The Innovation
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2024
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IF 33.2
Mengjie Jia,Wenjun Miao,Yiliang Li,Yajie Guo,Jieying Zeng,Yan Gao,Xinting Li,Yufan Wang,Zhenghuan Zhao,Zichen Xu,Nancy Wang,Fang Yang,Jing Zhao,Yi Wang,Guixue Wang
This study leverages the unique advantages of polyprodrug systems and biomimetic technology to develop a novel biomimetic nanoformulation, in which neutrophil extracellular vesicles (NEVs) are coated onto reactive oxygen species (ROS)-sensitive probucol-based polyprodrug nanoparticles (NPPBNPs). This NEV-camouflaged biomimetic nanoformulation holds significant potential for the effective treatment of cerebral ischemia-reperfusion injury (CIRI), offering multifaceted therapeutic effects, such as ROS elimination, inhibition of oxidative stress-induced neuronal apoptosis, attenuation of glial hyperactivation, and suppression of pro-inflammatory mediator secretion. In a murine CIRI model, NPPBNPs markedly enhanced neuronal viability, ameliorated the ischemic penumbra, restored behavioral functions, and exhibited an acceptable safety profile. The therapeutic mechanism of NPPBNPs involves NEV-mediated camouflage, which enables selective targeting of the pathological endothelium, thereby reducing peripheral neutrophil recruitment and facilitating blood-brain barrier (BBB) transport. Upon internalization by neurons, astrocytes, and microglia within ischemic regions, NPPBNPs respond to elevated intracellular ROS levels by releasing probucol in a controlled manner, which synergistically mitigates oxidative stress and inflammatory responses in CIRI-affected areas. Collectively, this multifunctional biomimetic nanoformulation represents a promising and practical strategy for the safe and effective treatment of CIRI.
研究领域:
药学
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神经科学
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纳米技术
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生物医学工程
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产品关联
DOI
高影响因子
Biomaterials Science
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2022
·Vol. 10
·期 24
·7103-7116
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IF 7.59
Wuxuan Wang,Zheng Zhang,Yi Liu,Lingqi Kong,Wenyu Li,Wei Hu,Yucai Wang,Xinfeng Liu
Potent antioxidative drugs are urgently needed to treat ischemia-reperfusion (I/R) induced reactive oxygen species (ROS)-mediated cerebrovascular and neural injury during ischemia strokes. However, current antioxidative agents have limited application in such disease due to low blood–brain barrier (BBB) penetration. We herein designed a “neutrophil piggybacking” strategy based on albumin opsonized nanoparticles co-encapsulated with antioxidases catalase (CAT) and superoxide dismutase 1 (SOD1). The system utilized the natural potential of neutrophils to target inflamed tissues to deliver antioxidases to injured sites in the brain. In addition, the system was integrated with a selenium (Se)-containing crosslinker to inhibit ferroptosis. We showed that the nanoparticles opsonized in the hybrid form rather than with an albumin-shell structure exhibited enhanced neutrophil targeting and efficient BBB penetration in vitro and in vivo. We further showed that the neutrophil-mediated delivery of antioxidases effectively reduced oxidative damage and apoptosis of neurons in brain tissue in a transient middle cerebral artery occlusion (tMCAO) mouse model. Moreover, the successful delivery of Se with the nanoparticles increased the expression of glutathione peroxidase 4 (GPX4) and effectively inhibited neuronal ferroptosis, achieving a satisfactory neuroprotective effect in I/R injury mice. Our study demonstrated that the rationally designed nanomedicines using the “neutrophil piggybacking” strategy can efficiently penetrate the BBB, greatly expanding the application of nanomedicines in the treatment of central nervous system (CNS) diseases.
研究领域:
神经科学
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纳米医学
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药学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
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IF 5
Lei Li,Guojun He,Mingyu Shi,Juehua Zhu,Yongqing Cheng,Yang Chen,Jin Chen,Qun Xue
Cerebral small vessel disease (CSVD) is one of the most important causes of stroke and vascular dementia , so exploring effective treatment modalities for CSVD is warranted. This study aimed to explore the anti-inflammatory effects of Edaravone dexborneol (C.EDA) in a CSVD model. Mice with CSVD showed distinct cognitive decline, as assessed by the Morris water maze (MWM). Pathological staining verified leakage across the blood‒brain barrier (BBB), microglial proliferation, neuronal loss and demyelination . Western blot analysis demonstrated that M1 microglia dominated prophase and released proinflammatory molecules; the aryl hydrocarbon receptor (AHR) was found to participate in modulating nuclear factor-kappa B (NF-κB) signalling activation through tumour necrosis factor receptor-associated factor-6 (TRAF6). C.EDA treatment resulted in the polarization of microglia from the M1 to the M2 phenotype. Mice sequentially treated with C.EDA exhibited a significant improvement in cognitive function; expression of the anti-inflammatory cytokines and modulatory proteins AHR and TRAF6 was upregulated, while the levels of pNF-κBp65 and pIΚBα were downregulated. C.EDA promoted microglial activation towards the M2 phenotype by upregulating AHR expression, which prevented TRAF6 ubiquitination , promoted NF-κB RelA/p65 protein degradation and inhibited subsequent NF-κB phosphorylation. Mechanistically, the anti-inflammatory effect of C.EDA alleviated neuronal loss and myelin damage, while at the functional level, C.EDA improved cognitive function and thus showed good application prospects.
研究领域:
神经科学
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药理学
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神经退行性疾病
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炎症
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2021
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IF 4.432
Yao Hua,Limei Zhou,Weidong Yang,Wenji An,Xiaolin Kou,Jian Ren,Hailang Su,Rong Chen,Zhengping Zhang,Jianjun Zou,Zhihong Zhao
Intracerebral hemorrhage (ICH) is a devastating disease, and there is currently no specific pharmacological treatment that can improve clinical outcomes. Y-2 sublingual tablets, each containing 30 mg edaravone and 6 mg (+) - borneol , is undergoing a phase III clinical trial for treatment of ischemic stroke in China. The purpose of the present study is to investigate the efficacy and potential mechanism of Y-2 in a rat model of collagenase IV injection induced ICH. Sublingual administration of Y-2 at the dose of 1, 3 and 6 mg/kg improved ICH-induced sensorimotor dysfunction, alleviated cell death and histopathological change, restored the hippocampal long-term potentiation (LTP), reduced brain edema and maintained blood-brain barrier (BBB) integrality in ICH rats. Further study demonstrated that Y-2 could reduce inflammatory response and oxidative stress by decreasing the levels of myeloperoxidase (MPO), ionized calcium-binding adaptor protein-1 (Iba-1), inflammatory cytokines and oxidative products, inhibit transcription factor nuclear factor-κB (NF-κB) activation, cyclooxygenase-2 (COX-2) and matrix metallopeptidase 9 (MMP-9) expression in brain tissue around in the core regions of hematoma . Importantly, the protective efficacy of Y-2 from ICH-induced injury was superior to edaravone. In conclusion, Y-2 sublingual tablets might be a promising therapeutic agent for the treatment of ICH.
研究领域:
神经病学
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药理学
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实验性卒中研究
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产品关联
DOI
PubMed
高影响因子
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