Department of Neurology The First Affiliated Hospital of Guangzhou Medical University Guangzhou 510120 China.
Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences & The Fifth Affiliated Hospital Guangzhou Medical University Guangzhou 511436 China.
Adv Sci (Weinh). 2021 Mar 3;8(9):2004555. doi: 10.1002/advs.202004555. eCollection 2021 May.
Parkinson's disease (PD) is characterized by the progressive deterioration of dopamine (DA) neurons, and therapeutic endeavors are aimed at preventing DA loss. However, lack of effective brain delivery approaches limits this strategy. In this study, a "Trojan horse" system is used for substantia nigra-targeted delivery of a blood brain barrier-penetrating peptide (RVG29) conjugated to the surface of nanoparticles loaded with the natural autophagy inducer 4,4'-dimethoxychalcone (DMC) (designated as RVG-nDMC). Here, the neuroprotective effects of DMC are demonstrated in PD. Specifically, RVG-nDMC penetrates the blood brain barrier with enhanced brain-targeted delivery efficiency and is internalized by DA neurons and microglia. In vivo studies demonstrate that RVG-nDMC ameliorates motor deficits and nigral DA neuron death in PD mice without causing overt adverse effects in the brain or other major organs. Moreover, RVG-nDMC reverses tyrosine hydroxylase ubiquitination and degradation, alleviates oxidative stress in DA neurons, and exerts antiinflammatory effects in microglia. The "Trojan horse" strategy for targeted delivery of DMC thus provides a potentially powerful and clinically feasible approach for PD intervention.
帕金森病（PD）的特征是多巴胺（DA）神经元进行性恶化，治疗方法旨在预防 DA 丧失。然而，缺乏有效的脑内递药方法限制了这一策略。在这项研究中，使用“特洛伊木马”系统将穿透血脑屏障的肽（RVG29）连接到载有天然自噬诱导剂 4,4'-二甲氧基查耳酮（DMC）的纳米颗粒的表面，用于向黑质进行靶向递药（指定为 RVG-nDMC）。在这里，证明了 DMC 在 PD 中的神经保护作用。具体而言，RVG-nDMC 穿透血脑屏障，具有增强的脑靶向递药效率，并被 DA 神经元和小胶质细胞内化。体内研究表明，RVG-nDMC 改善了 PD 小鼠的运动功能障碍和黑质 DA 神经元死亡，而不会在大脑或其他主要器官中引起明显的不良反应。此外，RVG-nDMC 逆转了酪氨酸羟化酶的泛素化和降解，减轻了 DA 神经元中的氧化应激，并发挥了小胶质细胞的抗炎作用。因此，DMC 的靶向递药“特洛伊木马”策略为 PD 干预提供了一种潜在的强大且可行的临床方法。
