A micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugsA micro cell culture analog (mCCA) with 3-D hydrogel cultureof multiple cell lines to assess metabolism-dependent cytotoxicityof anti-cancer drugsJong Hwan Sungaand Michael L. Shuler*abReceived 29th August 2008, Accepted 26th January 2009First published as an Advance Article on the web 20th February 2009DOI: 10.1039/b901377fA microfluidic device with 3-D hydrogel cell cultures has been developed to test the cytotoxicity of anti-cancer drugs while reproducing multi-organ interactions. In this device, a micro cell culture analog(mCCA), cells embedded in 3-D hydrogels are cultured in separate chambers representing the liver,tumor, and marrow, which are connected by channels mimicking blood flow. While the microfluidicnetwork provides a platform for mimicking the pharmacokinetic and pharmacodynamic profiles ofa drug in humans, the 3-D hydrogel provides a more physiologically realistic environment to mimic thetissue than monolayer culture. Colon cancer cells (HCT-116) and hepatoma cells (HepG2/C3A) wereencapsulated in Matrigel and cultured in the tumor and the liver chamber in a mCCA, respectively.Myeloblasts (Kasumi-1) were encapsulated in alginate in the marrow chamber; a stiffer hydrogel wasnecessary to prevent cell migration out of the matrix. The cytotoxic effect of Tegafur, an oral prodrugof 5-fluorouracil (5-FU), on each cell line was tested using the mCCA with cell-embedded hydrogel. Thecomparison of experimental results using a 96-well microtiter plate and a mCCA demonstrated that themCCA was able to reproduce the metabolism of Tegafur to 5-FU in the liver and consequent death ofcells by 5-FU, while the cultures in a 96-well microtiter plate were unable to do so. The mCCA utilizing3-D hydrogel cell cultures has potential as a platform for pharmacokinetic-based drug screening ina more physiologically realistic environment.IntroductionDrug discovery is a multi-disciplinary process which takesa significant amount of time and money. Despite continuingadvances in technologies such as combinatorial chemistry andhigh-throughput screening (HTS), pharmaceutical companies havebeen suffering from decreasing productivity during the pastdecade.1It has been speculated that the major causes of attrition inthe drug development process are unforeseen toxicity and the lackof efficacy, which account for about 50% of the failures.2Furthermore,a large fraction of drug candidates (about 23%) fail atthe later stages of drug development process, after the majority ofthe drug development costs have been incurred.1Considering thatthe cost of clinical development of a drug is massive, in the range ofUS $500 to US $2000 million,3being able to predict the efficacy andthe toxicity of drugs in the earlier preclinical stages would greatlyimprove the productivity of the drug development process.During the preclinical phase, the evaluation of a New Chem-ical Entity (NCE) is typically performed using in vitro cell-basedassays, which are readily adaptable to a high-throughputformat.4However, current in vitro cell-based assays have limi-tations due primarily to the fact that only a single cell type is usedin the assay, and multi-organ interactions cannot be observed.Also, current multi-well plate systems are static systems in whichcells are simply incubated with medium containing testcompounds as a bolus dose. The in vivo situation is much morecomplicated; after administration, drugs undergo a complexprocess of absorption, distribution, metabolism and elimination(ADME), which is a time-dependent process. Consequently,changes in pharmacokinetic/pharmacodynamic profiles due
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