Yang Yan, Wang Yiling, Jiang Xinran, Mi Jiahao, Ge Dizhang, Tong Yuna, Zhu Yuxuan
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, People's Republic of China.
Department of Pharmacy, People's Hospital of Aba Tibetan and Qiang Autonomous Prefecture, Aba, 624000, People's Republic of China.
Int J Nanomedicine. 2024 Sep 26;19:9943-9959. doi: 10.2147/IJN.S479242. eCollection 2024.
Alzheimer's disease (AD), a neurodegenerative condition, stands as the most prevalent form of dementia. Its complex pathological mechanisms and the formidable blood-brain barrier (BBB) pose significant challenges to current treatment approaches. Oxidative stress is recognized as a central factor in AD, underscoring the importance of antioxidative strategies in its treatment. In this study, we developed a novel brain-targeted nanoparticle, Ce/Zr-MOF@Cur-Lf, for AD therapy.
Layer-by-layer self-assembly technology was used to prepare Ce/Zr-MOF@Cur-Lf. In addition, the effect on the intracellular reactive oxygen species level, the uptake effect by PC12 and bEnd.3 cells and the in vitro BBB permeation effect were investigated. Finally, the mouse AD model was established by intrahippocampal injection of Aβ, and the in vivo biodistribution, AD therapeutic effect and biosafety of the nanoparticles were researched at the animal level.
As anticipated, Ce/Zr-MOF@Cur-Lf demonstrated efficient BBB penetration and uptake by PC12 cells, leading to attenuation of HO-induced oxidative damage. Moreover, intravenous administration of Ce/Zr-MOF@Cur-Lf resulted in rapid brain access and improvement of various pathological features of AD, including neuronal damage, amyloid-β deposition, dysregulated central cholinergic system, oxidative stress, and neuroinflammation.
Overall, Ce/Zr-MOF@Cur-Lf represents a promising approach for precise brain targeting and multi-target mechanisms in AD therapy, potentially serving as a viable option for future clinical treatment.
阿尔茨海默病（AD）是一种神经退行性疾病，是最常见的痴呆形式。其复杂的病理机制以及强大的血脑屏障（BBB）给当前的治疗方法带来了重大挑战。氧化应激被认为是AD的核心因素，这突出了抗氧化策略在其治疗中的重要性。在本研究中，我们开发了一种用于AD治疗的新型脑靶向纳米颗粒Ce/Zr-MOF@Cur-Lf。
采用层层自组装技术制备Ce/Zr-MOF@Cur-Lf。此外，研究了其对细胞内活性氧水平的影响、对PC12和bEnd.3细胞的摄取效果以及体外血脑屏障渗透效果。最后，通过海马内注射Aβ建立小鼠AD模型，并在动物水平上研究了纳米颗粒的体内生物分布、AD治疗效果和生物安全性。
正如预期的那样，Ce/Zr-MOF@Cur-Lf表现出有效的血脑屏障穿透能力和被PC12细胞摄取的能力，从而减轻了HO诱导的氧化损伤。此外，静脉注射Ce/Zr-MOF@Cur-Lf导致其迅速进入大脑，并改善了AD的各种病理特征，包括神经元损伤、淀粉样β沉积、中枢胆碱能系统失调、氧化应激和神经炎症。
总体而言，Ce/Zr-MOF@Cur-Lf代表了一种在AD治疗中进行精确脑靶向和多靶点作用机制的有前景的方法，有可能成为未来临床治疗的可行选择。
