Polymeric Nanoparticles-Based Brain Delivery with Improved Therapeutic Efficacy of Ginkgolide B in Parkinson's Disease.
Polymeric Nanoparticles-Based Brain Delivery with Improved Therapeutic Efficacy of Ginkgolide B in Parkinson's Disease.
复制标题
DOI：
10.2147/ijn.s272831
复制
发表时间：
2020
影响因子：
8
通讯作者：
Chen T
中科院分区：
文献类型：
--
作者：
Zhao Y;Xiong S;Liu P;Liu W;Wang Q;Liu Y;Tan H;Chen X;Shi X;Wang Q;Chen T
银杏内酯B(GB)是一种银杏内酯衍生物，被认为具有神经保护作用，是治疗帕金森氏病(PD)的理想药物。尽管GB具有良好的治疗性能，但口服后的生物利用度很低，而且不容易在接受治疗的患者中获得足够的暴露，限制了其在帕金森病治疗中的临床应用。为了提高其药效，我们利用聚乙二醇-聚己内酯共聚(ε-PCL)纳米粒子作为包埋GB(GB-NPs)的方法。这些NPs促进了GB在血液中的持续释放，从而提高了其在大脑中积累和治疗帕金森病的能力。利用Madin-Darby犬肾(MDCK)细胞，我们能够证实这些NPs可以通过多种非特异性机制进入细胞，包括微吞饮作用、依赖于笼蛋白的内吞作用和脂筏/小窝介导的内吞作用。一旦内化，这些NPs往往积聚在内质网和溶酶体中。在斑马鱼中，我们确定这些NPs能够很容易地通过绒毛膜、胃肠道、血脑和血视网膜屏障进行运输。在1-甲基-4-苯基吡啶离子(MPP+)诱导的神经元损伤模型系统中，我们证实了这些纳米粒子的神经保护作用。在大鼠口服后，GB-NPs表现出比游离GB更理想的药代动力学，在大脑和血液中都达到了更高的GB浓度。利用小鼠帕金森病模型，我们证明了这些GB-NPs与游离GB相比具有更好的治疗效果和更低的毒性。综上所述，这些结果表明，包埋GB的纳米粒可显著改善其口服生物利用度、脑蓄积和生物活性，其机制可能与其在体内的缓释有关。
Ginkgolide B (GB) is a terpene lactone derivative of Ginkgo biloba that is believed to function in a neuroprotective manner ideal for treating Parkinson’s disease (PD). Despite its promising therapeutic properties, GB has poor bioavailability following oral administration and cannot readily achieve sufficient exposure in treated patients, limiting its clinical application for the treatment of PD. In an effort to improve its efficacy, we utilized poly(ethylene glycol)-co-poly(ε-caprolactone) (PEG-PCL) nanoparticles as a means of encapsulating GB (GB-NPs). These NPs facilitated the sustained release of GB into the blood, thereby improving its ability to accumulate in the brain and to treat PD. Using Madin-Darby canine kidney (MDCK) cells, we were able to confirm that these NPs could be taken into cells via multiple nonspecific mechanisms including micropinocytosis, clathrin-dependent endocytosis, and lipid raft/caveolae-mediated endocytosis. Once internalized, these NPs tended to accumulate in the endoplasmic reticulum and lysosomes. In zebrafish, we determined that these NPs were readily able to undergo transport across the chorion, gastrointestinal, blood–brain, and blood-retinal barriers. In a 1-methyl-4-phenylpyridinium ion (MPP+)-induced neuronal damage model system, we confirmed the neuroprotective potential of these NPs. Following oral administration to rats, GB-NPs exhibited more desirable pharmacokinetics than did free GB, achieving higher GB concentrations in both the brain and the blood. Using a murine PD model, we demonstrated that these GB-NPs achieved superior therapeutic efficacy and reduced toxicity relative to free GB. In conclusion, these results indicate that NPs encapsulation of GB can significantly improve its oral bioavailability, cerebral accumulation, and bioactivity via mediating its sustained release in vivo.