ROS-responsive dextran-benzeneboronic acid pinacol ester micelles encapsulating edaravone for the treatment and mechanism of cerebral ischemia-reperfusion injury.

IF 3.5 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Hexiang Zhao, Ping Yang, Mou Zhang, Wenshu Zheng, Renli Qi, Xiaofeng Zhu, Jinghui Li, Shipeng Li
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Abstract

Reperfusion, while essential for restoring blood supply, paradoxically exacerbates neuronal damage through cerebral ischemia-reperfusion injury (CIRI). This study aimed to develop a reactive oxygen species (ROS)-responsive drug delivery system (DDS) loaded with edaravone (EDA) to enhance targeted therapy for CIRI. The stimuli-responsive DDS was synthesized using dextran (DEX) as the biocompatible carrier and benzeneboronic acid pinacol ester (BAPE) as the ROS-sensitive moiety. The physicochemical characteristics of the DEX-BAPE/EDA (DB/EDA) micelles were systematically evaluated. In vitro studies assessed the anti-inflammatory, antioxidant, and anti-apoptotic effects of DB/EDA. Moreover, the neuroprotective efficacy of DB/EDA in vivo was analyzed via behavioral tests, infarct volume measurement, ELISA assays of inflammatory cytokines and OS markers, and Western blot analysis of Nrf2-related pathways. Pharmacokinetics and biosafety were analyzed through plasma profiling and H&E staining. DB/EDA exhibited high stability, efficient drug encapsulation, and ROS-responsive drug release. Cellular uptake studies confirmed enhanced internalization of DB/EDA micelles in BV2 cells. In the oxygen-glucose deprivation/reoxygenation (OGD/R) model, DB/EDA significantly suppressed TNF-α, IL-1β, IL-6, and MDA, restored SOD levels, and attenuated apoptosis. In the middle cerebral artery occlusion/reperfusion (MCAO/R) mice, DB/EDA administration effectively improves cognition and mitigates neuronal damage. Mechanistically, DB/EDA activated the Nrf2/HO-1 pathway, amplifying antioxidant and anti-inflammatory responses. Pharmacokinetic analysis revealed prolonged circulation and increased brain accumulation, and histopathological analysis demonstrated the safety profile of DB/EDA. The ROS-responsive DB/EDA nano-micelles provided targeted EDA delivery to ischemic brain regions, alleviating CIRI via Nrf2 activation, suggesting that DB/EDA is a promising strategy for CIRI treatment.

ros响应性右旋糖酐-苯硼酸松醇酯胶束包封依达拉奉治疗脑缺血再灌注损伤及其机制。
再灌注虽然对恢复血液供应至关重要,但矛盾的是,它通过脑缺血再灌注损伤(CIRI)加剧了神经元损伤。本研究旨在开发一种负载依达拉奉(EDA)的活性氧(ROS)应答药物递送系统(DDS),以增强对CIRI的靶向治疗。以葡聚糖(DEX)为生物相容性载体,苯硼酸松醇酯(BAPE)为ros敏感部分,合成了刺激响应型DDS。对DEX-BAPE/EDA (DB/EDA)胶束的理化特性进行了系统评价。体外研究评估了DB/EDA的抗炎、抗氧化和抗凋亡作用。此外,通过行为学实验、梗死体积测定、炎症因子和OS标志物ELISA检测以及nrf2相关通路的Western blot分析,分析DB/EDA在体内的神经保护作用。通过血浆谱和H&E染色分析药代动力学和生物安全性。DB/EDA具有高稳定性、高效包封和ros反应性释放等特点。细胞摄取研究证实了BV2细胞中DB/EDA胶束的内化增强。在氧葡萄糖剥夺/再氧化(OGD/R)模型中,DB/EDA显著抑制TNF-α、IL-1β、IL-6和MDA,恢复SOD水平,减轻细胞凋亡。在大脑中动脉闭塞/再灌注(MCAO/R)小鼠中,DB/EDA可有效改善认知,减轻神经元损伤。在机制上,DB/EDA激活Nrf2/HO-1通路,增强抗氧化和抗炎反应。药代动力学分析显示循环延长和脑蓄积增加,组织病理学分析显示DB/EDA的安全性。ros响应的DB/EDA纳米胶束提供靶向EDA递送到缺血脑区域,通过Nrf2激活减轻CIRI,表明DB/EDA是一种有前途的CIRI治疗策略。
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来源期刊
Metabolic brain disease
Metabolic brain disease 医学-内分泌学与代谢
CiteScore
5.90
自引率
5.60%
发文量
248
审稿时长
6-12 weeks
期刊介绍: Metabolic Brain Disease serves as a forum for the publication of outstanding basic and clinical papers on all metabolic brain disease, including both human and animal studies. The journal publishes papers on the fundamental pathogenesis of these disorders and on related experimental and clinical techniques and methodologies. Metabolic Brain Disease is directed to physicians, neuroscientists, internists, psychiatrists, neurologists, pathologists, and others involved in the research and treatment of a broad range of metabolic brain disorders.
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