Department of Mechanical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
Biomaterials. 2012 Jun;33(17):4353-61. doi: 10.1016/j.biomaterials.2012.02.054. Epub 2012 Mar 18.
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.
开发了一种三维微尺度灌注式双室（3D-μPTC）组织模型系统，以测试与肝脏代谢相结合的抗癌药物的细胞毒性。在两个串联连接的单独腔室内培养具有不同细胞色素 P450（CYP）亚型的肝细胞和多形性胶质母细胞瘤（GBM）脑癌细胞。两个腔室均包含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测试了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 细胞的毒性均低得多。与 2D 相比，在 TMZ 处理下，在 3D 中培养的 GBM 细胞的存活率更高。IFO 用于测试 CYP 相关的代谢作用。具有不同 CYP3A4 表达水平的细胞在激活 IFO 的能力上差异很大，这导致对 GBM 细胞产生强烈的代谢依赖性细胞毒性。这些结果表明，我们的 3D-μPTC 系统可以为测试抗癌药物的代谢依赖性毒性提供比当前的 2D 单层更接近生理的体外环境。因此，它可以用作更好地预测药物剂量和方案以实现个体化医学的重要平台。
