Abstract
Development of drugs based on potential anti-cancer chemotherapeutic agents has been hindered by its necessary tedious procedures and failure in the clinical trials because of unbearable toxicity and extremely low clinical efficacy. One of the technical challenges is the mismatch between laboratory settings and human body environments for the cancer cells responding upon treatments of the anti-cancer agents. This major limitation urges for applying more reliable platforms for evaluating drugs with a higher throughput and cell aggregates in a more natural configuration. Here, we adopt a microfluidic device integrated with a differential micromixer and multiple microwell-containing channels (50 microwells per channel) for parallel screening of suspending cell spheroids treated by drugs with different combinations. We optimize the culture conditions of the surfactant-coated microwells in order to facilitate the spheroid formation of the breast cancer cell line (MDA-MB-231). We propose a new drug cocktail combined with three known chemotherapeutic agents (paclitaxel, epirubicin, and aspirin) for the drug screening of the cancer cell-spheroids. Our results exhibit the differential responses between planar cell layers in traditional culture wells and cell-spheroids grown in our microfluidic device, in terms of the apoptotic rates under treatments of the drug cocktails with different concentrations. These results reveal a distinct drug resistance between planar cell layers and cell-spheroids. Together, this work offers important guidelines on applying the cell-spheroid microfluidic cultures for development of more efficacious anticancer drugs.
Highlights
In anticancer drug development, ~90% of the drug candidates fail in clinical trials per year due to intolerable toxicity and low efficiency [1,2]
We report a microfluidic assay for parallel drug screening on cancer cell-spheroids
These results revealed the difference between cell layers and spheroids on their desired apoptotic responses under the three-drug cocktail, and further demonstrated the applicability of the device architecture as a parallel drug screening platform using cell-spheroids for more promising anticancer drug cocktail development and optimization
Summary
In anticancer drug development, ~90% of the drug candidates fail in clinical trials per year due to intolerable toxicity and low efficiency [1,2]. Ruppen et al [23] developed a microfluidic platform using a spheroid model to predict more representative in vivo behaviors of tumor cells, suggesting that microfluidic systems for cell-spheroid culture can be considered as an in vitro tumor model and an anti-cancer drug screening platform [22]. We examined the cell growth via the spheroid size increments and cell viability tests, comparing to the results performed with the planar cell cultures Together, these results revealed the difference between cell layers and spheroids on their desired apoptotic responses under the three-drug cocktail, and further demonstrated the applicability of the device architecture as a parallel drug screening platform using cell-spheroids for more promising anticancer drug cocktail development and optimization. TThhrreeee iinnlleettss aarree sshhoowwnn oonn tthhee rriigghhtt--hhaanndd ssiiddee wwiitthh rreedd,, bblluuee,, aanndd yyeellllooww ddyyeess iinnffuusseedd vviiaa aa ssyyrriinnggee ppuummpp.
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