Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS.
Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS.
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DOI：
10.1021/mp300474m
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发表时间：
2013-05-06
影响因子：
4.9
通讯作者：
Gannon KS
中科院分区：
文献类型：
--
作者：
Papisov MI;Belov VV;Gannon KS
目前，对于涉及CNS的几种疾病没有有效的治疗方法，CNS受到血脑屏障、血CSF屏障和血蛛网膜屏障的保护。穿越这些障碍是困难的，特别是对于大分子药物和颗粒。然而，有重要的实验证据表明，大分子可以通过脑脊液（CSF）输送到CNS。CNS实质中的间质液的通量以及软脑膜间隙中的CSF的大通量被认为通常与CNS靶向药物递送的期望方向相反。另一方面，现有数据表明，衬在CNS表面的软脑膜层是不连续的，并且软脑膜间隙（LMS）与渗透到实质中的血管周围间隙的连续性为药物经由CSF深入脑内转运提供了未探索的途径。已发表的数据通常不支持大分子从LMS转运至CNS受到间质和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团的位置和体积，由四个过程组成：（i）CSF中溶质的脉动辅助对流转运，（ii）CSF主动“泵入”动脉周围空间，（iii）溶质从后者转运到实质和实质内，以及（iv）神经元摄取和轴突转运。最终的结果将取决于药物分子在这些过程中的行为，这些过程尚未得到系统的研究。迄今为止可用的数据表明，许多大分子和纳米颗粒可以以生物学上显著的量（>给药剂量的1%）递送至CNS; CSF中大分子和颗粒行为的机制研究可能导致比先前认为的显著更有效的软脑膜药物递送。
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 cerebro-spinal 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.
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影响因子：
3.7
作者：
Calias, Pericles;Papisov, Mikhail;Heartlein, Michael W.
通讯作者：
Heartlein, Michael W.
影响因子：
3.4
作者：
CSERR, HF;COOPER, DN;MILHORAT, TH
通讯作者：
MILHORAT, TH
影响因子：
6.1
作者：
Crawley, Allison C.;Marshall, Neil;Hemsley, Kim M.
通讯作者：
Hemsley, Kim M.
DOI：
10.1073/pnas.91.6.2076
发表时间：
1994-03-15
影响因子：
11.1
作者：
BOBO, RH;LASKE, DW;OLDFIELD, EH
通讯作者：
OLDFIELD, EH
影响因子：
4.7
作者：
Cahill, CM;Dray, A;Coderre, TJ
通讯作者：
Coderre, TJ