Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.
Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.
复制标题
DOI：
10.1371/journal.pone.0061694
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Han X
中科院分区：
文献类型：
--
作者：
Bleier BS;Kohman RE;Feldman RE;Ramanlal S;Han X
由于血脑屏障（BBB）限制大于500 Da的分子到达CNS，因此神经药物用于中枢神经系统（CNS）疾病的使用受到高度限制。开发一种绕过BBB的可靠方法将代表神经药理学的巨大进步，从而能够使用许多潜在的疾病修饰疗法。以前的尝试，如经颅导管植入已被证明是暂时的，并与多种并发症。在这里，我们描述了一种新的方法，创建一个半渗透性的窗口，在血脑屏障使用纯自体组织，使高分子量（HMW）药物输送到中枢神经系统。这种方法的灵感来自于人类内窥镜经鼻颅底手术技术的最新进展，涉及在BBB中的手术缺损内植入半透性鼻粘膜。粘膜移植物由此产生用于药物进入CNS的永久性经粘膜管道。本研究的主要目的是开发这种技术的小鼠模型，并使用它来评估跨粘膜渗透性，以便将药物直接递送到大脑。使用这个模型，我们证明，粘膜移植允许高达500 kDa的分子直接运输到大脑中的时间和分子量依赖的方式。在纹状体内发现了高达40 kDa的标记物，表明该技术在治疗帕金森病中的潜在作用。这项原理证明研究表明，粘膜移植是绕过BBB的第一种永久和稳定的方法，从而为HMW治疗剂直接进入CNS提供了途径。
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.
登录
查看更多内容
影响因子：
82.9
作者：
Gill, SS;Patel, NK;Heywood, P
通讯作者：
Heywood, P
影响因子：
2.6
作者：
Bleier, Benjamin S.;Wang, Eric W.;Schlosser, Rodney J.
通讯作者：
Schlosser, Rodney J.
影响因子：
3.3
作者：
FISHER, AN;ILLUM, L;SCHACHT, EH
通讯作者：
SCHACHT, EH
影响因子：
3.4
作者：
Bleier, Benjamin S.;Palmer, James N.;Cohen, Noam A.
通讯作者：
Cohen, Noam A.
影响因子：
3
作者：
Merkus, Frans W H M;van den Berg, Mascha P
通讯作者：
van den Berg, Mascha P