Kanazawa Takanori, Kurano Takumi, Ibaraki Hisako, Takashima Yuuki, Suzuki Toyofumi, Seta Yasuo
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
Pharmaceutics. 2019 Sep 15;11(9):478. doi: 10.3390/pharmaceutics11090478.
We previously reported that siRNA delivery to the brain is improved by the nose-to-brain delivery route and by conjugation with polyethylene glycol-polycaprolactone (PEG-PCL) polymer micelles and the cell-penetrating peptide, Tat (PEG-PCL-Tat). In this study, we evaluated the nose-to-brain delivery of siRNA targeting TNF-α (siTNF-α) conjugated with PEG-PCL-Tat to investigate its therapeutic effects on a transient middle cerebral artery occlusion (t-MCAO) rat model of cerebral ischemia-reperfusion injury. Intranasal treatment was provided 30 min after infarction induced via suturing. Two hours after infarction induction, the suture was removed, and blood flow was released. At 22 h post-reperfusion, we assessed the infarcted area, TNF-α production, and neurological score to determine the therapeutic effects. The infarcted area was observed over a wide range in the untreated group, whereas shrinkage of the infarcted area was observed in rats subjected to intranasal administration of siTNF-α with PEG-PCL-Tat micelles. Moreover, TNF-α production and neurological score in rats treated by intranasal administration of siTNF-α with PEG-PCL-Tat micelles were significantly lower than those in untreated and naked siTNF-α-treated rats. These results indicate that nose-to-brain delivery of siTNF-α conjugated with PEG-PCL-Tat micelles alleviated the symptoms of cerebral ischemia-reperfusion injury.
我们之前报道过，通过鼻脑给药途径以及与聚乙二醇-聚己内酯（PEG-PCL）聚合物胶束和细胞穿透肽Tat（PEG-PCL-Tat）偶联，可改善小干扰RNA（siRNA）向脑内的递送。在本研究中，我们评估了与PEG-PCL-Tat偶联的靶向肿瘤坏死因子-α（TNF-α）的siRNA（siTNF-α）的鼻脑递送情况，以研究其对大脑缺血再灌注损伤的短暂性大脑中动脉闭塞（t-MCAO）大鼠模型的治疗效果。在通过缝合诱导梗死30分钟后进行鼻内治疗。诱导梗死后两小时，移除缝线并恢复血流。在再灌注22小时后，我们评估梗死面积、TNF-α产生情况和神经学评分，以确定治疗效果。在未治疗组中观察到梗死面积广泛，而在经鼻内给予与PEG-PCL-Tat胶束偶联的siTNF-α的大鼠中观察到梗死面积缩小。此外，经鼻内给予与PEG-PCL-Tat胶束偶联的siTNF-α治疗的大鼠的TNF-α产生量和神经学评分显著低于未治疗组和经裸siTNF-α治疗的大鼠。这些结果表明，与PEG-PCL-Tat胶束偶联的siTNF-α的鼻脑递送减轻了脑缺血再灌注损伤的症状。
