Abstract
Microphysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. However, existing microfluidic devices are not yet able to deliver compounds to cell models in a way that reproduces the real physiological drug exposure. Here, we introduce a novel tumour-on-chip microfluidic system that mimics the pharmacokinetic profile of compounds on 3D tumour spheroids to evaluate their response to the treatments. We used this platform to test the response of SW620 colorectal cancer spheroids to irinotecan (SN38) alone and in combination with the ATM inhibitor AZD0156, using concentrations mimicking mouse plasma exposure profiles of both agents. We explored spheroid volume and viability as a measure of cancer cells response and changes in mechanistically relevant pharmacodynamic biomarkers (γH2AX, cleaved-caspase 3 and Ki67). We demonstrate here that our microfluidic tumour-on-chip platform can successfully predict the efficacy from in vivo studies and therefore represents an innovative tool to guide drug dose and schedules for optimal efficacy and pharmacodynamic assessment, while reducing the need for animal studies.
Highlights
Microphysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years
Following Matrigel encapsulation, spheroids were exposed to a constant flow of 20 μL/min, each flow path delivering SN38 or SN38 + AZD0156 into the Ibidi chips to mimic in vivo PK profiles, and using various treatment schedules
As a first step to compare the response of SW620 cells treated in the 3D chip microfluidic set up versus 3D plate, we explored differences in tumour spheroid size and viability following 6 days of treatment with SN38 and combination with AZD0156 using exposures as shown in Fig. 2a, b
Summary
Microphysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. We introduce a microfluidic platform able to mimic drug PK profiles and treatment schedules and to evaluate drug response on complex microenvironment tumour spheroids This platform is able to sequentially deliver specific drug concentrations at a constant flow rate mimicking up to eight concentration points on the PK profile for a specific drug. Various treatment schedules can be explored to further guide the design of in vivo or clinical studies, preventing long and expensive dose scheduling clinical studies This platform includes a single channel microfluidic Ibidi chip (Ibidi GmbH, Germany), that we adapted to handle eight tumour spheroids encapsulated in Matrigel droplets. By comparing the outcome from in vivo studies and in vitro microfluidic platform experiments, we were able to demonstrate the predictive ability of our novel system for anticancer drug assessment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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
