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Radiopharmaceuticals can be used for targetspecific functional diagnostics, such as PET or SPECT imaging, or radionuclide therapy of diseased tissue, depending on the incorporated radionuclide. Following initial in vitro testing, radiopharmaceutical candidates are usually further characterized in small animals. Since reduction, replacement and refinement (3R) of animal testing is a central precept in preclinical research it would be beneficial to replace at least some of these tests by alternative methods. Using micro physiological system technology, various organ-on-chip models can be created with human cell systems/organoids, which are operated in a circulatory system under defined physiological conditions. Here we present first attempts to introduce micro physiological systems for evaluating radiopharmaceuticals using the radiolabeled anti-EGFR antibody cetuximab as reference compound. In a micro physiological system equipped with six 96-well plate-like microwells in a flow chamber, binding of 64Cu and 68Ga-labeled cetuximab to cells and spheroids grown from A431 (EGFR-positive) and MDA-MB435S (EGFR-negative) cells was measured and compared to conventional microplates. Specific saturation binding of radiolabeled cetuximab at increasing concentrations was analyzed using a phosphor imaging system. The affinity of radiolabeled cetuximab towards A431 spheroids measured in the micro physiological system was in the same range as that of the spheroids in conventional microplates. Within the assays in micro physiological systems, the results showed a trend towards increased affinity for A431 monolayers compared to the spheroids. The values of binding capacity for radiolabeled cetuximab on 2D and 3D A431 cell culture models were in the same order of magnitude when measured in micro physiological systems or in microplates. Building on these first promising results, the work will continue on MPS modules containing advanced human spheroid/ organoid models.

Introducing micro physiological systems to evaluate new radiopharmaceuticals: A binding study with radiolabeled cetuximab