Intrastriatal convection-enhanced delivery results in widespread perivascular distribution in a pre-clinical model.
Intrastriatal convection-enhanced delivery results in widespread perivascular distribution in a pre-clinical model.
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DOI：
10.1186/2045-8118-9-2
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发表时间：
2012-01-20
影响因子：
7.3
通讯作者：
Gill SS
中科院分区：
文献类型：
--
作者：
Barua NU;Bienemann AS;Hesketh S;Wyatt MJ;Castrique E;Love S;Gill SS
对流增强递送（CED）是一种通过实质内微导管将药物直接递送至大脑的方法，是一种有前途的脑内药物治疗策略。通过在导管尖端建立压力梯度，药物可以以均匀的浓度输送到大量的间质液中。然而，影响 CED 输送药物血管周围分布的变量尚不完全清楚。本研究的目的是确定 CED 输送到大鼠纹状体的溶质的血管周围分布是否受到输注药物的分子量、血管扩张剂的共同输注、输注速率的改变或使用斜坡方案的影响。我们还想对溶质与纳米颗粒的分布进行初步比较。我们分析了 CED 进入大鼠纹状体后 10 分钟和 3 小时时 4、10、20、70、150 kDa 荧光素标记的葡聚糖和荧光纳米颗粒的血管周围分布。我们研究了局部血管舒张、缓慢输注速度和斜坡对溶质血管周围分布的影响。通过免疫组织化学鉴定与血管周围基底膜和血管内皮细胞的共定位。使用体视学方法对血管周围巨噬细胞对输注物的摄取进行量化。停止 CED 10 分钟后，无论分子量如何，都可以看到荧光素标记的葡聚糖在血管周围的广泛分布和巨噬细胞的摄取。然而，血管周围巨噬细胞摄取 4、10 和 20 kDa 荧光素标记的葡聚糖的比例明显高于摄取 150 kDa 葡聚糖的比例（p < 0.05，方差分析）。与血管扩张剂共同输注、缓慢输注速度和使用渐进方案并没有改变血管周围的分布。荧光纳米颗粒的 CED 表明颗粒与整个纹状体的血管周围基底膜共定位，但与可溶性葡聚糖不同，3 小时后不被血管周围巨噬细胞吸收。这项研究表明，广泛的血管周围分布以及与血管周围巨噬细胞的相互作用可能是溶质 CED 的不可避免的结果。必须仔细考虑 CED 提供的治疗药物（尤其是细胞毒性化疗）血管周围分布的潜在后果，以确保安全有效地转化为临床试验。
Convection-enhanced delivery (CED), a direct method for drug delivery to the brain through intraparenchymal microcatheters, is a promising strategy for intracerebral pharmacological therapy. By establishing a pressure gradient at the tip of the catheter, drugs can be delivered in uniform concentration throughout a large volume of interstitial fluid. However, the variables affecting perivascular distribution of drugs delivered by CED are not fully understood. The aim of this study was to determine whether the perivascular distribution of solutes delivered by CED into the striatum of rats is affected by the molecular weight of the infused agent, by co-infusion of vasodilator, alteration of infusion rates or use of a ramping regime. We also wanted to make a preliminary comparison of the distribution of solutes with that of nanoparticles. We analysed the perivascular distribution of 4, 10, 20, 70, 150 kDa fluorescein-labelled dextran and fluorescent nanoparticles at 10 min and 3 h following CED into rat striatum. We investigated the effect of local vasodilatation, slow infusion rates and ramping on the perivascular distribution of solutes. Co-localisation with perivascular basement membranes and vascular endothelial cells was identified by immunohistochemistry. The uptake of infusates by perivascular macrophages was quantified using stereological methods. Widespread perivascular distribution and macrophage uptake of fluorescein-labelled dextran was visible 10 min after cessation of CED irrespective of molecular weight. However, a significantly higher proportion of perivascular macrophages had taken up 4, 10 and 20 kDa fluorescein-labelled dextran than 150 kDa dextran (p < 0.05, ANOVA). Co-infusion with vasodilator, slow infusion rates and use of a ramping regime did not alter the perivascular distribution. CED of fluorescent nanoparticles indicated that particles co-localise with perivascular basement membranes throughout the striatum but, unlike soluble dextrans, are not taken up by perivascular macrophages after 3 h. This study suggests that widespread perivascular distribution and interaction with perivascular macrophages is likely to be an inevitable consequence of CED of solutes. The potential consequences of perivascular distribution of therapeutic agents, and in particular cytotoxic chemotherapies, delivered by CED must be carefully considered to ensure safe and effective translation to clinical trials.