Evaluation of drug combination for glioblastoma based on an intestine-liver metabolic model on microchip.

An intestine-liver-glioblastoma biomimetic system was developed to evaluate the drug combination therapy for glioblastoma. A hollow fiber (HF) was embedded into the upper layer of the microfluidic chip for culturing Caco-2 cells to mimic drug delivery as an artificial intestine. HepG2 cells cultured in the bottom chamber of the chip acted as an artificial liver for metabolizing the drugs. The dual-drug combination to glioblastoma U251 cells was evaluated based on the intestine-liver metabolic model. The drugs, irinotecan (CPT-11), temozolomide (TMZ) and cyclophosphamide (CP), were used to dynamically stimulate the cells by continuous infusion into the intestine unit. After intestine absorption and liver metabolism, the prodrugs were transformed to active metabolites, which induced glioblastoma cells apoptosis. The anticancer activity of the CPT-11 and TMZ combination is significantly enhanced compared to that of the single drug treatments. Combination index (CI) values of the combination groups, CPT-11 and TMZ, CPT-11 and CP, and TMZ and CP, at half maximal inhibitory concentration were 0.137, 0.288, and 0.482, respectively. The results indicated that the CPT-11 and TMZ combination was superior to the CPT-11 and CP group as well as the TMZ and CP group towards the U251 cells. The metabolism mechanism of CPT-11 and TMZ was further studied by coupling with mass spectrometric analysis. The biomimetic model enables the performance of long-term cell co-culture, drug delivery, metabolism and real-time analysis of drug effects, promising systematic in vitro mimicking of physiological and pharmacological processes.

[1]  D. Stamatialis,et al.  Polymeric hollow fiber membranes for bioartificial organs and tissue engineering applications , 2014 .

[2]  Jin‐Ming Lin,et al.  Efficient cell capture in an agarose–PDMS hybrid chip for shaped 2D culture under temozolomide stimulation , 2016 .

[3]  Radivoje Prodanovic,et al.  Controlled assembly of heterotypic cells in a core-shell scaffold: organ in a droplet. , 2016, Lab on a chip.

[4]  Rui Liu,et al.  Potentiation of paclitaxel activity by curcumin in human breast cancer cell by modulating apoptosis and inhibiting EGFR signaling , 2014, Archives of pharmacal research.

[5]  Andreas Hierlemann,et al.  Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis , 2014, Nature Communications.

[6]  Ziyi He,et al.  Engineering Cell‐Compatible Paper Chips for Cell Culturing, Drug Screening, and Mass Spectrometric Sensing , 2015, Advanced healthcare materials.

[7]  Ling Lin,et al.  Biomaterial-Based Microfluidics for Cell Culture and Analysis , 2016 .

[8]  M. Ellis,et al.  Hollow fibre membrane bioreactors for tissue engineering applications , 2014, Biotechnology Letters.

[9]  M Wessling,et al.  Integration of hollow fiber membranes improves nutrient supply in three-dimensional tissue constructs. , 2011, Acta biomaterialia.

[10]  Eric Leclerc,et al.  First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans , 2014, Biotechnology and bioengineering.

[11]  Jong Hwan Sung,et al.  A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip. , 2010, Lab on a chip.

[12]  R. McLendon,et al.  Irinotecan therapy in adults with recurrent or progressive malignant glioma. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  David A. Weitz,et al.  Controlled fabrication of polymer microgels by polymer-analogous gelation in droplet microfluidics , 2010 .

[14]  Deok-Ho Kim,et al.  Microfluidics-assisted in vitro drug screening and carrier production. , 2013, Advanced drug delivery reviews.

[15]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.

[16]  Jin‐Ming Lin,et al.  A novel approach for precisely controlled multiple cell patterning in microfluidic chips by inkjet printing and the detection of drug metabolism and diffusion. , 2016, The Analyst.

[17]  Jin-Ming Lin,et al.  An in vitro liver model on microfluidic device for analysis of capecitabine metabolite using mass spectrometer as detector. , 2015, Biosensors & bioelectronics.

[18]  Jin-Ming Lin,et al.  Characterization of drug permeability in Caco-2 monolayers by mass spectrometry on a membrane-based microfluidic device. , 2013, Lab on a chip.

[19]  T Ishizaki,et al.  Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice. , 1997, The Journal of pharmacology and experimental therapeutics.

[20]  Zimple Matharu,et al.  Liver injury-on-a-chip: microfluidic co-cultures with integrated biosensors for monitoring liver cell signaling during injury. , 2015, Lab on a chip.

[21]  K. Kohn,et al.  Correlations between S and G2 arrest and the cytotoxicity of camptothecin in human colon carcinoma cells. , 1996, Cancer research.

[22]  R. Iyer,et al.  Hollow fiber integrated microfluidic platforms for in vitro Co-culture of multiple cell types , 2016, Biomedical microdevices.

[23]  A. Jayaraman,et al.  A programmable microfluidic cell array for combinatorial drug screening. , 2012, Lab on a chip.

[24]  Ying Zhu,et al.  Cell-based drug combination screening with a microfluidic droplet array system. , 2013, Analytical chemistry.

[25]  Xuexia Lin,et al.  Online multi-channel microfluidic chip-mass spectrometry and its application for quantifying noncovalent protein-protein interactions. , 2015, The Analyst.

[26]  D. Ingber,et al.  Microfluidic organs-on-chips , 2014, Nature Biotechnology.

[27]  Haifang Li,et al.  Strategy for signaling molecule detection by using an integrated microfluidic device coupled with mass spectrometry to study cell-to-cell communication. , 2013, Analytical chemistry.

[28]  M. Ramesh,et al.  Irinotecan and its active metabolite, SN-38: review of bioanalytical methods and recent update from clinical pharmacology perspectives. , 2010, Biomedical chromatography : BMC.

[29]  Uwe Marx,et al.  Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro. , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[30]  M. Tan,et al.  Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[31]  Jong Hwan Sung,et al.  Microfluidic Gut-liver chip for reproducing the first pass metabolism , 2017, Biomedical Microdevices.

[32]  K. Mishima,et al.  Pharmacokinetic study of temozolomide on a daily-for-5-days schedule in Japanese patients with relapsed malignant gliomas: first study in Asians , 2007, International Journal of Clinical Oncology.

[33]  Ángel E. Mercado-Pagán,et al.  Development and evaluation of elastomeric hollow fiber membranes as small diameter vascular graft substitutes. , 2015, Materials science & engineering. C, Materials for biological applications.

[34]  D. Beebe,et al.  The present and future role of microfluidics in biomedical research , 2014, Nature.

[35]  D. Huh,et al.  Organs-on-chips at the frontiers of drug discovery , 2015, Nature Reviews Drug Discovery.

[36]  Josue A. Goss,et al.  Microfluidic heart on a chip for higher throughput pharmacological studies. , 2013, Lab on a chip.

[37]  Ali Khademhosseini,et al.  Organs-on-a-chip: a new tool for drug discovery , 2014, Expert opinion on drug discovery.

[38]  Guoliang Zhang,et al.  Hollow fiber culture accelerates differentiation of Caco-2 cells , 2013, Applied Microbiology and Biotechnology.

[39]  Jin-Ming Lin,et al.  Microfluidic isolation of highly pure embryonic stem cells using feeder-separated co-culture system , 2013, Scientific Reports.

[40]  Pan Liu,et al.  Cellulose-based hydrogels with excellent microstructural replication ability and cytocompatibility for microfluidic devices , 2013, Cellulose.

[41]  F. Levi-Schaffer,et al.  Role of reactive oxygen species (ROS) in apoptosis induction , 2000, Apoptosis.

[42]  Daniel C Leslie,et al.  A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice , 2012, Science Translational Medicine.

[43]  Wei Zhang,et al.  A Strategy for Depositing Different Types of Cells in Three Dimensions to Mimic Tubular Structures in Tissues , 2012, Advanced materials.

[44]  Paul Wilmes,et al.  A microfluidics-based in vitro model of the gastrointestinal human–microbe interface , 2016, Nature Communications.

[45]  E. Verpoorte,et al.  An alternative approach based on microfluidics to study drug metabolism and toxicity using liver and intestinal tissue , 2010 .

[46]  I. Buschmann,et al.  The “Artificial Artery” as In Vitro Perfusion Model , 2013, PloS one.

[47]  Roger D Kamm,et al.  A high-throughput microfluidic assay to study neurite response to growth factor gradients. , 2011, Lab on a chip.

[48]  Shoji Takeuchi,et al.  Metre-long cell-laden microfibres exhibit tissue morphologies and functions. , 2013, Nature materials.

[49]  L. Grochow,et al.  Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[50]  Jin-Ming Lin,et al.  Microfluidic technologies in cell isolation and analysis for biomedical applications. , 2017, The Analyst.

[51]  F. Lokiec,et al.  Irinotecan (CPT-11) metabolites in human bile and urine. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[52]  Feng Xu,et al.  Engineering a Brain Cancer Chip for High-throughput Drug Screening , 2016, Scientific Reports.

[53]  Thomas C. Ferrante,et al.  Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro , 2015, Nature Methods.

[54]  D. Zink,et al.  The performance of primary human renal cells in hollow fiber bioreactors for bioartificial kidneys. , 2011, Biomaterials.

[55]  Qiushui Chen,et al.  Qualitative and quantitative analysis of tumor cell metabolism via stable isotope labeling assisted microfluidic chip electrospray ionization mass spectrometry. , 2012, Analytical chemistry.

[56]  T. Seo,et al.  Circumferential alignment of vascular smooth muscle cells in a circular microfluidic channel. , 2014, Biomaterials.

[57]  W. Sun,et al.  Bioprinting cell-laden matrigel for radioprotection study of liver by pro-drug conversion in a dual-tissue microfluidic chip , 2011, Biofabrication.

[58]  Boris Stoeber,et al.  Design, microfabrication, and characterization of a moulded PDMS/SU-8 inkjet dispenser for a Lab-on-a-Printer platform technology with disposable microfluidic chip. , 2016, Lab on a chip.

[59]  F. Sonntag,et al.  A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. , 2015, Lab on a chip.

[60]  Xingyu Jiang,et al.  Engineering a 3D vascular network in hydrogel for mimicking a nephron. , 2013, Lab on a chip.