Permeability across a novel microfluidic blood-tumor barrier model.
Permeability across a novel microfluidic blood-tumor barrier model.
复制标题
新型微流体血液肿瘤屏障模型的渗透性。
DOI：
10.1186/s12987-017-0050-9
复制
发表时间：
2017-01-23
影响因子：
7.3
通讯作者：
Lockman PR
中科院分区：
文献类型：
--
作者：
Terrell-Hall TB;Ammer AG;Griffith JI;Lockman PR
缺乏可翻译的体外血液-肿瘤屏障（BTB）模型给开发治疗CNS肿瘤的药物以及我们理解肿瘤存在时血脑屏障处血管如何变化带来了挑战。在这项研究中，我们描述了一种新的微流体模型的BTB（和BBB模型作为参考），它结合了流动和诱导内皮细胞上的剪切应力。使用的细胞系包括与CTX-TNA 2大鼠星形胶质细胞（BBB）或Met-1转移性鼠乳腺癌细胞（BTB）共培养的人脐静脉内皮细胞。细胞能够通过多孔界面跨微流体区室通信。我们通过比较三种被动渗透性标记物和一种外排标记物的渗透性来表征该器械。磺酰罗丹明101在BTB模型中的渗透性（13.1 ± 1.3 × 10−3，n = 4）显著（p < 0.05）高于BBB模型（2.5 ± 0.3 × 10−3，n = 6）。在BTB模型中观察到600 Da至60 kDa分子的类似渗透性增加。P-gp的功能在两种模型中都是完整的，并且与最近发表的体内数据一致。具体而言，罗丹明123通过BBB模型的渗透率（0.6 ± 0.1 × 10−3，n = 4）在P-gp抑制剂维拉帕米存在下增加了14倍（14.7 ± 7.5 × 10−3，n = 3），加入环孢素A增加了8倍（8.8 ± 1.8 × 10−3，n = 3）。在BTB模型中观察到类似的值。动态微流体体外BTB模型是一种新的市售模型，其包含剪切应力，并且具有与体内数据相似的渗透性和外排特性。
The lack of translatable in vitro blood-tumor barrier (BTB) models creates challenges in the development of drugs to treat tumors of the CNS and our understanding of how the vascular changes at the BBB in the presence of a tumor. In this study, we characterize a novel microfluidic model of the BTB (and BBB model as a reference) that incorporates flow and induces shear stress on endothelial cells. Cell lines utilized include human umbilical vein endothelial cells co-cultured with CTX-TNA2 rat astrocytes (BBB) or Met-1 metastatic murine breast cancer cells (BTB). Cells were capable of communicating across microfluidic compartments via a porous interface. We characterized the device by comparing permeability of three passive permeability markers and one marker subject to efflux. The permeability of Sulforhodamine 101 was significantly (p < 0.05) higher in the BTB model (13.1 ± 1.3 × 10−3, n = 4) than the BBB model (2.5 ± 0.3 × 10−3, n = 6). Similar permeability increases were observed in the BTB model for molecules ranging from 600 Da to 60 kDa. The function of P-gp was intact in both models and consistent with recent published in vivo data. Specifically, the rate of permeability of Rhodamine 123 across the BBB model (0.6 ± 0.1 × 10−3, n = 4), increased 14-fold in the presence of the P-gp inhibitor verapamil (14.7 ± 7.5 × 10−3, n = 3) and eightfold with the addition of Cyclosporine A (8.8 ± 1.8 × 10−3, n = 3). Similar values were noted in the BTB model. The dynamic microfluidic in vitro BTB model is a novel commercially available model that incorporates shear stress, and has permeability and efflux properties that are similar to in vivo data.