Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles
Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles
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DOI：
10.7150/thno.35791
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhou, Jiangbing
中科院分区：
文献类型：
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作者：
Deng, Gang;Ma, Chao;Zhou, Jiangbing
中风是一种致命的疾病，没有有效的药物治疗，这是由于两个主要原因。首先，大多数疗法不能有效地渗透到大脑中。其次，单一药物治疗可能是不够的，有效的中风治疗需要靶向多个互补的靶点。在这里，我们致力于开发单组分、多功能纳米粒(NPs)，用于将格列本脲靶向输送到脑内用于治疗中风。方法：我们放射性标记格列本脲，静脉给药给卒中小鼠，并用正电子发射断层扫描-计算机断层扫描(PET/CT)测定其在脑中的蓄积。为了识别功能纳米材料以改善药物向大脑的输送，我们开发了一种化学提取方法，并测试了它用于从草药石蒜中分离纳米材料。为了评估治疗效果，我们合成了格列本脲纳米粒，并在卒中小鼠身上进行了评估。结果：我们发现格列本脲对脑缺血的穿透能力有限。我们鉴定了白桦酸(BA)能够形成NPs，静脉给药后，白桦酸作为抗氧化剂有效地渗透到大脑并显著减少缺血诱导的脑梗塞。我们发现BA纳米粒可以增强格列本脲的释放，从而产生比格列本脲或BA纳米粒更大的治疗效果。结论：本研究为鉴定功能纳米材料提供了一个新的方向，并为实现抗水肿和抗氧化联合治疗提供了一种简单的方法。由此产生的格列本脲负载BA纳米粒可能被转化为临床应用，以改善中风的临床治疗。
Stroke is a deadly disease without effective pharmacotherapies, which is due to two major reasons. First, most therapeutics cannot efficiently penetrate the brain. Second, single agent pharmacotherapy may be insufficient and effective treatment of stroke requires targeting multiple complementary targets. Here, we set to develop single component, multifunctional nanoparticles (NPs) for targeted delivery of glyburide to the brain for stroke treatment.Methods: To characterize the brain penetrability, we radiolabeled glyburide, intravenously administered it to stroke-bearing mice, and determined its accumulation in the brain using positron emission tomography-computed tomography (PET/CT). To identify functional nanomaterials to improve drug delivery to the brain, we developed a chemical extraction approach and tested it for isolation of nanomaterials from E. ulmoides, a medicinal herb. To assess the therapeutic benefits, we synthesized glyburide-loaded NPs and evaluated them in stroke-bearing mice.Results: We found that glyburide has a limited ability to penetrate the ischemic brain. We identified betulinic acid (BA) capable of forming NPs, which, after intravenous administration, efficiently penetrate the brain and significantly reduce ischemia-induced infarction as an antioxidant agent. We demonstrated that BA NPs enhance delivery of glyburide, leading to therapeutic benefits significantly greater than those achieved by either glyburide or BA NPs.Conclusion: This study suggests a new direction to identify functional nanomaterials and a simple approach to achieving anti-edema and antioxidant combination therapy. The resulting glyburide- loaded BA NPs may be translated into clinical applications to improve clinical management of stroke.