Thrombin-Responsive, Brain-Targeting Nanoparticles for Improved Stroke Therapy
Thrombin-Responsive, Brain-Targeting Nanoparticles for Improved Stroke Therapy
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凝血酶响应、脑靶向纳米颗粒可改善中风治疗
DOI：
10.1021/acsnano.8b04787
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发表时间：
2018-08-01
期刊：
影响因子：
17.1
通讯作者：
Zhou, Jiangbing
中科院分区：
文献类型：
--
作者：
Guo, Xing;Deng, Gang;Zhou, Jiangbing
目前对缺血性卒中的治疗是不够的。缺乏有效的药理学方法可以主要归因于难以克服血脑屏障。在这里，我们报告了一个简单的策略，合成蛋白酶反应，脑靶向纳米粒子，以改善中风的治疗。所得到的纳米颗粒通过缩小或扩大它们的尺寸来响应缺血微环境中富集的蛋白酶，包括凝血酶或基质金属蛋白酶-9。靶向递送使用与蛋白质结合的配体的表面缀合来实现，所述蛋白质被鉴定为使用蛋白质阵列在缺血脑中富集。通过筛选各种制剂，我们发现AMD 3100缀合的尺寸可收缩纳米颗粒（ASNP）表现出最大的递送效率。脑靶向作用主要由AMD 3100介导，AMD 3100与缺血脑组织中富集的CXCR 4相互作用。我们发现ASNP显著增强了格列本脲的疗效，格列本脲是一种有前途的中风治疗药物，其疗效受到其毒性的限制。由于其穿透缺血性脑的高效率和低毒性，我们预计ASNPs有可能转化为临床应用，以改善中风患者的治疗。
Current treatments for ischemic stroke are insufficient. The lack of effective pharmacological approaches can be mainly attributed to the difficulty in overcoming the blood brain barrier. Here, we report a simple strategy to synthesize protease-responsive, brain-targeting nanoparticles for the improved treatment of stroke. The resulting nanoparticles respond to proteases enriched in the ischemic microenvironment, including thrombin or matrix metalloproteinase-9, by shrinking or expanding their size. Targeted delivery was achieved using surface conjugation of ligands that bind to proteins that were identified to enrich in the ischemic brain using protein arrays. By screening a variety of formulations, we found that AMD3100-conjugated, size-shrinkable nanoparticles (ASNPs) exhibited the greatest delivery efficiency. The brain targeting effect is mainly mediated by AMD3100, which interacts with CXCR4 that is enriched in the ischemic brain tissue. We showed that ASNPs significantly enhanced the efficacy of glyburide, a promising stroke therapeutic drug whose efficacy is limited by its toxicity. Due to their high efficiency in penetrating the ischemic brain and low toxicity, we anticipate that ASNPs have the potential to be translated into clinical applications for the improved treatment of stroke patients.