacología , Puntos Cuánticos/química , Puntos Cuánticos/uso terapéuticoRESUMEN
Nanoparticle-based theranostics combines tumor imaging and cancer therapy in one platform, but the synthesis of theranostic agents is impeded by chemical groups on the surface and the size and morphology of the components. Strategies to construct a multifunctional platform for bioimaging and photothermal therapy (PTT) are urgently needed. A new upconversion-magnetic agent (FeCUPs) based on hollow carbon spheres, which is both a photothermal agent and a dual carrier of luminescent and magnetic nanoparticles, provides an effective approach for tumor elimination. Methods: The morphology of FeCUPs was characterized for the construction and size adjustment of the theranostic agent using transmission electron microscopy, high-resolution transmission electron microscopy, energy dispersive spectroscopy and high angle annular dark field scanning transmission electron microscopy. The distribution of FeCUPs was tracked under in-situ upconversion luminescence (UCL) imaging and magnetic resonance imaging (MRI) in vivo. Photothermal therapy was carried out on tumor-bearing mice, after which the toxicity of PTT was evaluated by a blood biochemistry test and histological section analysis. Results: Stable and uniform loading of luminescent nanocomposites on three-dimensional carbon materials is reported for the first time. Based on the mechanism of synthesis, the size of the hybrid particles was adjusted from micrometers to nanometers. External magnetic field-enhanced photothermal therapy with multi-model imaging was accomplished using FeCUPs. Moreover, no cancer recurrence was found during 14 days of recovery without PTT. Conclusions: Hollow carbon spheres, photothermal agents loaded with upconversion nanoparticles inside and magnetic nanoparticles outside were prepared for photothermal therapy. The aggregation of FeCUPs in tumors by the local magnetic field was verified by MRI and UCL imaging, and PTT was enhanced.
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Diagnóstico por Imagen/métodos , Hipertermia Inducida/métodos , Nanopartículas/administración & dosificación , Neoplasias/diagnóstico , Neoplasias/terapia , Fototerapia/métodos , Nanomedicina Teranóstica/métodos , Animales , Carbono/administración & dosificación , Carbono/farmacocinética , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Mediciones Luminiscentes , Imagen por Resonancia Magnética , Magnetismo , Ratones , Nanopartículas/química , Nanopartículas/ultraestructuraRESUMEN
Carbon dots (CDs) with low biotoxicity, high photostability, and well-controlled size are highly desirable imaging agents for optical bioimaging. However, most of the CDs triggered by ultraviolet/blue light present visible/first near-infrared emissions shorter than 820 nm, impairing their imaging applications in vivo by low penetration depth. Hence, developing novel CD-based materials with second near-infrared (NIR-II) emission located in 1000-1700 nm region is an urgent task. Here, a novel NIR-II-emitting CD-based nanoprobe triggered by 808 nm laser is developed. The designed CDs with 900-1200 nm luminescence possess high quantum yield (QY-0.4%) and high biocompatibility, which have proven to be effective probes for in vivo NIR-II bioimaging. Notably, nearly 65% CDs are excreted from mouse urine within 6 h, demonstrating the rapid renal clearance of CDs. Furthermore, the designed CDs also exhibit high photothermal efficiency (30.6%), making them ideal materials for thermal ablation of cancer. Our findings pave the way of designing a multifunctional CD-based theranostic platform for simultaneously integrating the advanced NIR-II bioimaging and photothermal therapy of cancer.
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Carbono/metabolismo , Rayos Infrarrojos , Riñón , Imagen Óptica/métodos , Puntos Cuánticos/metabolismo , Nanomedicina Teranóstica/métodos , Animales , Carbono/química , Carbono/farmacocinética , Células HeLa , Humanos , Riñón/diagnóstico por imagen , Riñón/metabolismo , Ratones , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Sondas Moleculares/farmacocinética , Fantasmas de Imagen , Fototerapia , Puntos Cuánticos/química , Espectroscopía Infrarroja CortaRESUMEN
The anterograde neuroanatomical tracing technique plays a crucial role in studying and charting the complex interconnections of the nervous system. But there are several major limitations for traditional neural tracers, such as complex immunohistochemical staining procedures, low fluorescence intensity and quick fluorescence quenching. Carbon dots (CDs) as fluorescent bio-probes have been widely used in the biological studies due to their superior optical properties, excellent chemical stability, low toxicity, and easy modifications. In this study, biotinylated dextran amine (BDA) and red fluorescent carbonized polymer dots (CPDs) are successfully conjugated to develop a brand-new generation of fluorescent nano-neural tracers: BDA-CPDs. They are successfully applied as fluorescent probes for in vitro and in vivo bioimaging. In vitro biodistribution of BDA-CPDs shows that they distribute mainly in lysosomes and endoplasmic reticulum. Moreover, two metabolic pathways of BDA-CPDs are found through the investigation of in vivo biodistribution of BDA-CPDs. Furthermore, they can be taken up and anterogradely transported by neurons within the peripheral nervous system of rats. Our results suggest that BDA-CPDs have many advantages over traditional tracers, such as low toxicity, high photoluminescence intensity, excellent photostability and easy procedures. Anterograde pathway tracing with BDA-CPDs is a simple, direct and economical way of studying the connections in the nervous system. Therefore, BDA-CPDs are reliable and valuable fluorescent anterograde neural tracers.
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Biotina/análogos & derivados , Carbono/química , Dextranos/química , Colorantes Fluorescentes/química , Nanopartículas/química , Neuronas/citología , Polímeros/química , Animales , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacocinética , Biotina/química , Biotina/farmacocinética , Carbono/farmacocinética , Línea Celular , Dextranos/farmacocinética , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neuronas/química , Polímeros/farmacocinética , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
STUDY OBJECTIVE: To evaluate the detection rate and accuracy of sentinel lymph node (SLN) mapping using cervical and fundal injections of carbon nanoparticles (CNPs) in laparoscopic surgery of endometrioid endometrial cancer (EC) and to identify uterine lymphatic drainage pathways validated by mapping. DESIGN: A prospective consecutive study (Canadian Task Force classification II-2). SETTING: An academic research center. PATIENTS: Consecutive patients with a pathologic diagnosis of early-stage EC scheduled for primary laparoscopic-assisted staging surgery (laparoscopic hysterectomy, bilateral salpingo-oophorectomy, or comprehensive lymphadenectomy). INTERVENTIONS: Enrolled patients underwent laparoscopic SLN mapping with a 50-mg CNP tracer injection. Fifty patients received fundal subserosal injections at 4 sites (the fundal group), whereas 65 patients received cervical submucosal injections at 2 sites (the cervical group). After SLN mapping, all patients underwent laparoscopic staging surgery. MEASUREMENTS AND MAIN RESULTS: No allergic reactions to CNPs were observed in either group. The overall SLN detection rates were 100% and 92% in the cervical and fundal groups, and the bilateral SLN detection rates were 97% and 68% (p < .001), respectively. A total of 12 metastatic SLNs were accurately detected in 5 patients. The sensitivity of metastatic lymph node detection was 100% in the cervical group, which is higher than that in the fundal group (80%). The false-negative rates were 0% and 20%, respectively, in the cervical and fundal groups. Furthermore, we verified 3 uterine lymphatic pathways using the 2 injection methods. The upper paracervical pathway was the most common drainage pathway in both groups (91.4% in the cervical group vs 80.24% in the fundal group), whereas the infundibulopelvic pathway was observed only in the fundal group (15.11%). CONCLUSION: SLN mapping by CNPs in laparoscopic surgery for EC is a safe and effective alternative, with a higher detection rate and better accuracy with cervical injections than fundal injections. The upper paracervical pathway was the most common lymphatic pathway, whereas the infundibulopelvic pathway was only displayed in fundal injections.
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Carbono , Carcinoma Endometrioide/patología , Neoplasias Endometriales/patología , Laparoscopía/métodos , Nanopartículas , Estadificación de Neoplasias/métodos , Ganglio Linfático Centinela/diagnóstico por imagen , Adulto , Anciano , Carbono/administración & dosificación , Carbono/farmacocinética , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/cirugía , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/cirugía , Femenino , Humanos , Histerectomía/métodos , Ganglios Linfáticos/patología , Metástasis Linfática , Vasos Linfáticos/diagnóstico por imagen , Vasos Linfáticos/patología , Vasos Linfáticos/cirugía , Persona de Mediana Edad , Nanopartículas/administración & dosificación , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Salpingooforectomía , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela/métodosRESUMEN
In this work, we presented ternary nanoparticles [poly(carboxybetaine methacrylate) (pCBMA)(peptide dendrimer-modified carbon dots (CD-D)/doxorubicin (DOX))] based on peptide dendritic carbon dots (CDs) to realize tumor-specific drug delivery and highly efficient cancer therapy. The versatile nanoparticles could achieve "stealth" delivery in blood due to the antifouling zwitterion coating. Meanwhile, charge changes of the zwitterions could be moderated during their transportation toward/inside tumor cells, where subtle environmental pH variations acted as potent stimuli to actualize desired functions. In particular, the detachment of the zwitterionic "coat" at the tumor site resulted in the exposure of abundant peripheral guanidine groups on peptide dendritic carbon dots (CD-D/DOX) owing to the extracellular pH environment (pH 6.8)-induced charge conversion. Consequently, the positively charged CD-D/DOX (+7.02 mV) interacted with the negatively charged cancer cell membrane to enhance cellular uptake. After endocytosis, tumor intracellular microenvironments (acidic conditions and high glutathione (GSH) levels) could lead to effective disintegration of the CD-D/DOX entities due to acid-induced protonation of guanidine groups and glutathione-induced cleavage of peptide dendritic components on CDs, and then effective endosomal escape and fast doxorubicin hydrochloride (DOX·HCl) release (73.2% accumulative release within 4 h) were achieved successively. This strategy enabled a 9.19-fold drug release rate at tumor sites in comparison with the one in the physiological environment. Moreover, the excellent fluorescence properties of CDs endowed the pCBMA(CD-D/DOX) with fluorescence bioimaging function. In view of the above-mentioned advantages, pCBMA(CD-D/DOX) exhibited outstanding antitumor activities both in vitro and in vivo, demonstrating much higher antitumor efficacy and less side effects than the free DOX·HCl.
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Carbono , Doxorrubicina , Portadores de Fármacos , Nanopartículas , Neoplasias Experimentales , Péptidos , Animales , Carbono/química , Carbono/farmacocinética , Carbono/farmacología , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Femenino , Células Hep G2 , Humanos , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Péptidos/química , Péptidos/farmacocinética , Péptidos/farmacología , Microambiente Tumoral/efectos de los fármacosRESUMEN
Drug delivery systems for doxorubicin (DOX) have attracted tremendous interest nowadays for the improved efficacy and/or reduced toxicity. Due to the aromatic structures and hydrophobic domains, carbon nanoparticle suspension injection (CNSI), a clinical applied reagent for lymph node mapping, strongly adsorbs DOX and holds great potential in cancer therapy. Herein, we evaluated the therapeutic effects of CNSI-DOX to establish its delivery applications for cancer drugs. CNSI adsorbed DOX from solution quickly after the mixing, and the release of DOX from CNSI followed a pH-dependent way. CNSI-DOX and free DOX had nearly identical inhibitive effects on cancer cells, while the vehicle CNSI was nontoxic. CNSI-DOX largely prolonged the life span of ascites tumor bearing mice after the intraperitoneally injection and the ascites weights showed significant decreases. CNSI-DOX also inhibited the growth of subcutaneous xenografts following the same administration route. The therapeutic efficacy of CNSI-DOX was similar to that of free DOX in ascites tumor model, but slightly lower in subcutaneous xenografts model. The advantage of using CNSI was majorly reflected by the reduced toxicity of DOX according to the bodyweight changes, serum biochemical indicators and histopathological observations. The LD50 (median lethal dose) value of CNSI-DOX was 43.8â¯mg/kg bodyweight, nearly three times of that of free DOX (15.2â¯mg/kg bodyweight). Our results suggested that CNSI might be used for DOX delivery through "off label" use to benefit the patients immediately.
Asunto(s)
Carbono , Doxorrubicina , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas , Neoplasias Experimentales/tratamiento farmacológico , Carbono/química , Carbono/farmacocinética , Carbono/farmacología , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Células HeLa , Humanos , Células MCF-7 , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patologíaRESUMEN
Samples collected from 12 rivers with typical vegetation types in the permafrost regions on the Qinghai-Tibetan Plateau were incubated in the laboratory, and the relationships among the vegetation types, river discharges, the compositions of dissolved organic carbon (DOC), permafrost areas, riverine DOC concentration, biodegradability of dissolved organic carbon (BDOC), and the biodegradation kinetics were examined. The results showed that the DOC concentrations of typical vegetation types in the basin, such as alpine meadow (AM), alpine swamp meadow-alpine meadow (ASM-AM), alpine meadow-alpine steppe (AM-AS), and alpine meadow-alpine steppe-bare soil (AM-AS-BL), were (5.17±0.21), (5.02±0.50), (3.55±0.25), and (2.79±0.41) mg ·L-1, respectively. The values for the bioavailability of river DOC of different vegetation types were (23.54±2.62)%, (23.66±3.31)%, (18.17±5.26)%, and (11.72±15.56)%, respectively. Correspondingly, the riverine DOC aromaticity increased along with the vegetation cover, while the biodegradation and degradation rates decreased gradually. During the incubation, the reaction of BDOC was in accordance with the first-order kinetics equation. Furthermore, the BDOC in continuous permafrost regions of the rivers was greater than that in the non-continuous permafrost regions. The BDOC in higher discharges were lower than those with lower discharges. Taken together, the results suggested that the vegetation types were the main controlling factors for the BDOC, and BDOC was also related to the discharge and permafrost.
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Carbono/farmacocinética , Plantas/metabolismo , Ríos/química , Disponibilidad Biológica , Hielos Perennes , TibetRESUMEN
Bioavailable dissolved organic carbon (BDOC), nitrogen (BDON) and their degradation rate constants were measured for the Chilika Lagoon, India. Long-term laboratory incubation experiments (90â¯days) were conducted at a constant temperature (25⯰C) to quantify the bioavailable dissolved organic matter (DOM) and the possible degradation rate coefficients. The results showed that 41⯱â¯12% of dissolved organic carbon (DOC) and 47⯱â¯17% of dissolved organic nitrogen (DON) were BDOC and BDON respectively, with their stoichiometry found to be higher than the Redfield ratio. A first order exponential non-linear fitting routine was used to estimate pool sizes. The degradation rate constant (k) for the BDOC varied from 0.127-0.329â¯d-1 and BDON from 0.043-0.306â¯d-1 during the study period. Half-lives of the BDOC and BDON ranged from 2.1-5.4 and 2.2-15.9â¯days, respectively. Overall, the results showed that a fraction of the labile DON was transported from the lagoon to the adjacent coastal sea.
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Carbono/farmacocinética , Nitrógeno/farmacocinética , Aguas Salinas/química , Disponibilidad Biológica , Carbono/análisis , India , Nitrógeno/análisis , Ríos , Aguas Salinas/análisis , Análisis Espacio-Temporal , Clima TropicalRESUMEN
The distribution of surface modified carbon dots (CDs) in the pumpkin seedlings was studied by visualization techniques and their potential phytotoxicity was investigated at both the physiological and biochemical levels. The average size of carbon dots was approximately 4 nm. The fluorescent peaks of bared CDs, CD-PEI and CD-PAA were between 420 nm and 500 nm, indicating CDs could emit blue and green fluorescence. Fluorescent images showed that all three types of CDs could accumulate in the pumpkin roots and translocate to the shoots, although the distribution pattern of each CDs was obviously different. At the biochemical level, the elevated antioxidant enzymes in pumpkin roots suggest that all the CDs could potentially trigger the antioxidant defense systems in pumpkin seedlings. Additionally, such alteration was greater in the roots than in the shoots. Our study represents a new perspective on CD visualization in plant tissues and provide useful information for the potential toxicity of different types of CDs to terrestrial plants, which is of importance to agricultural application.