RESUMEN
Hydrogen sulfide (H2S) is a central signaling and antioxidant biomolecule involved in various biological processes. As inappropriate levels of H2S in the human body are closely related to various diseases, including cancer, a tool capable of detecting H2S with high selectivity and sensitivity in living systems is urgently required. In this work, we intended to develop a biocompatible and activatable fluorescent molecular probe for detecting H2S generation in living cells. The 7-nitro-2,1,3-benzoxadiazole-imbedded naphthalimide (1) probe presented here responds specifically to H2S and produces readily detectable fluorescence at 530 nm. Interestingly, probe 1 exhibited significant fluorescence responses to changes in endogenous H2S levels as well as high biocompatibility and permeability in living HeLa cells. This allowed for the real-time monitoring of endogenous H2S generation as an antioxidant defense response in the oxidatively stressed cells.
Asunto(s)
Sulfuro de Hidrógeno , Naftalimidas , Humanos , Antioxidantes/farmacología , Colorantes Fluorescentes , Células HeLa , Naftalimidas/farmacología , Transducción de Señal , Azoles/químicaRESUMEN
The endogenous H2S-driven theranostic H2S-Gem has been invented. The theranostic prodrug H2S-Gem is selectively activated in cancer cells, releasing active gemcitabine with a simultaneous fluorescence turn-on. H2S-Gem selectively inhibited cancer cell growth compared to the mother chemotherapeutic gemcitabine. Overall, it is a unique protocol for tracking and transporting chemotherapeutic agents to tumor areas without the guidance of tumor-directive ligands.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Sulfuro de Hidrógeno/farmacología , Profármacos/farmacología , Antimetabolitos Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Desoxicitidina/química , Desoxicitidina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Fluorescencia , Células HeLa , Humanos , Sulfuro de Hidrógeno/química , Ligandos , Profármacos/química , Nanomedicina Teranóstica , GemcitabinaRESUMEN
Identification of bacterial strains is critical for the theranostics of bacterial infections and the development of antibiotics. Many organic fluorescent probes have been developed to overcome the limitations of conventional detection methods. These probes can detect bacteria with "off-on" fluorescence change, which enables the real-time imaging and quantitative analysis of bacteria in vitro and in vivo. In this review, we outline recent advances in the development of fluorescence-based dyes capable of detecting bacteria. Detection strategies are described, including specific interactions with bacterial cell wall components, bacterial and intracellular enzyme reactions, and peptidoglycan synthesis reactions. These include theranostic probes that allow simultaneous bacterial detection and photodynamic antimicrobial effects. Some examples of other miscellaneous detections in bacteria have also been described. In addition, this review demonstrates the validation of these fluorescent probes using a variety of biological models such as gram-negative and -positive bacteria, antibiotic-resistant bacteria, infected cancer cells, tumor-bearing, and infected mice. Prospects for future research are outlined by presenting the importance of effective in vitro and in vivo detection of bacteria and development of antimicrobial agents.
RESUMEN
Nitroreductases belong to a member of flavin-containing enzymes that can reduce nitroaromatic compounds to amino derivatives with NADH as an electron donor. NTR activity is known to be elevated in the cancerous environment and is considered an advantageous target in therapeutic prodrugs for the treatment of cancer. Here, we developed a ratiometric fluorescent molecule for observing NTR activity in living cells. This can provide a selective and sensitive response to NTR with a distinct increase in fluorescence ratio (FI530/FI630) as well as color changes. We also found a significant increase in NTR activity in cervical cancer HeLa and lung cancer A549 cells compared to non-cancerous NIH3T3. We proposed that this new ratiometric fluorescent molecule could potentially be used as a NTR-sensitive molecular probe in the field of cancer diagnosis and treatment development related to NTR activity.
Asunto(s)
Pruebas de Enzimas/métodos , Colorantes Fluorescentes/química , Sondas Moleculares/química , Nitrorreductasas/metabolismo , Células A549 , Animales , Muerte Celular , Cromatografía Líquida de Alta Presión , Endocitosis , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Ratones , Sondas Moleculares/síntesis química , Células 3T3 NIH , Espectrometría de FluorescenciaRESUMEN
Intracellular viscosity is a physicochemical factor that determines the outcomes of various biological processes, while nitric oxide (NO) is an essential signaling molecule that controls many cellular processes, including oxidative stress. Anticipating that both may be interrelated with a variety of pathologies, their simultaneous measurement would be highly valuable for the investigation of the pathological condition of cells. However, the development of a sensor for such simultaneous detection has not been attempted yet. Herein, we present the synthesis of naphthalimide-4-(4-nitrophenyl)thiosemicarbazide, probe 1, and its application to living cells under conditions of lipopolysaccharide or nystatin treatment, adopted as oxidative stress and altered intracellular viscosity models, respectively. The probe showed increased fluorescence in response to elevation of viscosity and NO levels at 470 and 550 nm, respectively, in the solution studies. When the probe was used for a confocal microscopic study of HeLa cells under stressed conditions, simultaneous monitoring of viscosity and NO level elevations was possible through fluorescence imaging using band-pass filters of 420-475 and 505-600 nm, respectively, upon excitation at a wavelength of 405 nm. Interestingly, both the cellular viscosity and NO levels increased together under lipopolysaccharide or nystatin treatment. Therefore, we suggest that probe 1 is a fluorescent chemical probe that enables the monitoring of alterations in intracellular viscosity and NO levels in living cells, which would be valuable in studies of various cellular damage models.
Asunto(s)
Colorantes Fluorescentes , Naftalimidas , Células HeLa , Humanos , Microscopía Fluorescente , Óxido Nítrico , Nitrofenoles , Semicarbacidas , ViscosidadRESUMEN
Aromatic nitro compounds are reduced to their corresponding amino derivatives by nitroreductases (NTR), while identification and characterization of the corresponding enzymes in mammalian systems are yet unrevealed. However, mammalian NTR activity has been considered as a favorable target in development of theranostic agents for cancer and hypoxia of solid tumors. Currently, small molecule-based fluorescent probes have emerged as a valuable assay tool for NTR activity. However, there has been a limit to comparing NTR activity between different cells, since most probes have relied on fluorescence changes that are affected by not only enzymatic activity but also nonenzymatic factors. Here, we developed a self-calibrating bipartite fluorescent probe, consisting of NTR-sensitive nitronaphthalimide and nonsensitive coumarin moieties. Thereby, it was possible to compare the relative NTR activity by monitoring fluorescence ratios in noncancerous and some cancerous cells and to demonstrate for certain that the elevated NTR activity is associated with cancer cells and hypoxia states.
Asunto(s)
Materiales Biocompatibles/química , Hipoxia de la Célula , Colorantes Fluorescentes/química , Neoplasias/metabolismo , Nitrorreductasas/metabolismo , Materiales Biocompatibles/síntesis química , Calibración , Colorantes Fluorescentes/síntesis química , Ensayo de Materiales , Estructura Molecular , Nitrorreductasas/análisis , Imagen Óptica , Tamaño de la PartículaRESUMEN
Phototherapy, including photodynamic therapy and photothermal therapy, has the potential to treat several types of cancer. However, to be an effective anticancer treatment, it has to overcome limitations, such as low penetration depth, low target specificity, and resistance conferred by the local tumor microenvironment. As a non-invasive technique, low-intensity ultrasound has been widely used in clinical diagnosis as it exhibits deeper penetration into the body compared to light. Recently, sonodynamic therapy (SDT), a combination of low-intensity ultrasound with a chemotherapeutic agent (sonosensitizer), has been explored as a promising alternative for cancer therapy. As all known cancer treatments such as chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, and drug delivery have been advanced independently enough to complement others substantially, the combination of these therapeutic modalities with SDT is opportune. This review article highlights the recent advances in SDT in terms of sonosensitizers and their formulations and anticancer therapeutic efficacy. Also discussed is the potential of SDT in combination with other modalities to address unmet needs in precision medicine.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Animales , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Humanos , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Medicina de Precisión , Terapia por UltrasonidoRESUMEN
A red-emitting and ratiometric fluorescence probe 1 for detecting H2O2, based on a styrylnaphthalimide-boronate ester was developed. Upon a H2O2-mediated hydrolysis of boronate ester, probe 1 was transformed to 2 with a ratiometric fluorescence change, decrease at 535 and increase at 640â¯nm. It was also found that the fluorescent reaction of 1 with H2O2 in solution could be completed within 10â¯min and the detection limit was estimated to be 0.30⯵M. Moreover, this ratiometric change was highly selective for H2O2 over other redox species, metal ions, and anions. Also, this system was found to be capable of detecting H2O2 in the pH range of 6-9. Furthermore, probe 1 was preferentially accumulated into the endoplasmic reticulum (ER) in the live HeLa cells, and an increased H2O2 level in the presence of an ER stress inducer, thapsigargin was revealed.
Asunto(s)
Ácidos Borónicos/química , Colorantes Fluorescentes/química , Peróxido de Hidrógeno/análisis , Naftalimidas/química , Estirenos/química , Ácidos Borónicos/síntesis química , Estrés del Retículo Endoplásmico/efectos de los fármacos , Colorantes Fluorescentes/síntesis química , Células HeLa , Humanos , Límite de Detección , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Naftalimidas/síntesis química , Estirenos/síntesis química , Tapsigargina/farmacologíaRESUMEN
We describe a near-infrared (NIR) fluorescent probe 1 for the selective detection of GSH over Hcy and Cys under physiological conditions. Probe 1 was composed of Cy7 as a NIR dye and 2-mercaptopyridine as a GSH-reactive site and fluorescence quencher. In the presence of GSH, the 2-mercaptopyridine functionality of probe 1 was replaced by the thiolate group of GSH through a nucleophilic substitution reaction with a fluorescence increase at 818 nm. The probe was found to be highly selective for GSH over Hcy, Cys, and other tested potential interferants, including ROS and metal ions. In addition, probe 1 successfully displayed fluorescence changes in response to changing the GSH concentrations in MDA-MB-231 cells in the presence of external agents i.e., N-acetyl-l-cysteine (NAC; as GSH inducer) or buthionine sulfoximine (BSO; as GSH inhibitor). We envision that probe 1 will serve as a promising sensing tool for monitoring the changes of the GSH level and the understanding of the roles of GSH under physiological and pathological conditions.