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      Drug cytotoxicity and signaling pathway analysis with three-dimensional tumor spheroids in a microwell-based microfluidic chip for drug screening.

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          Abstract

          Currently, there has been a growing need for developing in vitro models to better reflect organism response to chemotherapy at tissue level. For this reason, a microfluidic platform was developed for mimicking physiological microenvironment of solid tumor with multicellular tumor spheroids (MTS) for anticancer drug screening. Importantly, the power of this system over traditional systems is that it is simple to operate and high integration in a more physiologically relevant context. As a proof of concept, long-term MTS cultures with uniform structure were realized on the microfluidic based platform. The response of doxorubicin and paclitaxel on different types of spheroids were simultaneously performed by in situ Live/Dead fluorescence stain to provide spatial distribution of dead cells as well as cytotoxicity information. In addition, the established platform combined with microplate reader was capable to determine the cytotoxicity of different sized MTS, showing a more powerful tool than cell staining examination at the end-point of assay. The HCT116 spheroids were then lysed on chip followed by signaling transduction pathway analysis. To our knowledge, the on chip drug screening study is the first to address the drug susceptibility testing and the offline detailed drug signaling pathway analysis combination on one system. Thus, this novel microfluidic platform provides a useful tool for drug screening with tumor spheroids, which is crucial for drug discovery and development.

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          Author and article information

          Journal
          Anal. Chim. Acta
          Analytica chimica acta
          Elsevier BV
          1873-4324
          0003-2670
          Oct 22 2015
          : 898
          Affiliations
          [1 ] School of Medicine, Tsinghua University, Beijing 100084, China; Key Lab of Chemical Genomics, School of Chemical Biology & Biotechnology, Graduate School at Shenzhen, Peking University, Shenzhen 518055, China.
          [2 ] State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; Key Laboratory of Metabolomics at Shenzhen, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
          [3 ] State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; Key Laboratory of Metabolomics at Shenzhen, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China. Electronic address: liuhx@sz.tsinghua.edu.cn.
          [4 ] Key Lab of Chemical Genomics, School of Chemical Biology & Biotechnology, Graduate School at Shenzhen, Peking University, Shenzhen 518055, China.
          [5 ] School of Medicine, Tsinghua University, Beijing 100084, China; State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
          Article
          S0003-2670(15)01240-4
          10.1016/j.aca.2015.10.006
          26526913
          27398fe3-3768-433b-8e8f-40efe4ef5f9e
          History

          Signaling pathway,Microfluidic chip,Cell apoptosis,Anticancer drug screening,Tumor spheroid

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