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Trojan Horse Delivery of 4,4′‐Dimethoxychalcone for Parkinsonian Neuroprotection
Advanced Science ( IF 14.3 ) Pub Date : 2021-03-03 , DOI: 10.1002/advs.202004555
Wenlong Zhang 1 , Huaqing Chen 2 , Liuyan Ding 1 , Junwei Gong 3 , Mengran Zhang 3 , Wenyuan Guo 1 , Pingyi Xu 1 , Shiying Li 2 , Yunlong Zhang 3
Affiliation  

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.

中文翻译:

特洛伊木马传递 4,4'-二甲氧基查尔酮用于帕金森神经保护

帕金森病 (PD) 的特点是多巴胺 (DA) 神经元进行性恶化,治疗努力旨在防止 DA 损失。然而,缺乏有效的大脑输送方法限制了这一策略。在这项研究中,“特洛伊木马”系统用于黑质靶向递送血脑屏障穿透肽(RVG29),该肽与负载天然自噬诱导剂 4,4'-二甲氧基查耳酮(DMC)的纳米颗粒表面缀合(指定为 RVG-nDMC)。在这里,DMC 的神经保护作用在 PD 中得到了证明。具体来说,RVG-nDMC 能够穿透血脑屏障,增强大脑靶向递送效率,并被 DA 神经元和小胶质细胞内化。体内研究表明,RVG-nDMC 可以改善 PD 小鼠的运动缺陷和黑质 DA 神经元死亡,而不会对大脑或其他主要器官造成明显的不利影响。此外,RVG-nDMC 可逆转酪氨酸羟化酶泛素化和降解,减轻 DA 神经元的氧化应激,并在小胶质细胞中发挥抗炎作用。因此,DMC 靶向递送的“特洛伊木马”策略为 PD 干预提供了一种潜在强大且临床可行的方法。
更新日期:2021-05-05
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