ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics.
ABSTRACT
Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments. Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining. Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment. Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment.
Subject(s)
Autism Spectrum Disorder , Cognitive Dysfunction , Disease Models, Animal , Doublecortin Protein , Fullerenes , Mice, Inbred C57BL , Animals , Mice , Fullerenes/pharmacology , Fullerenes/chemistry , Autism Spectrum Disorder/drug therapy , Cognitive Dysfunction/drug therapy , Male , Social Behavior , Behavior, Animal/drug effects , Hippocampus/drug effects , Vascular Endothelial Growth Factor A/genetics , Neuroprotective Agents/pharmacology , Neurogenesis/drug effects , Autistic Disorder/drug therapyABSTRACT
DNA double-strand breaks (DSBs) yield highly determines radiotherapy efficacy. However, improving the inherent radiosensitivity of tumor DNA to promote radiation-induced DSBs remains a challenge. Using theoretical and experimental models, the underexplored impact of Z-DNA conformations on radiosensitivity, yielding higher DSBs than other DNA conformations, is discovered. Thereout, a radiosensitization strategy focused on inducing Z-DNA conformation, utilizing CBL@HfO2 nanocapsules loaded with a Z-DNA inducer CBL0137, is proposed. A hollow mesoporous HfO2 (HM-HfO2) acts as a delivery and an energy depositor to promote Z-DNA breakage. The nanocapsule permits the smart DSBs accelerator that triggers its radiosensitization with irradiation stimulation. Impressively, the CBL@HfO2 facilitates the B-Z DNA conformational transition, augmenting DSBs about threefold stronger than irradiation alone, generating significant tumor suppression with a 30% cure rate. The approach enables DSBs augmentation by improving the inherent radiosensitivity of DNA. As such, it opens up an era of Z-DNA conformation manipulation in radiotherapy.
Subject(s)
DNA Breaks, Double-Stranded , DNA, Z-Form , Nucleic Acid Conformation , DNA, Z-Form/chemistry , DNA Breaks, Double-Stranded/radiation effects , Humans , Animals , Mice , Nanocapsules/chemistry , Cell Line, Tumor , Radiation Tolerance , Radiation-Sensitizing Agents/chemistry , Neoplasms/radiotherapyABSTRACT
Radiotherapy commonly causes damage to healthy tissues, particularly radiation-induced skin injury (RISI) that affects a significant majority of patients undergoing radiotherapy. Effective treatments for RISI are lacking. This study focuses on the pathogenesis of RISI, which primarily involves oxidative stress. Excessive reactive oxygen species (ROS) generation during radiation induces damage to biological macromolecules, triggering oxidative stress and inflammation. To address this, ergothioneine (EGT), a natural and biocompatibile thiol compound with excellent antioxidant activity, is explored as a potential radiation-protective agent. By utilizing its specific transport and absorption in the skin tissue, as well as its efficient and stable clearance of radiation-induced "ROS storm", EGT is combined with sodium hyaluronate (NaHA) to develop a novel radiation protective dressing suitable for the skin. This EGT-NaHA dressing demonstrates an effective ability to scavenge free radicals and reduce oxidative stress in vitro and in vivo, reducing cellular apoptosis and inflammation. These results demonstrate the protective properties of EGT against RISI, with far-reaching implications for research and development in the field of radioprotection.
Subject(s)
Bandages , Ergothioneine , Hyaluronic Acid , Oxidative Stress , Radiation-Protective Agents , Skin , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Ergothioneine/pharmacology , Ergothioneine/chemistry , Animals , Oxidative Stress/drug effects , Oxidative Stress/radiation effects , Skin/drug effects , Skin/radiation effects , Skin/pathology , Mice , Humans , Radiation-Protective Agents/pharmacology , Radiation-Protective Agents/chemistry , Radiation-Protective Agents/therapeutic use , Reactive Oxygen Species/metabolism , Antioxidants/pharmacology , Antioxidants/chemistry , Apoptosis/drug effects , Apoptosis/radiation effects , Radiation Injuries/drug therapy , Radiation Injuries/prevention & controlABSTRACT
Excessive light exposure can damage photoreceptors and lead to blindness. Oxidative stress serves a key role in photo-induced retinal damage. Free radical scavengers have been proven to protect against photo-damaged retinal degeneration. Fullerol, a potent antioxidant, has the potential to protect against ultraviolet-B (UVB)-induced cornea injury by activating the endogenous stem cells. However, its effects on cell fate determination of Müller glia (MG) between gliosis and de-differentiation remain unclear. Therefore, we established a MG lineage-tracing mouse model of light-induced retinal damage to examine the therapeutic effects of fullerol. Fullerol exhibited superior protection against light-induced retinal injury compared to glutathione (GSH) and reduced oxidative stress levels, inhibited gliosis by suppressing the TGF-ß pathway, and enhanced the de-differentiation of MG cells. RNA sequencing revealed that transcription candidate pathways, including Nrf2 and Wnt10a pathways, were involved in fullerol-induced neuroprotection. Fullerol-mediated transcriptional changes were validated by qPCR, Western blotting, and immunostaining using mouse retinas and human-derived Müller cell lines MIO-M1 cells, confirming that fullerol possibly modulated the Nrf2, Wnt10a, and TGF-ß pathways in MG, which suppressed gliosis and promoted the de-differentiation of MG in light-induced retinal degeneration, indicating its potential in treating retinal diseases.
Subject(s)
Ependymoglial Cells , Retinal Degeneration , Animals , Mice , Humans , Ependymoglial Cells/metabolism , Retinal Degeneration/drug therapy , Retinal Degeneration/etiology , Retinal Degeneration/metabolism , Gliosis/drug therapy , Gliosis/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Retina/metabolism , Neuroglia , Transforming Growth Factor beta/metabolismABSTRACT
Lead halide perovskites (LHPs) are outstanding candidates for next-generation optoelectronic materials, with considerable prospects of use and commercial value. However, knowledge about their toxicity is scarce, which may limit their commercialization. Here, for the first time, we studied the cardiotoxicity and molecular mechanisms of representative CsPbBr3 nanoparticles in LHPs. After their intranasal administration to Institute of Cancer Research (ICR) mice, using advanced synchrotron radiation, mass spectrometry, and ultrasound imaging, we revealed that CsPbBr3 nanoparticles can severely affect cardiac systolic function by accumulating in the myocardial tissue. RNA sequencing and Western blotting demonstrated that CsPbBr3 nanoparticles induced excessive oxidative stress in cardiomyocytes, thereby provoking endoplasmic reticulum stress, disturbing calcium homeostasis, and ultimately leading to apoptosis. Our findings highlight the cardiotoxic effects of LHPs and provide crucial toxicological data for the product.
Subject(s)
Calcium Compounds , Nanoparticles , Animals , Mice , Calcium Compounds/toxicity , Myocardium , Oxides/toxicity , Nanoparticles/toxicityABSTRACT
Radiation-induced heart disease is a serious side effect of radiation therapy that can lead to severe consequences. However, effective and safe methods for their prevention and treatment are presently lacking. This study reports the crucial function of fullerenols in protecting cardiomyocytes from radiation injury. First, fullerenols are synthesized using a simple base-catalyzed method. Next, the as-prepared fullerenols are applied as an effective free radical scavenger and broad-spectrum antioxidant to protect against X-ray-induced cardiomyocyte injury. Their ability to reduce apoptosis via the mitochondrial signaling pathway at the cellular level is then verified. Finally, it is observed in animal models that fullerenols accumulate in the heart and alleviate myocardial damage induced by X-rays. This study represents a timely and essential analysis of the prevention and treatment of radiological myocardial injury, providing new insights into the applications of fullerenols for therapeutic strategies.
Subject(s)
Fullerenes , Radiation Injuries , Animals , Fullerenes/pharmacology , Fullerenes/therapeutic use , Antioxidants , Free Radical Scavengers , Myocytes, CardiacABSTRACT
Coronary heart disease (CHD) is one of the major causes of death and disability worldwide, especially in low- and middle-income countries and among older populations. Conventional diagnostic and therapeutic approaches have limitations such as low sensitivity, high cost and side effects. Nanotechnology offers promising alternative strategies for the diagnosis and treatment of CHD by exploiting the unique properties of nanomaterials. In this review, we use bibliometric analysis to identify research hotspots in the application of nanotechnology in CHD and provide a comprehensive overview of the current state of the art. Nanomaterials with enhanced imaging and biosensing capabilities can improve the early detection of CHD through advanced contrast agents and high-resolution imaging techniques. Moreover, nanomaterials can facilitate targeted drug delivery, tissue engineering and modulation of inflammation and oxidative stress, thus addressing multiple aspects of CHD pathophysiology. We discuss the application of nanotechnology in CHD diagnosis (imaging and sensors) and treatment (regulation of macrophages, cardiac repair, anti-oxidative stress), and provide insights into future research directions and clinical translation. This review serves as a valuable resource for researchers and clinicians seeking to harness the potential of nanotechnology in the management of CHD. STATEMENT OF SIGNIFICANCE: Coronary heart disease (CHD) is the one of leading cause of death and disability worldwide. Nanotechnology offers new strategies for diagnosing and treating CHD by exploiting the unique properties of nanomaterials. This review uses bibliometric analysis to uncover research trends in the use of nanotechnology for CHD. We discuss the potential of nanomaterials for early CHD detection through advanced imaging and biosensing, targeted drug delivery, tissue engineering, and modulation of inflammation and oxidative stress. We also offer insights into future research directions and potential clinical applications. This work aims to guide researchers and clinicians in leveraging nanotechnology to improve CHD patient outcomes and quality of life.
Subject(s)
Coronary Disease , Nanostructures , Humans , Quality of Life , Coronary Disease/diagnosis , Coronary Disease/therapy , Nanotechnology , Nanostructures/therapeutic use , InflammationABSTRACT
Radiation-induced colitis is a serious clinical problem worldwide. However, the current treatment options for this condition have limited efficacy and can cause side effects. To address this issue, colon-targeted fullerenol@pectin@chitosan gel microspheres (FPCGMs) are developed, which can aggregate on colon tissue for a long time, scavenge free radicals generated in the process of radiation, and regulate intestinal flora to mitigate damage to colonic tissue. First, FPCGMs exhibit acid resistance and colon-targeted release properties, which reduce gastrointestinal exposure and extend the local colonic drug residence time. Second, fullerenol, which has a superior scavenging ability and chemical stability, reduces oxidative stress in colonic epithelial cells. Based on this, it is found that FPCGMs significantly reduce inflammation in colonic tissue, mitigated damage to tight junctions of colonic epithelial cells, and significantly relieved radiation-induced colitis in mice. Moreover, 16S ribosomal DNA (16S rDNA) sequencing results show that the composition of the intestinal flora is optimized after FPCGMs are utilized, indicating that the relative abundance of probiotics increases while harmful bacteria are inhibited. These findings suggest that it is a promising candidate for treating radiation-induced colitis.
Subject(s)
Colitis , Gastrointestinal Microbiome , Mice , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Microspheres , Intestinal Mucosa , Colon/microbiology , Colitis/drug therapy , Disease Models, Animal , Mice, Inbred C57BLABSTRACT
Lead-based perovskite nanoparticles (Pb-PNPs) have found extensive applications across diverse fields. However, because of poor stability and relatively strong water solubility, the potential toxicity of Pb-PNPs released into the environment during their manufacture, usage, and disposal has attracted significant attention. Inhalation is a primary route through which human exposure to Pb-PNPs occurs. Herein, the toxic effects and underlying molecular mechanisms of Pb-PNPs in the respiratory system are investigated. The in vitro cytotoxicity of CsPbBr3 nanoparticles in BEAS-2B cells is studied using multiple bioassays and electron microscopy. CsPbBr3 nanoparticles of different concentrations induce excessive oxidative stress and cell apoptosis. Furthermore, CsPbBr3 nanoparticles specifically recruit the TGF-ß1, which subsequently induces epithelial-mesenchymal transition. In addition, the biodistribution and lung toxicity of representative CsPbBr3 nanoparticles in ICR mice are investigated following intranasal administration. These findings indicate that CsPbBr3 nanoparticles significantly induce pulmonary inflammation and epithelial-mesenchymal transition and can even lead to pulmonary fibrosis in mouse models. Above findings expose the adverse effects and molecular mechanisms of Pb-PNPs in the lung, which broadens the safety data of Pb-PNPs.
Subject(s)
Lead , Lung , Mice , Humans , Animals , Mice, Inbred ICR , Lead/toxicity , Tissue DistributionABSTRACT
Poor therapeutic outcomes of antioxidants in ophthalmologic clinical applications, including glutathione during photoreceptor degeneration in retinitis pigmentosa (RP), are caused by limited anti-oxidative capacity. In this study, fullerenols are synthesized and proven to be highly efficient in vitro radical scavengers. Fullerenol-based intravitreal injections significantly improve the flash electroretinogram and light/dark transition tests performed for 28 days on rd1 mice, reduce the thinning of retinal outer nuclear layers, and preserve the Rhodopsin, Gnat-1, and Arrestin expressions of photoreceptors. RNA-sequencing, RT-qPCR, and Western blotting validate that mitochondrial DNA (mt-DNA)-encoded genes of the electron transport chain (ETC), such as mt-Nd4l, mt-Co1, mt-Cytb, and mt-Atp6, are drastically downregulated in the retinas of rd1 mice, whereas nuclear DNA (n-DNA)-encoded genes, such as Ndufa1 and Atp5g3, are abnormally upregulated. Fullerenols thoroughly reverse the abnormal mt-DNA and n-DNA expression patterns of the ETC and restore mitochondrial function in degenerating photoreceptors. Additionally, fullerenols simultaneously repress Flap endonuclease 1 (FEN1)-mediated mt-DNA cleavage and mt-DNA leakage via voltage-dependent anion channel (VDAC) pores by downregulating the transcription of Fen1 and Vdac1, thereby inactivating the downstream pro-inflammatory cGAS-STING pathway. These findings demonstrate that fullerenols can effectively alleviate photoreceptor degeneration in rd1 mice and serve as a viable treatment for RP.
Subject(s)
Retinal Degeneration , Retinitis Pigmentosa , Mice , Animals , DNA, Mitochondrial/genetics , DNA, Mitochondrial/therapeutic use , Retinal Degeneration/drug therapy , Retinal Degeneration/genetics , Retinal Degeneration/metabolism , Retinitis Pigmentosa/drug therapy , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/metabolism , Mitochondria/metabolism , Disease Models, AnimalABSTRACT
The development of quantitative analytical methods to assess the heterogeneous distribution and penetration of nanodrugs in solid tumors is of great importance for anticancer nanomedicine. Herein, Expectation-Maximization (EM) iterate algorithm and threshold segmentation methods were used to visualize and quantify the spatial distribution patterns, penetration depth and diffusion features of two-sized hafnium oxide nanoparticles (s-HfO2 NPs in 2 nm and l-HfO2 NPs in 50 nm sizes) in mouse models of breast cancer using synchrotron radiation micro-computed tomography (SR-µCT) imaging technique. The three-dimensional (3D) SR-µCT images were reconstructed based on the EM iterate algorithm thus clearly displayed the size-related penetration and distribution within the tumors after intra-tumoral injection of HfO2 NPs and X-ray irradiation treatment. The obtained 3D animations clearly show that a considerable amount of s-HfO2 and l-HfO2 NPs diffused into tumor tissues at 2 h post-injection and displayed the obvious increase in the tumor penetration and distribution area within the tumors at day 7 after combination with low-dose X-ray irradiation treatment. A thresholding segmentation for 3D SR-µCT image was developed to assess the penetration depth and quantity of HfO2 NPs along the injection sites in tumors. The developed 3D-imaging techniques revealed that the s-HfO2 NPs presented more homogeneous distribution pattern, diffused more quickly and penetrated more deeply within tumor tissues than the l-HfO2 NPs did. Whereas, the low-dose X-ray irradiation treatment greatly enhanced the wide distribution and deep penetration of both s-HfO2 and l-HfO2 NPs. This developed method may provide quantitative distribution and penetration information for the X-ray sensitive high-Z metal nanodrugs in the cancer imaging and therapy.
Subject(s)
Nanoparticles , Neoplasms , Mice , Animals , X-Ray Microtomography , Synchrotrons , Imaging, Three-Dimensional/methodsABSTRACT
In recent years, with the deepening research, metal zinc oxide (ZnO) nanomaterials have become a popular research object in the biological field, particularly in biomedicine and food safety, which is attributed to their unique physicochemical properties such as high surface area and volume ratio, luminescence effect, surface characteristics and biological activities. Herein, this review provides a detailed overview of the ZnO nanomaterial-mediated biological applications that involve anti-bacterial, anti-tumor, anti-inflammation, skin care, biological imaging and food packaging applications. Importantly, the corresponding action mechanisms of ZnO nanomaterials are pointed. Additionally, the structure and structure-dependent physicochemical properties, the common synthesis methods and the biosafety of ZnO nanoparticles are revealed in brief. Finally, the significance and future challenges of ZnO nanomaterial applications are concluded.
ABSTRACT
Lead-based perovskite nanoparticles (Pb-PNPs) with superior optoelectronic properties are promising alternatives for the next generation of photovoltaics materials. This raises a great concern about their potential exposure toxicity in biological systems. However, little is known about their adverse effects on the gastrointestinal tract system so far. Here, the aim is to investigate the biodistribution, biotransformation, potential gastrointestinal tract toxicity, and effect on the gut microbiota after oral exposure to the CsPbBr3 perovskite nanoparticles (CPB PNPs). The advanced synchrotron radiation based microscopic X-ray fluorescence scanning and X-ray absorption near-edge spectroscopy demonstrate that high doses of CPB (CPB-H) PNPs can gradually transform into different lead-based compounds, subsequently accumulating in the gastrointestinal tract, especially the colon. Meanwhile, the pathological changes of stomach, small intestine, and colon reveal that CPB-H PNPs have higher gastrointestinal tract toxicity than Pb(Ac)2 , consequently leading to colitis-like symptoms. More importantly, 16S rRNA gene sequencing analysis discloses that CPB-H PNPs cause more significant alterations in the richness and diversity of the gut microbiota related to inflammation, intestinal barrier, and immune function than Pb(Ac)2 . The findings may contribute to shedding light on understanding the adverse effects on gastrointestinal tract and gut microbiota of Pb-PNPs.
Subject(s)
Colitis , Gastrointestinal Microbiome , Nanoparticles , Humans , Dysbiosis , Lead/pharmacology , RNA, Ribosomal, 16S/metabolism , Tissue Distribution , Colitis/chemically induced , Nanoparticles/adverse effectsABSTRACT
Radiation gastroenteritis represents one of the most prevalent and hazardous complications of abdominopelvic radiotherapy, which not only severely reduces patients' life quality but also restricts radiotherapy efficacy. However, there is currently no clinically available oral radioprotector for this threatening disease due to its complex pathogenesis and the harsh gastrointestinal environment. To this end, this study developed a facile but effective oral radioprotector, ergothioneine hyaluronate (EGT@HA) gel, protecting against radiation gastroenteritis by synergistically regulating oxidative stress, inflammation, and gut microbiota. In vitro and cellular experiments verified the chemical stability and free radical scavenging ability of EGT and its favorable cellular radioprotective efficacy by inhibiting intracellular reactive oxidative species (ROS) generation, DNA damage, mitochondrial damage, and apoptosis. At the in vivo level, EGT@HA with prolonged gastrointestinal residence mitigated radiation-induced gastrointestinal tissue injury, apoptosis, neutrophil infiltration, and gut flora dysbiosis. For the first time, this work investigated the protective effects of EGT@HA gel on radiation gastroenteritis, which not only hastens the advancement of the novel gastrointestinal radioprotector but also provides a valuable gastrointestinal radioprotection paradigm by synergistically modulating oxidative stress, inflammation, and gut microbiota disturbance.
Subject(s)
Ergothioneine , Gastroenteritis , Gastrointestinal Microbiome , Radiation Injuries , Humans , Ergothioneine/genetics , Ergothioneine/pharmacology , Antioxidants/pharmacology , Dysbiosis/drug therapy , Dysbiosis/prevention & control , Apoptosis , Inflammation/drug therapy , Inflammation/prevention & controlABSTRACT
Aluminum (Al) has been classified as a cumulative environmental pollutant that endangers human health. There is increasing evidence to suggest the toxic effects of Al, but the specific action on human brain development remains unclear. Al hydroxide (Al(OH)3), the most common vaccine adjuvant, is the major source of Al and poses risks to the environment and early childhood neurodevelopment. In this study, we explored the neurotoxic effect of 5 µg/ml or 25 µg/ml Al(OH)3 for six days on neurogenesis by utilizing human cerebral organoids from human embryonic stem cells (hESCs). We found that early Al(OH)3 exposure in organoids caused a reduction in the size, deficits in basal neural progenitor cell (NPC) proliferation, and premature neuron differentiation in a time and dose-dependent manner. Transcriptomes analysis revealed a markedly altered Hippo-YAP1 signaling pathway in Al(OH)3 exposed cerebral organoid, uncovering a novel mechanism for Al(OH)3-induced detrimental to neurogenesis during human cortical development. We further identified that Al(OH)3 exposure at day 90 mainly decreased the production of outer radial glia-like cells(oRGs) but promoted NPC toward astrocyte differentiation. Taken together, we established a tractable experimental model to facilitate a better understanding of the impact and mechanism of Al(OH)3 exposure on human brain development.
Subject(s)
Human Embryonic Stem Cells , Neural Stem Cells , Child, Preschool , Humans , Aluminum Hydroxide/metabolism , Neurogenesis , Organoids/metabolismABSTRACT
Carbon monoxide (CO) is an endogenous signaling molecule with broad therapeutic effects. Here, a multifunctional X-ray-triggered carbon monoxide (CO) and manganese dioxide (MnO2 ) generation nanoplatform based on metal carbonyl and scintillating nanoparticles (SCNPs) is reported. Attributed to the radioluminescent characteristic of SCNPs, UV-responsive Mn2 (CO)10 is not only indirectly activated to release CO by X-ray but can also be degraded into MnO2 . A high dose of CO can be used as a glycolytic inhibitor for tumor suppression; it will also sensitize tumor cells to radiotherapy. Meanwhile MnO2 , as the photolytic byproduct of Mn2 (CO)10 , has both glutathione (GSH) depletion and Fenton-like Mn2+ delivery properties to produce highly toxic hydroxyl radical (â OH) in tumors. Thus, this strategy can realize X-ray-activated CO release, GSH depletion, and â OH generation for cascade cancer radiosensitization. Furthermore, X-ray-activated Mn2+ in vivo demonstrates an MRI contrast effect, making it a potential theranostic nanoplatform.
Subject(s)
Nanoparticles , Neoplasms , Humans , Manganese Compounds/pharmacology , Manganese Compounds/therapeutic use , Oxides/pharmacology , Carbon Monoxide/pharmacology , Carbon Monoxide/therapeutic use , X-Rays , Neoplasms/drug therapy , Neoplasms/metabolism , Cell Line, Tumor , Glutathione/metabolism , Hydrogen Peroxide/therapeutic useABSTRACT
A key characteristic of radiation-induced oral mucositis (RIOM) is oxidative stress mediated by the "reactive oxygen species (ROS) storm" generated from water radiolysis, resulting in severe pathological lesions, accompanied by a disturbance of oral microbiota. Therefore, a sprayable in situ hydrogel loaded with "free radical sponge" fullerenols (FOH) is developed as antioxidant agent for RIOM radioprotection. Inspired by marine organisms, 3,4,5-trihydroxyphenylalanine (TOPA) which is enriched in ascidians is grafted to clinically approved temperature-switchable Pluronic F127 to produce gallic acid (containing the TOPA fragment)-modified Pluronic F127 (MGA) hydrogels to resist the fast loss of FOH via biomimetic adhesion during oral movement and saliva erosion. Based on this, progressive RIOM found in mice is alleviated by treatment of FOH-loaded MGA hydrogels whether pre-irradiation prophylactic administration or post-irradiation therapeutic administration, which contributes to maintaining the homeostasis of oral microbiota. Mechanistically, FOH inhibits cell apoptosis by scavenging radiation-induced excess ROS and up-regulates the inherent enzymatic antioxidants, thereby protecting the proliferation and migration of mucosal epithelial cells. In conclusion, this work not only provides proof-of-principle evidence for the oral radioprotection of FOH by blocking the "ROS storm", but also provides an effective and easy-to-use hydrogel system for mucosal in situ administration.
Subject(s)
Microbiota , Radiation Injuries , Stomatitis , Urochordata , Animals , Mice , Antioxidants/pharmacology , Reactive Oxygen Species , Temperature , Poloxamer , Hydrogels , Stomatitis/drug therapy , Stomatitis/etiology , Stomatitis/prevention & control , HomeostasisABSTRACT
Oral squamous cell carcinoma (OSCC) is one of the most common oral malignancies. Radiotherapy is the primary noninvasive treatment of OSCC for avoiding surgery-induced facial deformities and impaired oral function. However, the specificity of in situ OSCC limits radiotherapeutic effects because of the hypoxia-induced low radiosensitivity of tumors and the low radiation tolerance of surrounding normal tissues. Here, we design a highly efficient and low-toxic radiosensitization strategy. On the one hand, biocompatible poly(vinyl pyrrolidone)-modified tantalum nanoparticles (Ta@PVP NPs) not only have strong X-ray deposition capability to upregulate oxidative stress but also have photothermal conversion efficiency to improve hypoxia for tumor radiosensitivity. On the other hand, to optimize the spatial distribution of Ta@PVP NPs within tumors, mussel-inspired catechol with bioadhesive properties is grafted on tumor microenvironment-responsive sodium alginate (DAA) to form in situ hydrogels for precision radiotherapy. On this basis, we find that Ta@PVP-DAA hydrogels effectively inhibit OSCC development in mice under photothermal-assisted radiotherapy without facial deformities and damage to surrounding normal tissues. Overall, our work not only promotes the exploration of Ta@PVP NPs as new radiosensitizers for OSCC but also develops a nanocomposite hydrogel system strategy as a promising paradigm for the precision treatment of orthotopic tumors.
Subject(s)
Carcinoma, Squamous Cell , Mouth Neoplasms , Animals , Mice , Nanogels , Carcinoma, Squamous Cell/drug therapy , Tantalum/pharmacology , Mouth Neoplasms/drug therapy , Hydrogels/pharmacology , Tumor MicroenvironmentABSTRACT
Tungsten-based nanomaterials (TNMs) with diverse nanostructures and unique physicochemical properties have been widely applied in the biomedical field. Although various reviews have described the application of TNMs in specific biomedical fields, there are still no comprehensive studies that summarize and analyze research trends of the field as a whole. To identify and further promote the development of biomedical TNMs, a bibliometric analysis method is used to analyze all relevant literature on this topic. First, general bibliometric distributions of the dataset by year, country, institute, referenced source, and research hotspots are recognized. Next, a comprehensive review of the subjectively recognized research hotspots in various biomedical fields, including biological sensing, anticancer treatments, antibacterials, and toxicity evaluation, is provided. Finally, the prospects and challenges of TNMs are discussed to provide a new perspective for further promoting their development in biomedical research.