Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
J Control Release. 2018 May 10;277:173-182. doi: 10.1016/j.jconrel.2018.03.019. Epub 2018 Mar 26.
Parkinson's disease (PD) remains one of the most common neurodegenerative movement disorders with limited treatment options available. A dopamine derivative N-3,4-bis(pivaloyloxy)-dopamine (BPD) previously developed in our group has demonstrated superior therapeutic outcome compared to levodopa in a PD mice model. To further improve the therapeutic performance of BPD, a brain targeted drug delivery system was designed using a 29 amino-acid peptide (RVG29) derived from rabies virus glycoprotein as the targeting ligand. RVG29 functionalized liposomes (RVG29-lip) showed significantly higher uptake efficiency in murine brain endothelial cells and dopaminergic cells, and high penetration efficiency across the blood brain barrier (BBB) in vitro. In vivo and ex vivo distribution studies demonstrated RVG29-lip selectively distributed to the brain, striatum and substantia nigra. Furthermore, BPD loaded RVG29-lip (BPD-RVG29-lip) exhibited improved therapeutic efficacy in a PD mouse model, while causing no obvious systemic toxicity after intravenous administration. Thus, BPD-RVG29-lip represents a highly promising approach for the brain targeted treatment of PD.
帕金森病（PD）仍然是最常见的神经退行性运动障碍之一，可用的治疗选择有限。我们小组之前开发的一种多巴胺衍生物 N-3,4-双（特戊酰氧基）-多巴胺（BPD）在 PD 小鼠模型中与左旋多巴相比显示出更好的治疗效果。为了进一步提高 BPD 的治疗性能，设计了一种使用源自狂犬病病毒糖蛋白的 29 个氨基酸肽（RVG29）作为靶向配体的脑靶向药物传递系统。RVG29 功能化脂质体（RVG29-lip）在小鼠脑内皮细胞和多巴胺能细胞中的摄取效率显著更高，并且在体外具有很高的血脑屏障（BBB）穿透效率。体内和离体分布研究表明，RVG29-lip 选择性地分布到大脑、纹状体和黑质。此外，负载 BPD 的 RVG29-lip（BPD-RVG29-lip）在 PD 小鼠模型中表现出改善的治疗效果，而静脉注射后没有明显的全身毒性。因此，BPD-RVG29-lip 代表了一种用于 PD 脑靶向治疗的很有前途的方法。
