Towards personalized medicine with a three-dimensional micro-scale perfusion-based two-chamber tissue model system.
Towards personalized medicine with a three-dimensional micro-scale perfusion-based two-chamber tissue model system.
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DOI：
10.1016/j.biomaterials.2012.02.054
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发表时间：
2012-06
期刊：
影响因子：
14
通讯作者：
Honkakoski, Paavo
中科院分区：
文献类型：
--
作者：
Ma, Liang;Barker, Jeremy;Zhou, Changchun;Li, Wei;Zhang, Jing;Lin, Biaoyang;Foltz, Gregory;Kublbeck, Jenni;Honkakoski, Paavo
关键词：
建立了一种基于微尺度灌注的三维双腔（3D-μPTC）组织模型系统，用于检测抗癌药物的细胞毒性和肝脏代谢。将具有不同细胞色素P450（CYP）亚型的肝细胞和多形性胶质母细胞瘤（GBM）脑癌细胞在串联连接的两个单独的室中培养。两个腔室都含有使用无溶剂方法用可生物降解的聚乳酸（PLA）制造的3D组织工程支架。我们使用该模型系统来测试抗癌药物的细胞毒性，包括替莫唑胺（TMZ）和异环磷酰胺（IFO）。对于肝细胞，TMZ在2D和3D细胞培养条件下对GBM细胞显示出低得多的毒性。与2D相比，3D培养的GBM细胞在TMZ处理下具有更高的活力。IFO用于检测CYP相关代谢效应。具有不同CYP 3A 4表达水平的细胞在其激活IFO的能力方面存在显著差异，这导致对GBM细胞的强烈代谢依赖性细胞毒性。这些结果表明，我们的3D-μPTC系统可以提供一个比目前的2D单层更符合生理学的体外环境，用于测试抗癌药物的代谢依赖性毒性。因此，它可以作为一个重要的平台，更好地预测药物剂量和个性化医疗的时间表。
A three-dimensional micro-scale perfusion-based two-chamber (3D-μPTC) tissue model system was developed to test the cytotoxicity of anticancer drugs in conjunction with liver metabolism. Liver cells with different cytochrome P450 (CYP) subtypes and glioblastoma multiforme (GBM) brain cancer cells were cultured in two separate chambers connected in tandem. Both chambers contained a 3D tissue engineering scaffold fabricated with biodegradable poly(lactic acid) (PLA) using a solvent-free approach. We used this model system to test the cytotoxicity of anticancer drugs, including temozolomide (TMZ) and ifosfamide (IFO). With the liver cells, TMZ showed a much lower toxicity to GBM cells under both 2D and 3D cell culture conditions. Comparing 2D, GBM cells cultured in 3D had much high viability under TMZ treatment. IFO was used to test the CYP-related metabolic effects. Cells with different expression levels of CYP3A4 differed dramatically in their ability to activate IFO, which led to strong metabolism-dependent cytotoxicity to GBM cells. These results demonstrate that our 3D-μPTC system could provide a more physiologically realistic in vitro environment than the current 2D monolayers for testing metabolism-dependent toxicity of anticancer drugs. It could therefore be used as an important platform for better prediction of drug dosing and schedule towards personalized medicine.
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