Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2013 Apr 24;8(4):e61694. doi: 10.1371/journal.pone.0061694. Print 2013.
Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.
由于血脑屏障（BBB）的存在，限制了大于 500Da 的分子进入中枢神经系统（CNS），因此用于治疗中枢神经系统疾病的神经药物的应用受到了极大的限制。开发一种可靠的方法来绕过 BBB 将是神经药理学的巨大进步，使许多潜在的疾病修饰治疗方法得以应用。以前的尝试，如经颅导管植入，已被证明是暂时的，并伴有多种并发症。在这里，我们描述了一种使用纯自体组织在 BBB 上创建半渗透窗的新方法，以允许将高分子量（HMW）药物递送到 CNS。这种方法的灵感来自于最近在人类经鼻内镜颅底外科技术方面的进展，涉及将半渗透的鼻腔黏膜移植到 BBB 的手术缺损中。黏膜移植物因此为药物进入 CNS 创造了一个永久性的跨黏膜通道。本研究的主要目的是开发这种技术的小鼠模型，并利用它评估跨黏膜通透性，以便直接将药物递送到大脑。使用这种模型，我们证明黏膜移植物允许分子高达 500 kDa 的物质以时间和分子量依赖的方式直接进入大脑。高达 40 kDa 的标志物被发现存在于纹状体中，这表明该技术在治疗帕金森病方面具有潜在的作用。这项原理验证研究表明，黏膜移植代表了第一种绕过 BBB 的永久性和稳定方法，为 HMW 治疗药物直接进入 CNS 提供了途径。
