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A Cell-Culture Reactor for the On-Line Evaluation of Radiopharmaceuticals: Evaluation of the Lumped Constant of FDG in Human Glioma Cells

Institutes of Biotechnology, Medicine, and Nuclear Chemistry and Department of Electronics, Jülich Research Center, Jülich, Germany

Correspondence: For correspondence or reprints contact: Manfred Biselli, PhD, Institute of Biotechnology, Forschungszentrum Jülich GmbH, Jülich D-52425, Germany.

ABSTRACT

A fluidized-bed cell-culture reactor with on-line radioactivity detection was developed for the in vitro evaluation of radiopharmaceuticals. The technique was applied to measure the dependency of the lumped constant (LC) of FDG on the glucose concentration in the culture medium in a human glioma cell line. Methods: Human glioblastoma cells (86HG39) immobilized in open porous microcarriers were cultivated in a continuously operating fluidized-bed bioreactor. At different glucose concentrations in the culture medium, step inputs (0.1 MBq/mL) of FDG were performed and the cellular uptake of FDG was measured on-line and compared with analyzed samples. From these results, the LC of FDG and its dependency on the glucose concentration were calculated. Results: This fluidized-bed technique enabled precise and reproducible adjustment of all relevant experimental parameters, including radiotracer time—concentration course, medium composition, pH, dissolved oxygen and temperature under steady-state conditions, and an on-line determination of the intracellular radiotracer uptake. The immobilized glioma cells formed stable, 3-dimensional, tumor-like spheroids and were continuously proliferating, as proven by an S-phase portion of 25%–40%. For further examination of the cells, an enzymatic method for detachment from the carriers without cellular destruction was introduced. In the FDG experiments, a significant dependency of the LC on the glucose level was found. For normoglycemic glucose concentrations, the LC was determined to be in the range of 0.7 ±0.1, whereas in hypoglycemia LC increased progressively up to a value of 1.22 ± 0.01 at a glucose concentration of 3 mmol/L. Conclusion: The bioreactor represents an improved in vitro model for the on-line evaluation of radiotracers and combines a wide range of experimental setups and 3-dimensional, tissue-like cell cultivation with a technique for on-line radioactivity detection.

Key Words: cell culture • FDG • fluidized bed • in vitro • lumped constant