Assessment of metabolism-dependent drug efficacy and toxicity on a multilayer organs-on-a-chip.
Pharmaceutical development is greatly hindered by the poor predictive power of existing in vitro models for drug efficacy and toxicity testing. In this work, we present a new and multilayer organs-on-a-chip device that allows for the assessment of drug metabolism, and its resultant drug efficacy and cytotoxicity in different organ-specific cells simultaneously. Four cell lines representing the liver, tumor (breast cancer and lung cancer), and normal tissue (gastric cells) were cultured in the compartmentalized micro-chambers of the multilayer microdevice. We adopted the prodrug capecitabine (CAP) as a model drug. The intermediate metabolites 5'-deoxy-5-fluorocytidine (DFUR) of CAP that were metabolized from liver and its active metabolite 5-fluorouracil (5-FU) from the targeted cancer cells and normal tissue cells were identified using mass spectrometry. CAP exhibited strong cytoxicity on breast cancer and lung cancer cells, but not in normal gastric cells. Moreover, the drug-induced cytotoxicity on cells varied in various target tissues, suggesting the metabolism-dependent drug efficacy in different tissues as exisits in vivo. This in vitro model can not only allow for characterizing the dynamic metabolism of anti-cancer drugs in different tissues simultaneously, but also facilitate the assessment of drug bioactivity on various target tissues in a simple way, indicating the utility of this organs-on-chip for applications in pharmacodynamics/pharmacokinetics studies, drug efficacy and toxicity testing.
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China. jhqin@dicp.a.cn and University of Chinese Academy of Sciences, Beijing, 100049, China.
Zhongyu
Z
Li
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China. jhqin@dicp.a.cn and University of Chinese Academy of Sciences, Beijing, 100049, China.
Yaqiong
Y
Guo
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China. jhqin@dicp.a.cn and University of Chinese Academy of Sciences, Beijing, 100049, China.
Yue
Y
Yu
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China. jhqin@dicp.a.cn and University of Chinese Academy of Sciences, Beijing, 100049, China.
Cong
C
Xu
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China. jhqin@dicp.a.cn and University of Chinese Academy of Sciences, Beijing, 100049, China.
Hui
H
Xu
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China. jhqin@dicp.a.cn.
Jianhua
J
Qin
D000072283:A549 Cells; D021522:Bioartificial Organs; D000069287:Capecitabine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D004867:Equipment Design; D019544:Equipment Failure Analysis; D017022:Flow Injection Analysis / Q000295:instrumentation / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D056656:Lab-On-A-Chip Devices; D064688:Metabolic Flux Analysis / Q000295:instrumentation / Q000379:methods; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques / Q000295:instrumentation* / Q000379:methods; D046888:Tissue Array Analysis / Q000295:instrumentation; D018675:Toxicity Tests / Q000295:instrumentation* / Q000379:methods; D014781:Viscera / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000069287:Capecitabine