Massachusetts General Hospital, Shriners Hospitals for Children-Boston, and Harvard Medical School, 51 Blossom Street, Boston, Massachusetts 02114, United States.
Mol Pharm. 2013 May 6;10(5):1522-32. doi: 10.1021/mp300474m. Epub 2013 Feb 12.
Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF, and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebrospinal fluid (CSF). The flux of the interstitial fluid in the CNS parenchyma, as well as the macro flux of CSF in the leptomeningeal space, are believed to be generally opposite to the desirable direction of CNS-targeted drug delivery. On the other hand, the available data suggest that the layer of pia mater lining the CNS surface is not continuous, and the continuity of the leptomeningeal space (LMS) with the perivascular spaces penetrating into the parenchyma provides an unexplored avenue for drug transport deep into the brain via CSF. The published data generally do not support the view that macromolecule transport from the LMS to CNS is hindered by the interstitial and CSF fluxes. The data strongly suggest that leptomeningeal transport depends on the location and volume of the administered bolus and consists of four processes: (i) pulsation-assisted convectional transport of the solutes with CSF, (ii) active "pumping" of CSF into the periarterial spaces, (iii) solute transport from the latter to and within the parenchyma, and (iv) neuronal uptake and axonal transport. The final outcome will depend on the drug molecule behavior in each of these processes, which have not been studied systematically. The data available to date suggest that many macromolecules and nanoparticles can be delivered to CNS in biologically significant amounts (>1% of the administered dose); mechanistic investigation of macromolecule and particle behavior in CSF may result in a significantly more efficient leptomeningeal drug delivery than previously thought.
目前，针对涉及中枢神经系统（CNS）的几种疾病还没有有效的治疗方法，因为中枢神经系统受到血脑、血脑脊液和血蛛网膜屏障的保护。穿透这些屏障中的任何一个都很困难，尤其是对于大分子药物和颗粒物质而言。然而，有大量实验证据表明，大分子可以通过脑脊液（CSF）递送到中枢神经系统。中枢神经系统实质间隙液的通量以及软脑膜空间中的 CSF 宏观通量，通常与中枢神经系统靶向药物递送的理想方向相反。另一方面，现有数据表明，覆盖中枢神经系统表面的软脑膜层并非连续的，软脑膜空间（LMS）与穿透实质的血管周围空间的连续性为通过 CSF 将药物输送到大脑深处提供了一条未被探索的途径。已发表的数据通常不支持大分子从 LMS 向 CNS 转运受到间隙液和 CSF 通量阻碍的观点。这些数据强烈表明，软脑膜转运取决于给药剂量的位置和体积，并且由四个过程组成：（i）与 CSF 一起的溶质的脉动辅助对流转运，（ii）将 CSF 主动“泵入”到动脉周围空间，（iii）溶质从后者向实质内的转运，以及（iv）神经元摄取和轴突转运。最终结果将取决于药物分子在这些过程中的行为，而这些过程尚未得到系统研究。迄今为止获得的数据表明，许多大分子和纳米颗粒可以以生物上有意义的量（>给予剂量的 1%）递送到 CNS；对 CSF 中大分子和颗粒物质行为的机制研究可能会导致比以前认为的更有效的软脑膜药物递送。
