Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery
Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery
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DOI：
10.1113/jp275105
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发表时间：
2018-02-01
影响因子：
5.5
通讯作者：
Thorne, Robert G.
中科院分区：
文献类型：
--
作者：
Pizzo, Michelle E.;Wolak, Daniel J.;Thorne, Robert G.
尽管大分子对于中央免疫监视的抗体运输等生理过程以及一些正在进行的鞘内临床试验很重要，但控制大分子从脑脊液 (CSF) 到大脑和脊髓的中央分布的精确机制仍然知之甚少。在本研究中，我们利用离体荧光和体内三维磁共振成像阐明了大鼠鞘内输注后 IgG 和较小的单域抗体 (sdAb) 如何以大小依赖性方式分布在整个大脑中。抗体分布的特点是在大脑表面扩散，并沿着所有血管类型的血管周围空间广泛分布到大脑深部区域，sdAb 到达的大脑区域是 IgG 的四到七倍。血管周围运输涉及所有口径的血管以及假定的平滑肌和星形胶质细胞基底膜室。通往平滑肌基底膜室的血管周围通路也表现出大小依赖性。使用电子显微镜显示蛛网膜下腔血管软脑膜覆盖物上的气孔，作为允许脑脊液中的物质进入血管周围空间的潜在接入点。渗透剂共输注显着增强了来自 CSF 的较大抗体的血管周围通路，鞘内 0.75m 甘露醇将 IgG 访问的每个切片区域的血管周围轮廓数量增加了约 50%。本研究的结果揭示了内源性 IgG 的潜在分布机制，内源性 IgG 是脑脊液中最丰富的蛋白质之一，并为理解和改善大分子通过鞘内途径向中枢神经系统的药物递送提供了新的见解。
The precise mechanisms governing the central distribution of macromolecules from the cerebrospinal fluid (CSF) to the brain and spinal cord remain poorly understood, despite their importance for physiological processes such as antibody trafficking for central immune surveillance, as well as several ongoing intrathecal clinical trials. In the present study, we clarify how IgG and smaller single-domain antibodies (sdAb) distribute throughout the whole brain in a size-dependent manner after intrathecal infusion in rats using exvivo fluorescence and invivo three-dimensional magnetic resonance imaging. Antibody distribution was characterized by diffusion at the brain surface and widespread distribution to deep brain regions along the perivascular spaces of all vessel types, with sdAb accessing a four- to seven-fold greater brain area than IgG. Perivascular transport involved blood vessels of all caliber and putative smooth muscle and astroglial basement membrane compartments. Perivascular access to smooth muscle basement membrane compartments also exhibited size-dependence. Electron microscopy was used to show stomata on leptomeningeal coverings of blood vessels in the subarachnoid space as potential access points allowing substances in the CSF to enter the perivascular space. Osmolyte co-infusion significantly enhanced perivascular access of the larger antibody from the CSF, with intrathecal 0.75m mannitol increasing the number of perivascular profiles per slice area accessed by IgG by approximate to 50%. The results of the present study reveal potential distribution mechanisms for endogenous IgG, which is one of the most abundant proteins in the CSF, as well as provide new insights with respect to understanding and improving the drug delivery of macromolecules to the central nervous system via the intrathecal route.