Abstract
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Objectives Capturing cellular adaptation under interventions may give insight in tumor biology and therapy. However, noise in the measurements prevents the online modeling in a short time window. We propose a continuously infused microfluidic radioassay (CIMR) system to trace real-time the pharmacokinetics by piecewise modeling.
Methods The CIMR system consists of a microfluidic slide integrated with a Timepix positron camera. The medium with radioactive tracer is driven by the pump from the medium reservoir via the medium monitoring chamber into the cell culture chamber. The medium monitoring chamber and the cell culture chamber were simultaneously measured by a positron camera with very high efficiency during the measurements. Time activity curves (TACs) were generated to describe the changes of mean event density versus time. The calibrated radioactivity of the medium in the cell chamber was estimated based on the measured TAC of the medium chamber after correction of delay and dispersion. The short time cellular pharmacokinetics was estimated using a piece-wise cellular Patlak model. Time-activity data were analyzed using a sliding time window of 6 min. The physical precision and biological stability of the CIMR system was tested on human breast cancer cells SkBr3 incubated with medium of 3 different glucose concentrations (5 mM, 2.5 mM & 0.5 mM). The piecewise modeling was first tested with simulated noisy data generated using a cellular two-compartment model with variable pharmacokinetic parameters. Furthermore, SkBr3 were measured with [18F]FDG on the CIMR system for 30 min. Then the glucose transporter inhibitor Cytochalasin B (2 µM) was added to the radioactive medium and the measurements were continued for 55 min. The experiment was repeated 3 times.
Results The test under static culturing condition showed that CIMR has high-quality dynamic measurements and high biological stability (variation of 18.5% for 5 mM, 15.1% for 2.5 mM and 5.4% for 0.5 mM). Based on the simulations, the estimated real-time Ki reproduces the ground truth with an average error of 4.4±2.8%. Under the Cytochalasin B intervention, the estimated Ki changes from ~0.037 min-1 to ~0.007 min-1, which is reproducible in the 3 SkBr3 samples (variation of 25.5±19.3%).
Conclusions The preliminary results demonstrated the feasibility of tracking cellular pharmacokinetics over time using high-quality dynamic data obtained from CIMR system, although tuning of the medium activity profile and further experimental validation are still on-going. $$graphic_C2450A5B-6F5F-4A57-A145-CCD0E211AD93$$
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