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BACKGROUND: Our study aims to investigate the mechanisms through which Fc receptor-like A (FCRLA) promotes renal cell carcinoma (RCC) and to examine its significance in relation to tumor immune infiltration. MATERIALS AND METHODS: The correlation between FCRLA and data clinically related to RCC was explored using The Cancer Genome Atlas (TCGA), then validated using Gene Expression Omnibus (GEO) gene chip data. Enrichment and protein-protein interaction (PPI) network analyses were performed for FCRLA and its co-expressed genes. FCRLA was knocked down in RCC cell lines to evaluate its impact on biological behavior. Then the potential downstream regulators of FCRLA were determined by western blotting, and rescue experiments were performed for verification. The relevance between FCRLA and various immune cells was analyzed through GSEA, TIMER, and GEPIA tools. TIDE and ESTIMATE algorithms were used to predict the effect of FCRLA in immunotherapy. RESULTS: Fc receptor-like A was associated with clinical and T stages and could predict the M stage (AUC = 0.692) and 1-3- and 5-year survival rates (AUC = 0.823, 0.834, and 0.862) of RCC patients. Higher expression of FCLRA predicted an unfavorable overall survival (OS) in TCGA-RCC and GSE167573 datasets (p = 0.03, p = 0.04). FCRLA promoted the malignant biological behavior of RCC cells through the pERK1/2/-MMP2 pathway and was associated with tumor immune microenvironment in RCC. CONCLUSION: Fc receptor-like A is positively correlated with poor outcomes in RCC patients and plays an oncogenic role in RCC through the pERK1/2-MMP2 pathway. Patients with RCC might benefit from immunotherapy targeting FCRLA.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Receptores Fc/genética , Receptores Fc/metabolismo , Pronóstico , Microambiente Tumoral/inmunología , Masculino , Proliferación Celular , Femenino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Mapas de Interacción de Proteínas , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismoRESUMEN
Growth factor holds great promise for bone regeneration, and spatiotemporal control of their expressing through site-specific reactions is crucial but challenging for on-demand therapy. In this study, we present the development of a novel unnatural amino acids (UAAs)-triggered therapeutic switch (UATS) system, composed of an orthogonal aminoacyl-tRNA-synthase (aaRS)-tRNA pair and a bone morphogenetic protein 2 (BMP2) gene harboring premature stop codon, which enable in situ and on-demand initiation of the expression of BMP2. The resulting UATS system allowed specifically control of base expressing on the BMP2 mRNA that switched to the BMP2 protein with complete structure and function to facilitate bone regeneration. Our investigations showed that the UATS system exhibits remarkable attributes of rapid, sensitive, reversible, and sustained BMP2 expression both in vitro and in vivo settings. Moreover, the implantation of microencapsulated cells with UATS system is applied to a mouse femur defect model, demonstrating high effciency in controlled expressing of BMP2 protein and substantial repair of bone defect following oral administration of UAAs. Therefore, our findings underscore the great potential of UATS system for on-demand awakening of functional growth factor, thus offering promising prospects in the realm of regenerative medicine.
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INTRODUCTION: In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL. METHODS: In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117-) in 169 APL patients treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen. RESULTS: The median follow-up period was 63.0 months. CD117- was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117- subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117- APL (p = 0.023). By multivariate analysis, CD117- was an independent adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) (p = 0.022 and p = 0.014, respectively). CONCLUSIONS: To sum up, CD117- is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk-adapted therapeutic strategies in APL management.
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Nanomaterials possess unusual physicochemical properties including unique optical, magnetic, electronic properties, and large surface-to-volume ratio. However, nanomaterials face some challenges when they were applied in the field of biomedicine. For example, some nanomaterials suffer from the limitations such as poor selectivity and biocompatibility, low stability, and solubility. To address the above-mentioned obstacles, functional nucleic acid has been widely served as a powerful and versatile ligand for modifying nanomaterials because of their unique characteristics, such as ease of modification, excellent biocompatibility, high stability, predictable intermolecular interaction and recognition ability. The functionally integrating functional nucleic acid with nanomaterials has produced various kinds of nanocomposites and recent advances in applications of functional nucleic acid decorated nanomaterials for cancer imaging and therapy were summarized in this review. Further, we offer an insight into the future challenges and perspectives of functional nucleic acid decorated nanomaterials.
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Nanoestructuras , Neoplasias , Ácidos Nucleicos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/diagnóstico por imagen , Nanoestructuras/química , Ácidos Nucleicos/administración & dosificación , Ácidos Nucleicos/química , AnimalesRESUMEN
BACKGROUND: The innovative combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has established a new chapter of curative approach in acute promyelocytic leukemia (APL). The disease characteristics and prognostic influence of additional cytogenetic abnormalities (ACA) in APL with modern therapeutic strategy need to be elucidated. METHODS: In the present study, we retrospectively investigated disease features and prognostic power of ACA in 171 APL patients treated with ATRA-ATO-containing regimens. RESULTS: Patients with ACA had markedly decreased hemoglobin levels than that without ACA (p = 0.021). Risk stratification in the ACA group was significantly worse than that in the non-ACA group (p = 0.032). With a median follow-up period of 62.0 months, worse event-free survival (EFS) was demonstrated in patients harboring ACA. Multivariate analysis showed that ACA was an independent adverse factor for EFS (p = 0.033). By further subgroup analysis, in CD34 and CD56 negative APL, patients harboring ACA had inferior EFS (p = 0.017; p = 0.037). CONCLUSIONS: To sum up, ACA remains the independent prognostic value for EFS, we should build risk-adapted therapeutic strategies in the long-term management of APL when such abnormalities are detected.
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Arsenicales , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Supervivencia sin Progresión , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tretinoina/uso terapéutico , Aberraciones Cromosómicas , Óxidos/uso terapéutico , Arsenicales/uso terapéutico , Resultado del TratamientoRESUMEN
A novel fluorescent strategy has been developed by using an enzymatic reaction modulated DNA assembly on graphitic carbon nitride nanosheets (CNNS) for the detection of acetylcholinesterase (AChE) activity and its inhibitors. The two-dimensional and ultrathin-layer CNNS-material was successfully synthesized through a chemical oxidation and ultrasound exfoliation method. Because of its excellent adsorption selectivity to ssDNA over dsDNA and superior quenching ability toward the fluorophore labels, CNNS were employed to construct a sensitive fluorescence sensing platform for the detection of AChE activity and inhibition. The detection was based on enzymatic reaction modulated DNA assembly on CNNS, which involved the specific AChE-catalyzed reaction-mediated DNA/Hg2+ conformational change and subsequent signal transduction and amplification via hybridization chain reaction (HCR). Under the excitation at 485 nm, the fluorescence signal from 500 to 650 nm (λmax = 518 nm) of the developed sensing system was gradually increased with increasing concentration of AChE. The quantitative determination range of AChE is from 0.02 to 1 mU/mL and the detection limit was 0.006 mU/mL. The developed strategy was successfully applied to the assay of AChE in human serum samples, and can also be used to effectively screen AChE inhibitors, showing great promise providing a robust and effective platform for AChE-related diagnosis, drug screening, and therapy.
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Acetilcolinesterasa , Grafito , Humanos , Fluorescencia , ADN , Grafito/químicaRESUMEN
The eutrophication of coastal water has been a critical environmental problem in China's offshore areas. How to effectively assess the status of coastal waters is key for pollution treatment and environmental protection. In recent years, eutrophication-symptom-based and multi-indicator methods, termed "phase II" methods, have been gradually adopted to assess the eutrophication status in some coastal waters in China and have achieved success. The cumulative quantile is typically selected to determine the characteristic value of an indicator in "phase II" methods. The influence of small-scale damaged water bodies on eutrophication assessment may be exaggerated, which often leads to the overassessment of the eutrophication status. In this study, the area ratio method was integrated into the assessment of the estuarine trophic status (ASSETS) method in order to assess the eutrophication status of Xiamen Bay in 2016. The results indicated that, in 2016, the eutrophication status of Xiamen Bay coastal waters was moderate and exhibited spatiotemporal variation. The area ratio method can effectively reduce the effect of small-scale coastal waters with extremely high eutrophication on the overassessment of eutrophication at the broader scale, allowing the eutrophication status to be better reflected, even with limited observation data. The centralized distribution of pollution sources and poor hydrodynamic conditions are the main reasons for the aforementioned phenomenon. Controlling the pollution discharge from the Jiulong River in flood seasons is key to reducing eutrophication in Xiamen coastal waters.
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Bahías , Monitoreo del Ambiente , Monitoreo del Ambiente/métodos , Eutrofización , Ríos , Agua , ChinaRESUMEN
Two-photon carbon-based nanoprobes hold great potential for biomedical applications as a result of their advantages of low fluorescence background, deep tissue imaging penetration and enhanced spatial resolution. However, the development of an activatable two-photon fluorescence carbon-based nanoprobe that simultaneously has the ability to target desired organs or cells is highly desired but remained a largely unsolved challenge. Herein, we developed boronate affinity BCNP@MnO2 nanocomposites, constructed by one step in situ growth of MnO2 nanosheets on the surface of aminophenylboronic acid-functionalized CNPs (BCNPs) via a redox reaction, which can feature efficient fluorescence energy transfer quenching to the BCNPs, allowing for tumor-specific affinity recognition and two-photon fluorescence activation imaging. By utilizing the inherent two-photon optical properties and sialic acid (SA) specific targeting ability of the BCNPs, good biocompatibility of the nanocomposites as well as highly sensitive and selective responses of MnO2 nanosheets towards GSH, the developed nanocomposites have demonstrated specific two-photon fluorescence activation imaging in target cancer cells and nude mouse tissues. Therefore, our proposed novel strategy could be used for monitoring GSH-triggered two-photon fluorescence activation events in SA-overexpressed cancer cells and has promising applications in both biological exploration and clinical diagnosis.
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Compuestos de Manganeso , Nanopartículas , Animales , Carbono , Fluorescencia , Transferencia Resonante de Energía de Fluorescencia , Glutatión , Ratones , Ácido N-Acetilneuramínico , Nanopartículas/toxicidad , Imagen Óptica , Óxidos/toxicidadRESUMEN
DNA molecular probes have emerged as powerful tools for fluorescence imaging of microRNAs (miRNAs) in living cells and thus elucidating functions and dynamics of miRNAs. In particular, the highly integrated DNA probes that can be able to address the robustness, sensitivity and consistency issues in a single assay system were highly desired but remained largely unsolved challenge. Herein, we reported for the first time that the development of the novel DNA nanomachines that split-DNAzyme motif was highly integrated in a single DNA triangular prism (DTP) reactor and can undergo target-activated DNAzyme catalytic cascade circuits, allowing amplified sensing and imaging of tumor-related microRNA-21 (miR-21) in living cells. The DNA nanomachines have shown dynamic responses for target miR-21 with excellent sensitivity and selectivity and demonstrated the potential for living cell imaging of miR-21. With the advantages of facile modular design and assembly, high biostability, low cytotoxicity and excellent cellular internalization, the highly integrated DNA nanomachines enabled accurate and effective monitoring of miR-21 expression levels in living cells. Therefore, our developed strategy may afford a reliable and robust nanoplatform for tumor diagnosis and for related biological research.
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Técnicas Biosensibles , ADN Catalítico , MicroARNs , Sondas de ADN , MicroARNs/genéticaRESUMEN
DNA molecular probes have emerged as a powerful tool for RNA imaging. Hurdles in cell-specific delivery and other issues such as insufficient stability, limited sensitivity, or slow reaction kinetics, however, hinder the further application of DNA molecular probes in vivo. Herein, we report an aptamer-tethered DNA polymer for cell-specific transportation and amplified imaging of RNA in vivo via a DNA cascade reaction. DNA polymers are constructed through an initiator-triggered hybridization chain reaction using two functional DNA monomers. The prepared DNA polymers show low cytotoxicity and good stability against nuclease degradation and enable cell-specific transportation of DNA circuits via aptamer-receptor binding. Moreover, assembling the reactants of hairpins C1 and C2 on the DNA polymers accelerates the response kinetics and improves the sensitivity of the cascade reaction. We also show that the DNA polymers enable efficient imaging of microRNA-21 in live cells and in vivo via intravenous injection. The DNA polymers provide a valuable platform for targeted and amplified RNA imaging in vivo, which holds great implications for early clinical diagnosis and therapy.
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Sondas de ADN/metabolismo , MicroARNs/metabolismo , Imagen Molecular/métodos , Aptámeros de Nucleótidos/metabolismo , Línea Celular , Supervivencia Celular , Sondas de ADN/química , HumanosRESUMEN
A multifunctional theranostic nanoplatform, which integrates diagnostic and therapeutic functions in a single nanosystem, holds great promise for guiding disease treatment and improving the corresponding therapy efficacy. We report the development of a novel g-C3N4 nanosheet-based theranostic nanoassembly for both enhanced imaging of cancer-relevant mRNA in living cells and imaging-guided on-demand photodynamic therapy (PDT) for tumors. The nanoassembly was constructed by using highly fluorescent and water-dispersible g-C3N4 nanosheets which act as nanocarriers, enabling efficient and self-tracking transfection of the DNA hairpin probes. The presence of intracellular mRNA will initiate the DNA hairpin probes, ultimately resulting in an amplified fluorescence signal via hybridization and displacement with mRNA. Moreover, enhanced fluorescence imaging-guided precise PDT for tumors in living cells was also demonstrated, allowing the selective ablation of tumors without any obvious side effects. Therefore, the developed theranostic approach can provide a promising platform for low-abundance biomarker discovery and early treatment of related diseases.
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Imagen Molecular/métodos , Fotoquimioterapia/métodos , ARN Mensajero/metabolismo , ARN Neoplásico/metabolismo , Biomarcadores de Tumor/química , Biomarcadores de Tumor/metabolismo , Supervivencia Celular/efectos de los fármacos , Sondas de ADN/química , Sondas de ADN/uso terapéutico , Fluorescencia , Grafito/química , Grafito/uso terapéutico , Células HeLa , Humanos , Nanoestructuras/química , Nanoestructuras/uso terapéutico , Compuestos de Nitrógeno/química , Compuestos de Nitrógeno/uso terapéutico , Hibridación de Ácido Nucleico , ARN Mensajero/química , ARN Neoplásico/química , Nanomedicina TeranósticaRESUMEN
Detecting the interactions between small molecules and proteins was critical for disease theranostics and drug development. Here we propose a novel universal assay strategy for monitoring small molecule-protein interactions in solution using strand displacement amplification (SDA) mediated by protein binding to small molecule with DNAzyme-based chemiluminescence detection. The DNA polymerase and nicking enzyme assisted SDA could yield a great amount of peroxidase-mimicking DNAzyme sequences which cause signiï¬cantly chemiluminescence signals, while protein binding to the small molecule label would prevent DNA polymerase from extending nick site and DNAzyme sequence, and thus the chemiluminescence signals would obviously decrease. This strategy was demonstrated using folate and its binding protein (folate receptor), and the results revealed that the developed strategy enable offer a label-free, homogeneous, and highly sensitive chemiluminescence detection of folate receptor with a detection limit of 1pM. At the same time, it has been successfully used for folate receptor detection in human serum. The proposed chemiluminescence sensing method might provide a generic, robust, and high-throughput platform for detecting various small molecule-protein interactions for biological applications.
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ADN Catalítico/química , Receptores de Folato Anclados a GPI/metabolismo , Ácido Fólico/metabolismo , Nanoestructuras/química , Técnicas Biosensibles/métodos , Desoxirribonucleasa I/química , Receptores de Folato Anclados a GPI/sangre , Hemina/química , Humanos , Límite de Detección , Mediciones Luminiscentes/métodos , Luminol/química , Prueba de Estudio ConceptualRESUMEN
DNA nanowalkers moving progressively along a prescribed DNA track are useful tools in biosensing, molecular theranostics and biosynthesis. However, stochastic DNA nanowalkers that can perform in living cells have been largely unexplored. We report the development of a novel stochastic bipedal DNA walker that, for the first time, realizes direct intracellular base excision repair (BER) fluorescence activation imaging. In our design, the bipedal walker DNA was generated by BER-related human apurinic/apyrimidinic endonuclease 1 (APE1)-mediated cleavage of DNA sequences at an abasic site in the intracellular environment, and it autonomously travelled on spherical nucleic acid (SNA) surfaces via catalyzed hairpin assembly (CHA). Our nanomachine outperforms the conventional single leg-based DNA walker with an improved sensitivity, kinetics and walking steps. Moreover, in contrast to the single leg-based DNA walker, the bipedal DNA walker is capable of monitoring the fluorescence signal of reduced APE1 activity, thus indicating amplified intracellular imaging. This bipedal DNA-propelled DNA walker presents a simple and modular amplification mechanism for intracellular biomarkers of interest, providing an invaluable platform for low-abundance biomarker discovery leading to the accurate identification and effective treatment of cancers.
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A novel self-assembled protein-scaffolded CRISPR-Cas9 nanosystem for facile and efficient gene editing in a DNAzyme-controlled manner has been developed.
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Proteína 9 Asociada a CRISPR/genética , Sistemas CRISPR-Cas/genética , ADN Catalítico/genética , Nanoestructuras/química , Biotina/química , Línea Celular Tumoral , Edición Génica/métodos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Hibridación de Ácido Nucleico , ARN Guía de Kinetoplastida/genética , Estreptavidina/químicaRESUMEN
A novel and versatile platform for single-step amplified fluorescence detection of antibodies via specific proximity-induced hybridization chain assembly is developed.
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Anticuerpos/sangre , Técnicas Biosensibles/métodos , ADN/química , ADN/genética , Técnicas de Amplificación de Ácido Nucleico , Anticuerpos/metabolismo , ADN/metabolismo , Humanos , Límite de Detección , Espectrometría de FluorescenciaRESUMEN
DNA hydrogels are biocompatible and are suitable for many biomedical applications. However, to be useful imaging probes or drug carriers, the ordinary bulk size of DNA hydrogels must be overcome. Here we put forward a new strategy for fabricating a novel and simple protein-scaffolded DNA nanohydrogel, constructed through a direct DNA self-assembly using three types of streptavidin (SA)-based DNA tetrad for the activation of imaging and targeting therapy of cancer cells. The DNA nanohydrogels are easily prepared, and we show that by varying the initial concentration of DNA tetrad, it is possible to finely control their size within nanoscale range, which are favorable as carriers for intracellular imaging and transport. By further incorporating therapeutic agents and tumor-targeting MUC1 aptamer, these multifunctionalized SA-scaffolded DNA nanohydrogels (SDH) can specifically target cancer cells and selectively release the preloaded therapeutic agents via a structure switching when in an ATP-rich intracellular environment, leading to the activation of the fluorescence and efficient treatment of cancer cells. With the advantages of facile modular design and assembly, effective cellular uptake, and excellent biocompatibility, the method reported here has the potential for the development of new tunable DNA nanohydrogels with multiple synergistic functionalities for biological and biomedical applications.
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Antineoplásicos/farmacología , ADN/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Hidrogeles/química , Nanoestructuras/química , Aptámeros de Nucleótidos/química , Carbocianinas/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/química , Humanos , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Estreptavidina/químicaRESUMEN
We develop a novel amplified split aptamer sensor for highly sensitive detection and imaging of small molecules in living cells by using cationic block copolymer nanoparticles (BCNs) with entrapped fluorescent conjugated polymer as a delivery agent. The design of a split aptamer as the initiator of hybridization chain reaction (HCR) affords the possibility of enhancing the signal-to-background ratio and thus allows high-contrast imaging for small molecules with relatively weak interactions with their aptamers. The novel design of using fluorescent cationic BCNs as the nanocarrier enables efficient and self-tracking transfection of DNA probes. Results reveal that BCNs exhibit high fluorescence brightness allowing direct tracking of the delivery location. The developed amplified split aptamer sensor is shown to have high sensitivity and selectivity for in vitro quantitative detection of adenosine triphosphate (ATP) with a detection limit of 30 nM. Live cell studies show that the sensor provides a "signal on" approach for specific, high-contrast imaging of ATP. The DNA sensor based HCR system may provide a new generally applicable platform for detection and imaging of low-abundance biomarkers.
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Aptámeros de Nucleótidos/química , Técnicas Biosensibles/métodos , Nanopartículas/química , Polietilenglicoles/química , Polivinilos/química , Adenosina Trifosfato/análisis , Aptámeros de Nucleótidos/genética , Biomarcadores/análisis , ADN/química , ADN/genética , Sondas de ADN/química , Sondas de ADN/genética , Fluorenos/química , Fluorenos/toxicidad , Colorantes Fluorescentes/química , Colorantes Fluorescentes/toxicidad , Células HeLa , Humanos , Secuencias Invertidas Repetidas , Límite de Detección , Microscopía Fluorescente/métodos , Nanopartículas/toxicidad , Hibridación de Ácido Nucleico , Polietilenglicoles/toxicidad , Polivinilos/toxicidadRESUMEN
The efficient detection and in situ monitoring of telomerase activity is of great importance for cancer diagnosis and biomedical research. Here we report for the first time that the development of a novel multivalent self-assembled DNA polymer, constructed through telomerase primer sequence (ITS) triggered hybridization chain assembly using two functional hairpin probes (tumor-trageting aptamer modified H1 and signal probe modified H2), for sensitive detection and imaging of telomerase activity in living cells. After internalizing into the tumor cells by multivalent aptamer targeting, the ITS on DNA polymers can be elongated by intracellular telomerase to generate telomere repeat sequences that are complementary with the signal probe, which can proceed along the DNA polymers, and gradually light up the whole DNA polymers, leading to an enhanced fluorescence signal directly correlated with the activity of telomerase. Our results demonstrated that the developed DNA polymer show excellent performance for specifically detecting telomerase activity in cancer cells, dynamically monitoring the activity change of telomerase in response to telomerase-based drugs, and efficiently distinguishing cancer cells from normal cells. The proposed strategy may afford a valuable tool for the monitoring of telomerase activity in living cells and have great implications for biological and diagnostic applications.
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Aptámeros de Nucleótidos/química , ADN/química , Polímeros/química , Telomerasa/análisis , Aptámeros de Nucleótidos/genética , Aptámeros de Nucleótidos/metabolismo , Aptámeros de Nucleótidos/toxicidad , Carbocianinas/química , Línea Celular Tumoral , ADN/genética , ADN/metabolismo , ADN/toxicidad , Pruebas de Enzimas/métodos , Fluorescencia , Colorantes Fluorescentes/química , Humanos , Límite de Detección , Hibridación de Ácido Nucleico , Fosfoproteínas/metabolismo , Polímeros/metabolismo , Polímeros/toxicidad , Proteínas de Unión al ARN/metabolismo , NucleolinaRESUMEN
Spherical nucleic acid (SNA) constructs are promising new single entity materials, which possess significant advantages in biological applications. Current SNA-based drug delivery system typically employed single-layered ss- or ds-DNA as the drug carriers, resulting in limited drug payload capacity and disease treatment. To advance corresponding applications, we developed a novel DNA-programmed polymeric SNA, a long concatamer DNA polymer that is uniformly distributed on gold nanoparticles (AuNPs), by self-assembling from two short alternating DNA building blocks upon initiation of immobilized capture probes on AuNPs, through a supersandwich hybridization reaction. The long DNA concatamer of polymeric SNA enables to allow high-capacity loading of bioimaging and therapeutics agents. We demonstrated that both of the fluorescence signals and therapeutic efficacy were effectively inhibited in resultant polymeric SNA. By further modifying with the nucleolin-targeting aptamer AS1411, this polymeric SNA could be specifically internalized into the tumor cells through nucleolin-mediated endocytosis and then interact with endogenous ATP to cause the release of therapeutics agents from long DNA concatamer via a structure switching, leading to the activation of the fluorescence and selective synergistic chemotherapy and photodynamic therapy. This nanostructure can afford a promising targeted drug transport platform for activatable cancer theranostics.
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Antineoplásicos/farmacología , ADN/química , Portadores de Fármacos/química , Nanopartículas del Metal/química , Nanomedicina Teranóstica/métodos , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adenosina Trifosfato/metabolismo , Antineoplásicos/química , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/genética , Aptámeros de Nucleótidos/metabolismo , Clorofilidas , ADN/genética , ADN/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/metabolismo , Liberación de Fármacos , Femenino , Fluorescencia , Oro/química , Células HeLa , Humanos , Luz , Microscopía Confocal/métodos , Hibridación de Ácido Nucleico , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/genética , Oligodesoxirribonucleótidos/metabolismo , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/efectos de la radiación , Porfirinas/química , Porfirinas/farmacología , Porfirinas/efectos de la radiación , Oxígeno Singlete/metabolismoRESUMEN
DNA nanodevices that mimic natural biomolecular machines changing configurations in response to external inputs have enabled smart sensors to live cell imaging. We report for the first time the development of a dynamic DNA nanomachine that is anchored on a cell's surface and undergoes pH-responsive triplex-duplex conformation switching, allowing tunable sensing and imaging of extracellular pH. Results reveal that the DNA nanomachine can be stably anchored on the cell surface via multiple anchors, and the adjustment of C+G-C content in the switch element confers tunability of pH response windows. The anchored DNA nanomachine also demonstrates desirable sensitivity, excellent reversibility, and quantitative ability for extracellular pH detection and imaging. This cell surface-anchored pH-responsive DNA nanomachine can provide a useful platform for pH sensing in extracellular microenvironments and diagnostics of different pH-related diseases.