Kong Zhaohong, Jiang Jian, Deng Min, Deng Ming, Wu Huisheng
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430070, China.
Department of Orthopedics, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, No. 99 Zhangzhidong Road (former Ziyang Road), Wuchang District, Wuhan, 430070, Hubei Province, China.
J Nanobiotechnology. 2025 May 5;23(1):332. doi: 10.1186/s12951-025-03386-y.
The intricate pathogenesis of epilepsy, characterized by abnormal neuronal discharges and neuroinflammation, underscores the critical involvement of the adenosine triphosphate (ATP)-P2X purinoceptor 7 (P2 × 7) receptor pathway in inflammation activation. To address this, a reactive oxygen species (ROS)/electric-responsive d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-ferrocene-poloxamer nanomicelle (TFP@A) was engineered to deliver the P2 × 7 receptor antagonist A 438,079, aiming to provide a targeted therapeutic strategy for epilepsy management.
The study meticulously designed and characterized TFP@A for precise drug delivery through various techniques including transmission electron microscopy (TEM), dynamic light scattering (DLS), and high-performance liquid chromatography (HPLC). Cellular uptake and blood-brain barrier (BBB) permeability were evaluated using fluorescein isothiocyanate (FITC)-labeled TFP@A in vitro and in a brain endothelial cell line (bEnd.3) cell BBB model. In vivo distribution and safety assessments were conducted in an epilepsy mouse model. The impact of TFP@A on epilepsy was investigated through seizure analysis, electroencephalogram (EEG) recordings, and inflammatory pathway assessment.
TFP@A exhibited a robust drug release profile under ROS and electrical stimulation conditions. In vitro studies demonstrated its efficacy in scavenging ROS, reducing oxidative stress, and alleviating cell apoptosis in epilepsy models. Efficient cellular uptake, BBB penetration, and in vivo accumulation in the brain were observed. Notably, TFP@A effectively modulated the P2 × 7 receptor (P2 × 7R)-nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) pathway, inhibiting inflammatory mediators and promoting anti-inflammatory responses.
TFP@A loaded with the P2 × 7 receptor antagonist showcases potential therapeutic benefits in suppressing NLRP3 inflammasome activation, mitigating microglial-neuron crosstalk, and ameliorating epilepsy symptoms, positioning it as a promising avenue for targeted epilepsy treatment.
癫痫复杂的发病机制以神经元异常放电和神经炎症为特征，这突出了三磷酸腺苷（ATP）-P2X嘌呤受体7（P2×7）受体途径在炎症激活中的关键作用。为了解决这一问题，设计了一种活性氧（ROS）/电响应性聚乙二醇1000琥珀酸酯-α-生育酚（TPGS）-二茂铁-泊洛沙姆纳米胶束（TFP@A）来递送P2×7受体拮抗剂A 438,079，旨在为癫痫治疗提供一种靶向治疗策略。
本研究通过透射电子显微镜（TEM）、动态光散射（DLS）和高效液相色谱（HPLC）等多种技术精心设计并表征了TFP@A，以实现精确的药物递送。在体外和脑内皮细胞系（bEnd.3）细胞血脑屏障模型中，使用异硫氰酸荧光素（FITC）标记的TFP@A评估细胞摄取和血脑屏障（BBB）通透性。在癫痫小鼠模型中进行体内分布和安全性评估。通过癫痫发作分析、脑电图（EEG）记录和炎症途径评估来研究TFP@A对癫痫的影响。
TFP@A在ROS和电刺激条件下表现出强大的药物释放特性。体外研究证明了其在清除ROS、降低氧化应激以及减轻癫痫模型中细胞凋亡方面的功效。观察到其在细胞摄取、BBB穿透和脑内体内蓄积方面效率较高。值得注意的是，TFP@A有效调节了P2×7受体（P2×7R）-核苷酸结合寡聚化结构域样受体家族含pyrin结构域3（NLRP3）途径，抑制炎症介质并促进抗炎反应。
负载P2×7受体拮抗剂的TFP@A在抑制NLRP3炎性小体激活、减轻小胶质细胞与神经元的相互作用以及改善癫痫症状方面展现出潜在的治疗益处，使其成为靶向癫痫治疗的一个有前景的途径。
