Kim Ja-Hae, Kim Ji-Hye, Thomas Reju George, Choi Kang-Ho, Jeong Yong-Yeon
Department of Biomedical Sciences, Chonnam National University Medical School and Hwasun Hospital, Hwasun, South Korea.
Department of Nuclear Medicine, Chonnam National University Medical School and Hospital, Gwangju, South Korea.
Biomater Res. 2024 Oct 24;28:0097. doi: 10.34133/bmr.0097. eCollection 2024.
Cerebral ischemia impairs blood circulation, leading to elevated reactive oxygen species (ROS) production. A ROS-responsive delivery of drugs can enhance the therapeutic efficacy and minimize the side effects. There is insufficient evidence on the impact of ROS-responsive nanoparticles on ischemic stroke. We developed ROS-responsive chitosan-bilirubin (ChiBil) nanoparticles to target acute ischemic lesions and investigated the effect of atorvastatin-loaded ROS-responsive ChiBil. We randomly assigned rats with transient middle cerebral artery occlusion (MCAO) to 4 groups: saline, Statin, ChiBil, and ChiBil-Statin. These groups were treated daily via the tail vein for 7 d. Behavioral assessment, magnetic resonance (MR) imaging, evaluation of neuroinflammation, blood-brain barrier (BBB) integrity, apoptosis, and neurogenesis after stroke were conducted. In vitro, results showed nanoparticle uptake and reduced intracellular ROS, lipid peroxidation, and inflammatory cytokines (IL-6 and TNF-α). In vivo, results showed improved motor deficits and decreased infarct volumes on MR images in the ChiBil-Statin group compared with the Control group on day 7 ( < 0.05). Furthermore, the expression of inflammatory cytokines such as IL-1β and IL-6 was reduced in the ChiBil-Statin group compared with the Control group ( < 0.05). Improvements in BBB integrity, apoptosis, and neurogenesis were observed in the ChiBil-Statin group. The findings demonstrated that intravenous ROS-responsive multifunctional ChiBil-Statin could effectively deliver drugs to the ischemic brain, exerting marked synergistic pleiotropic neuroprotective effects. Therefore, ChiBil-Statin holds promise as a targeted therapy for ischemic vascular diseases characterized by increased ROS production, leading to new avenues for future research and potential clinical applications.
脑缺血会损害血液循环，导致活性氧（ROS）生成增加。对ROS有反应的药物递送可以提高治疗效果并将副作用降至最低。关于ROS响应性纳米颗粒对缺血性中风影响的证据不足。我们开发了对ROS有反应的壳聚糖-胆红素（ChiBil）纳米颗粒，以靶向急性缺血性病变，并研究了负载阿托伐他汀的ROS响应性ChiBil的效果。我们将短暂性大脑中动脉闭塞（MCAO）的大鼠随机分为4组：生理盐水组、他汀组、ChiBil组和ChiBil-他汀组。这些组每天通过尾静脉给药，持续7天。进行了行为评估、磁共振（MR）成像、神经炎症评估、血脑屏障（BBB）完整性评估、细胞凋亡评估和中风后神经发生评估。在体外，结果显示纳米颗粒摄取以及细胞内ROS、脂质过氧化和炎性细胞因子（IL-6和TNF-α）减少。在体内，结果显示与第7天的对照组相比，ChiBil-他汀组的运动功能障碍有所改善，MR图像上的梗死体积减小（<0.05）。此外，与对照组相比，ChiBil-他汀组中IL-1β和IL-6等炎性细胞因子的表达降低（<0.05）。在ChiBil-他汀组中观察到血脑屏障完整性、细胞凋亡和神经发生的改善。研究结果表明，静脉注射对ROS有反应的多功能ChiBil-他汀可以有效地将药物递送至缺血性脑，发挥显著的协同多效性神经保护作用。因此，ChiBil-他汀有望成为针对以ROS生成增加为特征的缺血性血管疾病的靶向治疗方法，为未来的研究和潜在的临床应用开辟新途径。
