RESUMEN
Phototherapy has garnered considerable interest for its potential to revolutionize conventional cancer treatment. Organic materials with near-infrared II (NIR-II, 1000-1700 nm) fluorescence and photothermal effects are key for precise tumor diagnosis and treatment, yet optimizing their output for higher resolution and reduced photodamage remains a challenge. Herein, a multifunctional NIR-II photosensitizer (LSC) has been developed using the aggregation-induced emission (AIE) technology. The utilization of thieno[3,2-b]thiophene as an electron-rich and bulky donor/acceptor bridge has allowed for the elongation of conjugation length and distortion of the AIE main chain. This strategic modification effectively enhances the electron push-pull effect, endowing the LSC with a Stokes shift of over 400 nm and AIE characteristics. We have successfully built-up stable nanoparticles called FA-LSC NPs using a nano-precipitation method. These nanoparticles exhibit high NIR-II fluorescent brightness (ε × QY = 1064 M-1 cm-1) and photothermal conversion efficiency (41%). Furthermore, the biocompatible FA-LSC NPs demonstrate effective tumor accumulation and exceptional photothermal therapeutic efficacy both in vitro and in vivo. These nanoparticles were applied to fluorescence-photothermal dual-mode imaging-guided photothermal ablation in a HeLa tumor xenograft mouse model, resulting in favorable photothermal clearance outcomes.
RESUMEN
Various signal molecules mediate complex physiological processes collectively in the Golgi. However, most currently accessible probes are questionable in illuminating the functions of these reactive species in Golgi because of the inability to irradiate these probes only at the desired Golgi location, which compromises specificity and accuracy. In this study, we rationally designed the first photocontrollable and Golgi-targeted fluorescent probe to in situ visualize the Golgi alkaline phosphatase (ALP). The designed probe with natural yellow fluorescence can provide access into Golgi and monitor the exact timing of accumulation in Golgi. On-demand photoactivation at only the desired Golgi location affords a significant emission response to ALP with illuminating red fluorescence at 710 nm. Through the photocontrollable fluorescence responsiveness to ALP, precise spatiotemporal recognition of Golgi ALP fluctuations is successfully performed. With this probe, for the first time, we revealed the Golgi ALP levels during cisplatin-induced acute kidney injury (AKI), which will further facilitate and complement the comprehensive exploration of ALP kinetics during physiological and pathological processes.
Asunto(s)
Fosfatasa Alcalina , Colorantes Fluorescentes , Aparato de Golgi , Aparato de Golgi/metabolismo , Fosfatasa Alcalina/metabolismo , Humanos , Animales , Colorantes Fluorescentes/química , Células HeLa , Ratones , Cisplatino/farmacologíaRESUMEN
Nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) constitutes an essential inflammasome sensor protein, pivotal in the orchestration of innate immunity. Given its paramount role, NLRP3 has recently emerged as an enticing therapeutic target for disorders associated with inflammation. In this study, we embarked on the design and synthesis of two series of compounds, endowed with the capacity to induce NLRP3 degradation via autophagy-tethering compounds (ATTECs)-an innovative targeted protein degradation technology. Notably, MC-ND-18 emerged as the most potent agent for effectuating NLRP3 degradation through autophagic mechanisms and concurrently exhibited marked anti-inflammatory efficacy in mice model of dextran sulfate sodium (DSS)-induced colitis. Consequently, we have successfully developed a pioneering NLRP3 protein degrader, offering a novel therapeutic avenue for ameliorating NLRP3-associated pathologies.
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Autofagia , Sulfato de Dextran , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Autofagia/efectos de los fármacos , Ratones , Humanos , Estructura Molecular , Relación Estructura-Actividad , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Inmunoterapia , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Ratones Endogámicos C57BL , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Proteolisis/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis químicaRESUMEN
Since hydrogen sulfide (H2S) is an important endogenous gaseous mediator, therapeutic manipulation of H2S is promising for anticancer treatment. In this work, we develop a novel theranostic nanoplatform with H2S-specific and photocontrolled synergistic activation for imaging-guided H2S depletion and downregulation along with promoted photothermal therapy. Such a nanoplatform is fabricated by integration of a H2S-responsive molecule probe that can generate a cystathionine-ß-synthase (CBS) inhibitor AOAA and a photothermal transducer into an NIR-light-responsive container. Our nanoplatform can turn on NIR fluorescence specifically in H2S-rich cancers, guiding further laser irradiation. Furthermore, prominent conversion of photoenergy into heat guarantees special container melting with controllable AOAA release for H2S-level downregulation. This smart regulation of the endogenous H2S level amplifies the PTT therapeutic effect, successfully suppressing colorectal tumor in living mice under NIR fluorescence imaging guidance. Thus, we believe that this nanoplatform may provide a powerful tool toward H2S-concerned cancer treatment with an optimized diagnostic and therapeutic effect.
Asunto(s)
Neoplasias Colorrectales , Regulación hacia Abajo , Sulfuro de Hidrógeno , Terapia Fototérmica , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/química , Animales , Terapia Fototérmica/métodos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/patología , Humanos , Ratones , Regulación hacia Abajo/efectos de los fármacos , Cistationina betasintasa/metabolismo , Cistationina betasintasa/antagonistas & inhibidores , Imagen Óptica , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Rayos Infrarrojos , Línea Celular Tumoral , Nanomedicina Teranóstica/métodosRESUMEN
Nitric oxide (NO), a ubiquitous gaseous transmitter in living systems, is closely associated with physiopathological processes in the endoplasmic reticulum and lysosomes. This free radical gas is very widely but very heterogeneously distributed in the biological microenvironment, which poses a great challenge to specifically detect its localized levels in certain subcellular regions. In this study, we proposed six subcellular targeting probes by rational molecular engineering and selected two probes with optimal performance for the precise spatiotemporal identification of endoplasmic reticulum (ER) and lysosomal NO fluctuations. The probes could rapidly undergo a N-nitrosation reaction with NO at a riveted subcellular location, blocking the initial photoinduced electron transfer (PET) process and generating bright fluorescence for precise mapping of NO in the ER and lysosomes. The screened probes have ultra-sensitive reactivity and ultra-low detection limits for NO, realizing the precise depiction of exogenous and endogenous NO in the corresponding subcellular area. Fluctuations in the subcellular levels of NO during inflammation were also successfully mapped by the probes. Our work will contribute to the accurate study of the physiological and pathological consequences of subcellular NO in various biological events.
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Colorantes Fluorescentes , Óxido Nítrico , Lisosomas , Retículo Endoplásmico , GasesRESUMEN
The increasing understanding of the intricate relationship between two crucial gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) in biological actions has generated significant interest. However, comprehensive monitoring of the dynamic fluctuations of endogenous NO and H2S remains a challenge. In this study, we have designed an innovative aggregation-induced reporter SAB-NH-SC with enhanced responsiveness to H2S for visualizing the fluctuations of intracellular NO and H2S. This probe leverages the hydrophilic properties of the pyridinium salt derivative, which can rapidly self-assemble into positively charged nanoparticles under physiological conditions, avoiding the introduction of organic solvents or tedious preparations. Notably, the reporter can repeatedly cycle S-nitrosation and SNO-transnitrosation reactions when successively treated with NO and H2S. Consequently, fluorescence alternation at 751 (H2S) and 639 nm (NO) facilitates the dynamic visualization of the alternating presence of H2S and NO within cells. This dynamic and reversible probe holds immense potential for unraveling the intricate interactions between NO and H2S in a complex network of biological applications.
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Gasotransmisores , Sulfuro de Hidrógeno , Nanopartículas , Óxido NítricoRESUMEN
Carbon monoxide shows great therapeutic potential in anti-cancer. In particular, the construction of multifunctional CO delivery systems can promote the precise delivery of CO and achieve ideal therapeutic effects, but there are still great challenges in design. In this work, a RSS and ROS sequentially activated CO delivery system is developed for boosting NIR imaging-guided on-demand photodynamic therapy. This designed system is composed of a CO releaser (BOD-CO) and a photosensitizer (BOD-I). BOD-CO can be specifically activated by hydrogen sulfide with simultaneous release of CO donor and NIR fluorescence that can identify H2S-rich tumors and guide light therapy, also depleting H2S in the process. Moreover, BOD-I generates 1O2 under long-wavelength light irradiation, enabling both PDT and precise local release of CO via a photooxidation mechanism. Such sequential activation of CO release by RSS and ROS ensured the safety and controllability of CO delivery, and effectively avoided leakage during delivery. Importantly, cytotoxicity and in vivo studies reveal that the release of CO combined with the depletion of endogenous H2S amplified PDT, achieving ideal anticancer results. It is believed that such theranostic nanoplatform can provide a novel strategy for the precise CO delivery and combined therapy involved in gas therapy and PDT.
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Monóxido de Carbono , Fotoquimioterapia , Especies Reactivas de Oxígeno , Fotoquimioterapia/métodos , Monóxido de Carbono/química , Especies Reactivas de Oxígeno/metabolismo , Humanos , Animales , Línea Celular Tumoral , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Ratones , Rayos Infrarrojos , Sulfuro de Hidrógeno/químicaRESUMEN
Proprotein convertase subtilisin/kexin type-9 (PCSK9), a secreted protein that is synthesized and spontaneously cleaved in the endoplasmic reticulum, has become a hot lipid-lowering target chased by pharmaceutical companies in recent years. Autophagosome-tethering compounds (ATTECs) represent a new strategy to degrade targeted biomolecules. Here, we designed and synthesized PCSK9·ATTECs that are capable of lowering PCSK9 levels via autophagy in vivo, providing the first report of the degradation of a secreted protein by ATTECs. OY3, one of the PCSK9·ATTECs synthesized, shows greater potency to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and improve atherosclerosis symptoms than treatment with the same dose of simvastatin. OY3 also significantly reduces the high expression of PCSK9 caused by simvastatin administration in atherosclerosis model mice and subsequently increases the level of low-density lipoprotein receptor, promoting simvastatin to clear plasma LDL-C and alleviate atherosclerosis symptoms. Thus, we developed a new candidate compound to treat atherosclerosis that could also promote statin therapy.
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Aterosclerosis , Proproteína Convertasa 9 , Ratones , Animales , Proproteína Convertasa 9/metabolismo , LDL-Colesterol/metabolismo , LDL-Colesterol/uso terapéutico , Simvastatina/farmacología , Simvastatina/uso terapéutico , Receptores de LDL/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , AutofagiaRESUMEN
Understanding biological events associated with H2Sn rather than mediated by H2S is of great significance but remains to be solved due to a lack of high-integrity imaging tools. In this study, we report a chemoselective probe for H2Sn over H2S through the molecular engineering of luminogens. Based on our search for H2Sn-activatable probes with high selectivity, we fabricate water-soluble and biocompatible nanoprobes. Such a designed nanoprobe shows rare aggregation-induced dual-color fluorescence responses to H2Sn, lighting up bright emissions at 588 and 750 nm, respectively. By use of this activatable dual-color fluorescence, high-integrity identification of intracellular H2Sn was successfully realized. Thus, our approach to H2Sn-activated multicolor fluorescent probes could provide valuable insight into interrogating H2Sn-mediated biological events.
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Sulfuro de Hidrógeno , Hidrógeno , Sulfuros , Colorantes Fluorescentes , Imagen Óptica/métodosRESUMEN
The poor water solubility of traditional activatable organic molecular probes usually limits their detection ability in physiological environment. In this work, a positively charged H2S probe was designed, which exhibited a significantly enhanced responsiveness to H2S in the aggregated state due to the increased positive charge density on the aggregate surface. Under physiological conditions, the probe could be activated by H2S with specificity and sensitivity to release near-infrared fluorescence signal. Moreover, endogenous H2S levels in living cells were successfully monitored by using this probe. We expect that this probe can provide a new strategy for the design of activatable probes to break the limitation of poor water solubility of conventional organic molecular probes.
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Colorantes Fluorescentes , Sulfuro de Hidrógeno , Humanos , Sondas Moleculares , Células HeLa , Imagen Óptica , AguaRESUMEN
Various signal molecules participate in complex biological processes in mitochondria. However, most currently available probes have problems in elucidating the functions of these active species in mitochondria due to the inability to light up these probes exclusively at the desired mitochondrial location, thereby compromising the specificity and accuracy. In this study, we present an on-demand photoactivation approach to the molecular design of optimized probes for precise spatiotemporal identification of mitochondrial H2S fluctuations. The designed probe with native yellow fluorescence can monitor the process into mitochondria but maintains nonfluorescent response to H2S during cellular delivery, providing the accurate timing of accumulation in mitochondria. On-demand photoactivation exclusively at the desired mitochondrial location affords a significant aggregation-enhanced and emissive response to H2S with lighting up red fluorescence at 690 nm, which is the only way to get such an emissive phenomenon and greatly improves the specificity and accuracy of targeting mitochondrial H2S. By using this photocontrolled fluorescence responsiveness to H2S, precise spatiotemporal identification of mitochondrial H2S fluctuations is successfully performed. Our work could facilitate advances toward interrogating the physiological and pathological consequences of mitochondrial H2S in various biological events.
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Sulfuro de Hidrógeno , Humanos , Colorantes Fluorescentes , Células HeLa , Mitocondrias , Microscopía FluorescenteRESUMEN
An H2O2-activated, endoplasmic reticulum-targeted theranostic probe was developed. This designed probe could be activated by H2O2, resulting in increased NIR fluorescence and photothermal signals, thus achieving specific recognition of H2O2 and further photothermal therapy in the endoplasmic reticulum of H2O2-overexpressing cancer cells.
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Nanopartículas , Neoplasias , Humanos , Terapia Fototérmica , Fototerapia/métodos , Peróxido de Hidrógeno , Nanomedicina Teranóstica/métodos , Retículo Endoplásmico , Línea Celular TumoralRESUMEN
Photothermal agents (PTAs) with minimized side effects are critical for transforming cancer photothermal therapy (PTT) into clinical applications. However, most currently available PTAs lack true selective activation to reduce side effects because of heavy spectral overlap between photothermal agents and their corresponding products. This study reports the construction of activatable PTAs with target-initiated large spectral separation for highly effective reduction of side effects. Such designed probes involve two H2O2-activatable PTAs, aza-BOD-B1 (single activatable site) and aza-BOD-B2 (multiple activatable site). After interacting with H2O2, aza-BOD-B1 only displays a mild absorption redshift (60 nm) from 750 nm to 810 nm with serious spectral overlap, resulting in a mild photothermal effect on normal tissues upon 808 nm light irradiation. In contrast, aza-BOD-B2 displays a large absorption spectral separation (150 nm) from 660 nm to 810 nm, achieving true selective activation to minimize side effects during PTT of cancer. Besides, in vitro and in vivo investigations demonstrated that aza-BOD-B2 can specifically induce photothermal ablation of cancer cells and tumors while leaving normal sites undamaged, whereas aza-BOD-B1 exhibits undesirable side effects on normal cells. Our study provides a practical solution to the problem of undesired side effects of phototherapy, an advance in precision medicine.
RESUMEN
γ-glutamyl transpeptidase (GGT) is a kind of cell-surface enzyme that is overexpressed in many cancer cells. It is of great significance to develop an ideal tool for the diagnosis of GGT-rich cancer cells. Here, we reported a simple-structured but effective imaging probe for the detection of GGT activity. In the presence of GGT, the γ-glutamyl linkage could be cleaved specifically to produce amino-substituted product, resulting in significant fluorescence enhancement at 578 nm. Moreover, we successfully employed the probe to monitor GGT activity in HepG2 cells. We envisaged that such a simple but effective imaging tool could improve the practical applications for bioimaging.
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Colorantes Fluorescentes , gamma-Glutamiltransferasa , Fluorescencia , Células Hep G2 , Humanos , AguaRESUMEN
Understanding the complex interplay among gasotransmitters is of great significance but remains technically challenging. In this study, we present the design and synthesis of a dually responsive BOD-NH-SC reporter for probing the dynamic and alternating existence of NO and H2 S in living cells. This designed reporter can repeatedly cycle S-nitrosation and transnitrosation reactions when successively treated with NO and H2 S, thus affording the interchange of NIR fluorescence at 645â nm (NO) and NIR II fluorescence at 936â nm (H2 S). In light of this unique fluorescence alternation between two colors, we synthesized water-soluble BOD-NH-SC dots to visualize the intracellular dynamics of NO and H2 S. These molecular probes thus provide a toolbox to elucidate the interplaying roles of NO and H2 S in the complex interaction networks of various signal transduction pathways.
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Fluorescent probes in the NIR-II region provide high bioimaging quality. Optimizing the probe structure to achieve NIR-II imaging is ongoing, but remains challenging. Herein, increasing the electron withdrawing ability of the substituent in monochlorinated BODIPY greatly adjusted the emission wavelength from the NIR-I to NIR-II region, giving an efficient design strategy of NIR-II probes.
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Compuestos de Boro/química , Colorantes Fluorescentes/química , Animales , Electrones , Células HCT116 , Halogenación , Células Hep G2 , Humanos , Ratones , Neoplasias/diagnóstico por imagen , Imagen Óptica , Espectrometría de Fluorescencia , Espectroscopía Infrarroja CortaRESUMEN
Activatable molecular probes hold great promise for targeted cancer imaging. However, the hydrophobic nature of most conventional probes makes them generate precipitated agglomerate in aqueous media, thereby annihilating their responsiveness to analytes and precluding their practical applications for bioimaging. This study reports the development of two small molecular probes with unprecedented aggregation enhanced responsiveness to H2S for in vivo imaging of H2S-rich cancers. The subtle modulation of the equilibrium between hydrophilicity and lipophilicity by N-methylpyridinium endows these designed probes with the capability of spontaneously self-assembling into nanoprobes under physiological conditions. Such probes in an aggregated state, rather than a molecular dissolved state, show NIR fluorescence light up and photoacoustic signals turn on upon H2S specific activation, allowing in vivo visualization and differentiation of cancers based on differences in H2S content. Thus, our study presents an effective design strategy which should pave the way to molecular design of optimized probes for precision cancer diagnostics.
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Colorantes Fluorescentes/química , Sulfuro de Hidrógeno/análisis , Imagen Óptica , Compuestos de Piridinio/química , Animales , Línea Celular Tumoral , Colorantes Fluorescentes/síntesis química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Estructura Molecular , Neoplasias Experimentales/diagnóstico por imagen , Compuestos de Piridinio/síntesis químicaRESUMEN
An activatable and mitochondrial-targetable fluorescent probe was developed. This designed probe showed ratiometric fluorescence and light-up near-infrared emission responsiveness to nitroreductase, achieving precise imaging of mitochondria in cancer cells by real-time monitoring of nitroreductase activity.
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Colorantes Fluorescentes/química , Mitocondrias/metabolismo , Neoplasias/metabolismo , Nitrorreductasas/metabolismo , Imagen Óptica/métodos , Células A549 , HumanosRESUMEN
We present an approach for constructing a H2S-specific nanoprobe by the entrapment of a small molecule probe within the hydrophobic interior of surface cross-linked micelles (SCMs), endowing the designed nanoprobes with good water solubility and biocompatibility. Importantly, the obtained nanoprobes displayed good responsiveness to H2S in both ratiometric fluorescence and light-up NIR emission modes, thus enabling accurate identification of H2S-rich colorectal cancer cells.
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Materiales Biocompatibles/química , Neoplasias Colorrectales/diagnóstico por imagen , Colorantes Fluorescentes/química , Sulfuro de Hidrógeno/análisis , Nanopartículas/química , Imagen Óptica , Materiales Biocompatibles/síntesis química , Colorantes Fluorescentes/síntesis química , Células HCT116 , Humanos , Micelas , Tamaño de la Partícula , Propiedades de Superficie , Agua/químicaRESUMEN
NIR-light-absorbing photosensitizers with the capability of selective localization and activation in tumor regions are of great importance for practical photodynamic therapy (PDT). Here, selenophenol substituted BODIPYs were designed and synthesized as new photosensitizers for PDT. One of these obtained BODIPYs, IBSeOV, possesses an intense and low energy absorption with a high singlet oxygen quantum yield (ΦΔ = 60%). Considering manganese dioxide (MnO2) nanosheets as versatile nanocarriers in cancer theranostics, nanosystem IBSeOV/MnO2 was then fabricated to furnish tumor environment selective activation. Such designed nanoplatform allowed for GSH-controllable 1O2 production and exhibited low cytotoxicity in dark but good photocytotoxicity to cancer cells. The in vivo antitumor outcome suggested the high treatment efficiency of IBSeOV/MnO2 for tumor therapy.