Integrated microfluidic system for cell co-culture and simulation of drug metabolism
Integrated microfluidic system for cell co-culture and simulation of drug metabolism
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用于细胞共培养和药物代谢模拟的集成微流体系统
DOI：
10.1039/c6ra10407j
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发表时间：
2016-01-01
期刊：
影响因子：
3.9
通讯作者：
Lin, Jin-Ming
中科院分区：
文献类型：
--
作者：
Jie, Mingsha;Li, Hai-Fang;Lin, Jin-Ming
在这项工作中，开发了一种多类型细胞微流控积分器，用于共培养并能够模拟药物的吸收、代谢和抗癌活性。为了建立体外药物吸收和代谢模型，将Caco-2、HepG2和U251细胞分别作为肠、肝和胶质母细胞瘤的模拟物进行共培养。用聚碳酸酯半透膜将HepG2细胞通道与Caco-2细胞通道隔开，并用窄通道阵列将其与U251细胞通道相连。在芯片上同时进行微流控细胞共培养、伊立替康(CPT-11)代谢和细胞毒性分析。这个模拟器官到器官的网络在微流环境下进行了长距离的药物转移。用荧光显像法监测药物的细胞毒性。采用高效液相色谱-串联质谱法对7-乙基-10-羟基喜树碱(SN-38)胞外/胞内CPT-11及其活性代谢产物进行了定性和定量表征。结果表明，前体药物CPT-11可被Caco-2细胞吸附，并通过多孔膜转移到HepG2细胞，然后由HepG2细胞转化为活性SN-38。代谢SN-38被抽吸出HepG2细胞，并通过连接通道阵列从HepG2细胞通道扩散到U251细胞通道，从而靶向U251细胞。我们的结果表明，这种动态3D设备为高通量药物筛选和个性化癌症治疗提供了潜在的应用。
In this work, a multi-type cell microfluidic integrator for cocultivation and enabling simulation of drug absorption, metabolism, and anticancer activity was developed. To organize an in vitro drug absorption and metabolism model, Caco-2, HepG2, and U251 cells were co-cultured as mimics of the intestine, liver, and glioblastoma, respectively. The HepG2 cell channel was separated from the Caco-2 cell channel by a polycarbonate semipermeable membrane, and connected with the U251 cell channel by a narrow channel array. Microfluidic cell co-culture, irinotecan (CPT-11) metabolism and cytotoxic analysis were performed simultaneously on the chip. This mimic organ-to-organ network carried out long-distance drug transfer under a microflow environment. The drug cytotoxicity assay was monitored by fluorescence visualization. The extra-/intra-cellular CPT-11 and its active metabolite of 7-ethyl-10-hydroxycamptothecin (SN-38) were qualitatively and quantitatively characterized by liquid chromatography-tandem mass spectrometry. It was revealed that prodrug CPT-11 was absorbed by Caco-2 cells and transferred to HepG2 cells through the porous membrane, then CPT-11 transformed to active SN-38 by HepG2 cells. Metabolic SN-38 was pumped out of HepG2 cells and diffused from the HepG2 cell channel toward the U251 cell channel through a connection channel array to targeting U251 cells. Our results suggest that this dynamic 3D device provides a potential application for high throughput drug screening and personalized cancer therapy.