Zhou Yi, Chen Fengjiao, Lin Yutao, Wang Qiyao, Hong Yirui, Zhao Sifang, Gao Kangyang, Liang Hongze, Cui Wei, Zhao Lingling
Translational Medicine Center of Pain, Emotion and Cognition, Health Science Center, Ningbo University, Zhejiang, 315211, China.
School of Materials Science and Chemical Engineering, Ningbo University, Zhejiang, 315211, China.
Adv Healthc Mater. 2025 Sep;14(25):e2501962. doi: 10.1002/adhm.202501962. Epub 2025 Jul 7.
Ischemic stroke is a leading cause of mortality and disability, with ischemia-reperfusion injury exacerbating neuronal damage and neuroinflammation due to pathologically activated reactive oxygen species (ROS) production in the ischemic penumbra. Edaravone, a free radical scavenger, is approved for the clinical treatment of ischemic stroke. However, edaravone directly decreases ROS even at low concentrations, which may inhibit the physiological effects of ROS and largely limit the clinical application of edaravone. To overcome this challenge, a ROS-response nanoparticle system, edaravone-loaded DEX-CDIPBE (DEX-CDIPBE-ED), is developed for the selectively releasing edaravone in the ischemic penumbra during reperfusion, mitigating oxidative stress while minimizing off-target effects. DEX-CDIPBE-ED produces potent antioxidant and neuroprotective effects in neuronal cells mimicking ischemic and/or reperfusion phases of ischemic stroke. DEX-CDIPBE-ED further prevents behavioral deficits, reduces oxidative stress, and inhibites neuroinflammation with a higher potency than edaravone in the ischemic penumbra in middle cerebral artery occlusion/reperfusion (MCAO/R)-treated rats. These findings highlight the potential of DEX-CDIPBE-ED as a pathological activated antioxidative therapy for ischemic stroke, offering enhanced neuroprotection and reduced systemic toxicity.
缺血性中风是导致死亡和残疾的主要原因，缺血再灌注损伤会加剧神经元损伤和神经炎症，这是由于缺血半暗带中病理性激活的活性氧（ROS）生成所致。依达拉奉是一种自由基清除剂，已被批准用于缺血性中风的临床治疗。然而，依达拉奉即使在低浓度下也会直接降低ROS，这可能会抑制ROS的生理作用，并在很大程度上限制依达拉奉的临床应用。为了克服这一挑战，开发了一种ROS响应纳米颗粒系统，即载有依达拉奉的DEX-CDIPBE（DEX-CDIPBE-ED），用于在再灌注期间在缺血半暗带中选择性释放依达拉奉，减轻氧化应激，同时将脱靶效应降至最低。DEX-CDIPBE-ED在模拟缺血性中风缺血和/或再灌注阶段的神经元细胞中产生强大的抗氧化和神经保护作用。在大脑中动脉闭塞/再灌注（MCAO/R）处理的大鼠中，DEX-CDIPBE-ED在缺血半暗带中进一步预防行为缺陷、降低氧化应激并抑制神经炎症，其效力高于依达拉奉。这些发现突出了DEX-CDIPBE-ED作为缺血性中风病理激活抗氧化疗法的潜力，提供了增强的神经保护作用并降低了全身毒性。
