RESUMO
The advent of drones has revolutionized various aspects of our lives, and in the realm of biological systems, molecular drones hold immense promise as "magic bullets" for major diseases. Herein, we introduce a unique class of fluorinated macromolecular amphiphiles, designed in the shape of jellyfish, serving as exemplary molecular drones for fluorine-19 MRI (19F MRI) and fluorescence imaging (FLI)-guided drug delivery, status reporting, and targeted cancer therapy. Functioning akin to their mechanical counterparts, these biocompatible molecular drones autonomously assemble with hydrophobic drugs to form uniform nanoparticles, facilitating efficient drug delivery into cells. The status of drug delivery can be tracked through aggregation-induced emission (AIE) of FLI and 19F MRI. Furthermore, when loaded with a heptamethine cyanine fluorescent dye IR-780, these molecular drones enable near-infrared (NIR) FL detection of tumors and precise delivery of the photosensitizer. Similarly, when loaded with doxorubicin (DOX), they enable targeted chemotherapy with fluorescence resonance energy transfer (FRET) FL for real-time status updates, resulting in enhanced therapeutic efficacy. Compared to conventional drug delivery systems, molecular drones stand out for their simplicity, precise structure, versatility, and ability to provide instantaneous status updates. This study presents prototype molecular drones capable of executing fundamental drone functions, laying the groundwork for the development of more sophisticated molecular machines with significant biomedical implications.
Assuntos
Doxorrubicina , Sistemas de Liberação de Medicamentos , Humanos , Animais , Sistemas de Liberação de Medicamentos/métodos , Doxorrubicina/química , Doxorrubicina/farmacologia , Halogenação , Camundongos , Nanopartículas/química , Corantes Fluorescentes/química , Substâncias Macromoleculares/química , Imagem Óptica/métodos , Imagem por Ressonância Magnética de Flúor-19/métodos , Neoplasias/tratamento farmacológico , Linhagem Celular TumoralRESUMO
The immune checkpoint blockade strategy has improved the survival rate of late-stage lung cancer patients. However, the low immune response rate limits the immunotherapy efficiency. Here, we report a ROS-responsive Fe3O4-based nanoparticle that undergoes charge reversal and disassembly in the tumor microenvironment, enhancing the uptake of Fe3O4 by tumor cells and triggering a more severe ferroptosis. In the tumor microenvironment, the nanoparticle rapidly disassembles and releases the loaded GOx and the immune-activating peptide Tuftsin under overexpressed H2O2. GOx can consume the glucose of tumor cells and generate more H2O2, promoting the disassembly of the nanoparticle and drug release, thereby enhancing the therapeutic effect of ferroptosis. Combined with Tuftsin, it can more effectively reverse the immune-suppressive microenvironment and promote the recruitment of effector T cells in tumor tissues. Ultimately, in combination with α-PD-L1, there is significant inhibition of the growth of lung metastases. Additionally, the hyperpolarized 129Xe method has been used to evaluate the Fe3O4 nanoparticle-mediated immunotherapy, where the ventilation defects in lung metastases have been significantly improved with complete lung structure and function recovered. The ferroptosis-enhanced immunotherapy combined with non-radiation evaluation methodology paves a new way for designing novel theranostic agents for cancer therapy.
Assuntos
Ferroptose , Imunoterapia , Imageamento por Ressonância Magnética , Espécies Reativas de Oxigênio , Ferroptose/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Camundongos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Isótopos de Xenônio/química , Nanopartículas de Magnetita/química , Linhagem Celular TumoralRESUMO
Smart lipids with fluorescence emission, thermal response, and polyethylene glycolation (PEGylation) functions can be highly valuable for formulation, image-traceable delivery, and targeted release of payloads. Herein, a series of jellyfish-shaped amphiphiles with a tetraphenylethene (TPE) core and four symmetrical amphiphilic side chains were conveniently synthesized and systematically investigated as smart lipids. Compared with regular amphiphilic TPE lipids and phospholipids, the unprecedented jellyfish-shaped molecular geometry was found to enable a series of valuable capabilities, including sensitive and responsive aggregation-induced emission of fluorescence (AIE FL) and real-time FL monitoring of drug uptake. Furthermore, the jellyfish-shaped geometry facilitated the concentration-dependent aggregation from unimolecular micelles at low concentrations to "side-by-side" spherical aggregates at high concentrations and a unique mode of AIE. In addition, the size and the arrangement of the amphiphilic side chains were found to dominate the aggregate stability, cell uptake, and thus the cytotoxicity of the amphiphiles. This study has unprecedentedly developed versatile smart TPE lipids with precise structures, and unique physicochemical and biological properties while the peculiar structure-property relationship may shed new light on the design and application of AIE fluorophores and functional lipids in biomedicine and materials science.
Assuntos
Corantes Fluorescentes , Micelas , Fluorescência , Membrana Celular , Corantes Fluorescentes/química , LipídeosRESUMO
OBJECTIVE: To analyze the factors affecting overall survival (OS) of adult patients with core-binding factor acute myeloid leukemia (CBF-AML) and establish a prediction model. METHODS: A total of 216 newly diagnosed patients with CBF-AML in the First Affiliated Hospital of Zhengzhou University from May 2015 to July 2021 were retrospectively analyzed. The 216 CBF-AML patients were divided into the training and the validation cohort at 7â¶3 ratio. The Cox regression model was used to analyze the clinical factors affecting OS. Stepwise regression was used to establish the optimal model and the nomogram. Receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA) were used to evaluate the model performance. RESULTS: Age(≥55 years old), peripheral blood blast(≥80%), fusion gene (AML1-ETO), KIT mutations were identified as independent adverse factors for OS. The area under the ROC curve at 3-year was 0.772 and 0.722 in the training cohort and validation cohort, respectively. The predicted value of the calibration curve is in good agreement with the measured value. DCA shows that this model performs better than a single factor. CONCLUSION: This prediction model is simple and feasible, and can effectively predict the OS of CBF-AML, and provide a basis for treatment decision.
Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Prognóstico , Estudos Retrospectivos , Pessoa de Meia-Idade , Feminino , Masculino , Mutação , Curva ROC , Fatores de Ligação ao Core/genética , Nomogramas , Adulto , Proteína 1 Parceira de Translocação de RUNX1/genética , Proteínas Proto-Oncogênicas c-kit/genética , Modelos de Riscos Proporcionais , Proteínas de Fusão Oncogênica/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genéticaRESUMO
BACKGROUND: Deciphering the molecular dynamics (MD) of rotaxanes is crucial for designing and refining their applications in molecular devices. This study employed fluorine-19 nuclear magnetic resonance (19F NMR) and magnetic resonance imaging (MRI) to unveil the interplay between mechanical bonds and steric hindrance in a series of fluorinated rotaxanes. RESULTS: 1H/19F NMR revealed stable "Z"-shaped wheel conformations minimizing steric clashes and favoring π-π interactions with the axle. Utilizing fluorines and axle protons as reporters, 1H/19F relaxation rates and solid-state 19F NMR studies demonstrated that mechanical bond primarily governs wheel motion, while steric hindrance dictates axle movement. Intriguingly, mechanical bond mainly affects local axle groups, leaving distant ones minimally impacted. MD simulations corroborated these findings. Temperature-dependent 19F NMR indicated that energy input enhances rotational motion and wheel conformational transitions. Furthermore, the drastic increase in 19F relaxation rates upon mechanical bond formation and steric hindrance enables sensitive and selective 19F MRI visualization of MD changes. SIGNIFICANCE: This study, by elucidating the roles of internal and external factors on rotaxane molecular dynamics using 19F NMR/MRI, offers valuable insights that can advance the field of rotaxane-based molecular devices.
RESUMO
Glycogen plays essential roles in glucose metabolism. Imaging glycogen in the liver, the major glycogen reservoir in the body, may shed new light on many metabolic disorders. 13C magnetic resonance spectroscopy (MRS) has become the mainstream method for monitoring glycogen in the body. However, the equipment of special hardware to standard clinical magnetic resonance imaging (MRI) scanners limits its clinical applications. Herein, we utilized endogenous glycogen as a T 2-based relaxation contrast agent for imaging glycogen metabolism in the liver in vivo. The in vitro results demonstrated that the transverse relaxation rate of glycogen strongly correlates with the concentration, pH, and field strength. Based on the Swift-Connick theory, we characterized the exchange property of glycogen and measured the exchange rate of glycogen as 31,847 Hz at 37 °C. Besides, the viscosity and echo spacing showed no apparent effect on the transverse relaxation rate. This unique feature enables visualization of glycogen signaling in vivo through T 2-weighted MRI. Two hours-post intraperitoneal injection of glucagon, a clinical drug to promote glycogenolysis and gluconeogenesis, the signal intensity of the mice's liver increased by 1.8 times from the T 2-weighted imaging experiment due to the decomposition of glycogen. This study provides a convenient imaging strategy to non-invasively investigate glycogen metabolism in the liver, which may find clinical applications in metabolic diseases.