NEO100 enables brain delivery of blood‒brain barrier impermeable therapeutics.
NEO100 enables brain delivery of blood‒brain barrier impermeable therapeutics.
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NEO100 能够向大脑输送血脑屏障不可渗透的治疗药物。
DOI：
10.1093/neuonc/noaa206
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发表时间：
2021
期刊：
影响因子：
15.9
通讯作者：
Chen,ThomasC
中科院分区：
文献类型：
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作者：
Wang,Weijun;Marín-Ramos,NagoreI;He,Haiping;Zeng,Shan;Cho,Hee-Yeon;Swenson,StephenD;Zheng,Long;Epstein,AlanL;Schönthal,AxelH;Hofman,FlorenceM;Chen,Ligang;Chen,ThomasC
背景颈动脉内注射甘露醇已经应用了几十年，以支持治疗药物进入大脑，否则不能有效地穿过血脑屏障（BBB）。然而，这一程序的复杂性和高风险性使其仅限于设备齐全的医疗中心使用。我们正在开发一种更直接的方法来安全地打开血脑屏障，基于动脉内（IA）注射NEO 100，一种高度纯化的版本的天然单萜紫苏醇。MethodsIn体外屏障渗透性NEO 100进行了评估，通过transepithelial/transendothelial电阻和抗体扩散试验。其作用机制通过蛋白质印迹、微阵列分析和电子显微镜进行了研究。在小鼠模型中，我们进行了超声引导下心内注射NEO 100，随后静脉内应用伊文思蓝、甲氨蝶呤、检查点抑制抗体或嵌合抗原受体（CAR）T细胞。它能够大大增加所有测试的治疗剂的脑进入，并且动物耐受性良好。机制的研究揭示了NEO 100对不同的血脑屏障运输途径的影响，沿着易位的紧密连接蛋白从膜到细胞质中的脑内皮cells.ConclusionWe设想，这个过程可以翻译成患者的形式，经股动脉导管插入术和插管的脑动脉，这是一个低风险的程序，常用于各种临床设置。与NEO 100结合，有望提供一种安全、广泛可用的方法，以增强任何治疗药物的脑内进入。
BackgroundIntracarotid injection of mannitol has been applied for decades to support brain entry of therapeutics that otherwise do not effectively cross the blood–brain barrier (BBB). However, the elaborate and high-risk nature of this procedure has kept its use restricted to well-equipped medical centers. We are developing a more straightforward approach to safely open the BBB, based on the intra-arterial (IA) injection of NEO100, a highly purified version of the natural monoterpene perillyl alcohol.MethodsIn vitro barrier permeability with NEO100 was evaluated by transepithelial/transendothelial electrical resistance and antibody diffusion assays. Its mechanism of action was studied by western blot, microarray analysis, and electron microscopy. In mouse models, we performed ultrasound-guided intracardiac administration of NEO100, followed by intravenous application of Evan’s blue, methotrexate, checkpoint-inhibitory antibodies, or chimeric antigen receptor (CAR) T cells.ResultsNEO100 opened the BBB in a reversible and nontoxic fashion in vitro and in vivo. It enabled greatly increased brain entry of all tested therapeutics and was well tolerated by animals. Mechanistic studies revealed effects of NEO100 on different BBB transport pathways, along with translocation of tight junction proteins from the membrane to the cytoplasm in brain endothelial cells.ConclusionWe envision that this procedure can be translated to patients in the form of transfemoral arterial catheterization and cannulation to the cerebral arteries, which represents a low-risk procedure commonly used in a variety of clinical settings. Combined with NEO100, it is expected to provide a safe, widely available approach to enhance brain entry of any therapeutic.