Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China.
National Institute on Drug Dependence & Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Int J Pharm. 2023 Apr 25;637:122724. doi: 10.1016/j.ijpharm.2023.122724. Epub 2023 Mar 22.
Depression is a serious psychiatric disorder with unsatisfactory outcomes due to difficulties in delivering therapeutic molecules from the periphery to the brain. Neuroinflammation plays a key role in neurobiology and the treatment of depression. Neutrophils can cross the blood-brain barrier (BBB) and infiltrate key brain regions related to the pathophysiology of depression during neuroinflammation. N-Acetyl Pro-Gly-Pro (PGP) peptides efficiently bind to CXCR2 receptors on the surface of neutrophils. The neuropeptide oxytocin demonstrated antidepressant properties in preclinical and clinical studies, but its inability to penetrate the BBB hampers its therapeutic applications. In this study, we established a novel drug delivery system based on neutrophil infiltration in key brain regions during neuroinflammation. PGP was used to modify oxytocin-loaded liposomes (PGP-OTL) as the target ligand. Systematic administration of PGP-OTL exhibited enhanced antidepressant properties resulting from elevated oxytocin concentrations, especially in the amygdala, a crucial depression-implicated brain region. Enhanced antidepressant effects of PGP-OTL, similar to the ones caused by central oxytocin infusion, were observed in behavioral measurement including forced swim and tail suspension tests. Our study demonstrated that PGP-OTL can "hitchhike" neutrophils and enhance delivery of therapeutics into the brain, thus providing the means for developing novel cell-liposome-based drug delivery strategies for depression therapy.
抑郁症是一种严重的精神疾病，由于难以将治疗分子从外周递送到大脑，其治疗效果并不理想。神经炎症在神经生物学和抑郁症治疗中起着关键作用。中性粒细胞可以穿过血脑屏障 (BBB)，并在神经炎症期间渗透到与抑郁症病理生理学相关的关键大脑区域。N-乙酰基脯氨酰-脯氨酸 (PGP) 肽可以有效地与中性粒细胞表面的 CXCR2 受体结合。神经肽催产素在临床前和临床研究中表现出抗抑郁特性，但由于其无法穿透血脑屏障，限制了其治疗应用。在这项研究中，我们建立了一种基于神经炎症期间中性粒细胞渗透到关键大脑区域的新型药物递送系统。PGP 用于修饰载有催产素的脂质体 (PGP-OTL) 作为靶配体。系统给予 PGP-OTL 表现出增强的抗抑郁特性，这是由于催产素浓度升高引起的，尤其是在杏仁核，这是一个与抑郁症有关的关键大脑区域。PGP-OTL 增强了抗抑郁作用，类似于中央催产素输注引起的作用，这在行为测量中得到了观察，包括强迫游泳和悬尾测试。我们的研究表明，PGP-OTL 可以“搭便车”中性粒细胞并增强治疗药物向大脑的递送，从而为开发新型基于细胞-脂质体的抑郁症治疗药物递送策略提供了手段。
