CONVECTION-ENHANCED DELIVERY OF MACROMOLECULES IN THE BRAIN
CONVECTION-ENHANCED DELIVERY OF MACROMOLECULES IN THE BRAIN
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DOI：
10.1073/pnas.91.6.2076
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发表时间：
1994-03-15
影响因子：
11.1
通讯作者：
OLDFIELD, EH
中科院分区：
文献类型：
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作者：
BOBO, RH;LASKE, DW;OLDFIELD, EH
对于许多化合物（神经营养因子、抗体、生长因子、遗传载体、酶），在脑中的缓慢扩散严重限制了药物直接给药至脑实质后的分布和作用。我们研究了对流作为一种手段，以提高分布的大分子和小分子In-111标记的转铁蛋白（In-111-Tf; M（r），80，000）和[C-14]蔗糖（M（r），359）在厘米的距离，通过保持一个压力梯度，在间质输注到白色物质，以产生大量的流量通过大脑皮层。对于In-111-Tf（V-d/V-i，6：1）和[C-14]蔗糖（V-d/V-i，13：1），含大于或等于1%浓度输注溶液的分布容积（V-d）随输注体积（V-i）线性增加。灌注后24小时，In-111-Tf的分布增加，更均匀，并已渗透到灰质。通过使用对流来补充简单扩散，可以在脑中获得大分子和小分子的增强分布，同时实现比全身水平大几个数量级的药物浓度。
For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules In-111-labeled transferrin (In-111-Tf; M(r), 80,000) and [C-14]sucrose (M(r), 359) over centimeter distances by maintaining a pressure gradient during interstitial infusion into white matter to generate bulk flow through the brain interstitium. The volume of distribution (V-d) containing greater than or equal to 1% concentration of infusion solution increased linearly with the infusion volume (V-i) for In-111-Tf(V-d/V-i, 6:1) and [C-14]sucrose (V-d/V-i, 13:1). Twenty-four hours after infusion, the distribution of In-111-Tf was increased and more homogeneous, and penetration into gray matter had occurred. By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.