Lee Moo-Yeal, Dordick Jonathan S, Clark Douglas S
Solidus Biosciences, Inc, Troy, NY, USA.
Methods Mol Biol. 2010;632:221-37. doi: 10.1007/978-1-60761-663-4_14.
Due to poor drug candidate safety profiles that are often identified late in the drug development process, the clinical progression of new chemical entities to pharmaceuticals remains hindered, thus resulting in the high cost of drug discovery. To accelerate the identification of safer drug candidates and improve the clinical progression of drug candidates to pharmaceuticals, it is important to develop high-throughput tools that can provide early-stage predictive toxicology data. In particular, in vitro cell-based systems that can accurately mimic the human in vivo response and predict the impact of drug candidates on human toxicology are needed to accelerate the assessment of drug candidate toxicity and human metabolism earlier in the drug development process. The in vitro techniques that provide a high degree of human toxicity prediction will be perhaps more important in cosmetic and chemical industries in Europe, as animal toxicity testing is being phased out entirely in the immediate future.We have developed a metabolic enzyme microarray (the Metabolizing Enzyme Toxicology Assay Chip, or MetaChip) and a miniaturized three-dimensional (3D) cell-culture array (the Data Analysis Toxicology Assay Chip, or DataChip) for high-throughput toxicity screening of target compounds and their metabolic enzyme-generated products. The human or rat MetaChip contains an array of encapsulated metabolic enzymes that is designed to emulate the metabolic reactions in the human or rat liver. The human or rat DataChip contains an array of 3D human or rat cells encapsulated in alginate gels for cell-based toxicity screening. By combining the DataChip with the complementary MetaChip, in vitro toxicity results are obtained that correlate well with in vivo rat data.
由于药物候选物的安全性不佳，且往往在药物开发过程后期才被发现，新化学实体向药物的临床进展仍然受阻，从而导致药物研发成本高昂。为了加快识别更安全的药物候选物，并改善药物候选物向药物的临床进展，开发能够提供早期预测毒理学数据的高通量工具至关重要。特别是，需要能够准确模拟人体体内反应并预测药物候选物对人体毒理学影响的体外细胞系统，以便在药物开发过程中更早地加速评估药物候选物的毒性和人体代谢。在欧洲的化妆品和化学工业中，能够高度预测人体毒性的体外技术可能更为重要，因为动物毒性试验在不久的将来将被完全淘汰。我们开发了一种代谢酶微阵列（代谢酶毒理学分析芯片，或MetaChip）和一种小型化三维（3D）细胞培养阵列（数据分析毒理学分析芯片，或DataChip），用于对目标化合物及其代谢酶生成产物进行高通量毒性筛选。人源或大鼠源MetaChip包含一系列封装的代谢酶，旨在模拟人或大鼠肝脏中的代谢反应。人源或大鼠源DataChip包含一系列封装在藻酸盐凝胶中的3D人源或大鼠源细胞，用于基于细胞的毒性筛选。通过将DataChip与互补的MetaChip相结合，可获得与大鼠体内数据相关性良好的体外毒性结果。
