Abstract

We present a microfluidic device to expose cancer cells to a dynamic, in vivo-like concentration profile of a drug, and quantify efficacy on-chip. About 30% of cancer patients receive drug therapy. In conventional cell culture experiments drug efficacy is tested under static concentrations, e.g. 1 μM for 48 hours, whereas in vivo, drug concentration follows a pharmacokinetic profile with an initial peak and a decline over time. With the rise of microfluidic cell culture models, including organs-on-chips, there are opportunities to more realistically mimic in vivo-like concentrations. Our microfluidic device contains a cell culture chamber and a drug-dosing channel separated by a transparent membrane, to allow for shear stress-free drug exposure and label-free growth quantification. Dynamic drug concentration profiles in the cell culture chamber were controlled by continuously flowing controlled concentrations of drug in the dosing channel. The control over drug concentrations in the cell culture chambers was validated with fluorescence experiments and numerical simulations. Exposure of HCT116 colorectal cancer cells to static concentrations of the clinically used drug oxaliplatin resulted in a sensible dose-effect curve. Dynamic, in vivo-like drug exposure also led to statistically significant lower growth compared to untreated control. Continuous exposure to the average concentration of the in vivo-like exposure seems more effective than exposure to the peak concentration (Cmax) only. We expect that our microfluidic system will improve efficacy prediction of in vitro models, including organs-on-chips, and may lead to future clinical optimization of drug administration schedules.

Highlights

  • Certain pharmacokinetic parameters of clinically relevant drug exposures are available and can in principle be used to inform the static drug concentrations used in cell culture studies.[6]

  • We designed a microfluidic system which has a bottom channel of limited depth (0.5 mm)

  • To expose cultured cells in a microfluidic chip to oxaliplatin concentration profiles that match the in vivo pharmacokinetics, a short peak of 20 μM needs to be given which declines over several hours to a lengthy exposure of 1– 2 μM (Fig. S17†).[2]

Read more

Summary

Introduction

Certain pharmacokinetic parameters of clinically relevant drug exposures are available and can in principle be used to inform the static drug concentrations used in cell culture studies.[6]. To expose cultured cells in a microfluidic chip to oxaliplatin concentration profiles that match the in vivo pharmacokinetics, a short peak of 20 μM needs to be given which declines over several hours to a lengthy exposure of 1– 2 μM (Fig. S17†).[2] Distribution half-life of oxaliplatin, i.e. the time it takes from the peak dose to halve, based on distribution of the drug from the vascular space to the tissues, is ∼20 minutes.

Results
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.