Department of Biomedical Sciences, Kent State University, Kent, OH, 44240, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
AAPS J. 2017 Dec 14;20(1):18. doi: 10.1208/s12248-017-0176-3.
Simvastatin (Sim), a lipid-lowering drug has been studied in chronic neuroinflammation associated with degenerative brain disorders due to its potential protective properties against inflammatory reaction, oxidative damage, neuronal dysfunction, and death. Meanwhile, potential application of Sim in neuroinflammation will require a suitable delivery system that can overcome notable challenges pertaining to poor blood-brain barrier (BBB) permeability and side/off-target effects. Herein, we engineered and characterized nano-sized polymersomes loaded with Sim (Sim-Ps) using PEG-PdLLA (methoxy polyethylene glycol-poly(D,L) lactic acid) diblock co-polymers. Studies in BV2 microglia indicated that Sim-Ps was superior to Sim alone in suppressing nitric oxide (NO) and proinflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) secretion against LPS activation. The effectiveness of Sim-Ps as compared with Sim alone, in attenuating NO and cytokine production by activated BV2 cells can be attributed to (a) colloidal stability of the delivery platform, (b) protracted release of biologically active Sim, and (c) particulate internalization coupled with enhanced Sim exposure to BV2 cells. Intranasal delivery in BALB/c mice demonstrated enhanced brain distribution with increasing time after administration. Overall data demonstrated suitability of PEG-PdLLA polymersomes in Sim delivery for potential application in treating neuroinflammation.
辛伐他汀（Sim）是一种降脂药物，由于其具有抗炎反应、氧化损伤、神经元功能障碍和死亡的潜在保护特性，因此已在与退行性脑疾病相关的慢性神经炎症中进行了研究。同时，Sim 在神经炎症中的潜在应用将需要一种合适的递送系统，该系统可以克服血脑屏障（BBB）通透性差和脱靶/副作用等显著挑战。在此，我们使用聚乙二醇-聚（D，L）乳酸（PEG-PdLLA）两亲性嵌段共聚物，设计并表征了载有 Sim 的纳米级聚合物囊泡（Sim-Ps）。在 BV2 小胶质细胞中的研究表明，Sim-Ps 在抑制 LPS 激活时的一氧化氮（NO）和促炎细胞因子（白细胞介素 6（IL-6）和肿瘤坏死因子-α（TNF-α）分泌方面优于单独使用 Sim。与单独使用 Sim 相比，Sim-Ps 可减轻激活的 BV2 细胞中 NO 和细胞因子的产生，这归因于（a）递药平台的胶体稳定性，（b）生物活性 Sim 的持续释放，以及（c）颗粒内化并增强了 Sim 与 BV2 细胞的接触。在 BALB/c 小鼠中的鼻内递送研究表明，给药后随着时间的增加，脑内分布增加。总体数据表明，PEG-PdLLA 聚合物囊泡适合用于 Sim 递送，可潜在应用于治疗神经炎症。
