Design of 3D spheroid models for drug-response studies of HER2-targeted radiopharmaceuticals

The development of targeted radionuclide- and chemotherapeutics-based drugs requires in vitro models that reflect the structural and molecular complexity of solid tumors. Here, we present a high-throughput 3D cell culture platform for targeted drug response studies. The platform was based on agarose micro-dishes that generate 81 tumor spheroids. The platform was validated across eight human and murine cancer cell lines that overexpress receptors of the HER family. The high spheroid yield supports robust quantitative analysis of binding of radiolabeled compounds, while spheroid trapping in microwells enables medium exchange for precise drug exposure. Therefore, we evaluated targeted radionuclide therapy of EMT-HER2 spheroids using the HER2-specific affibody PEP48937 labelled with terbium-161. We demonstrated both HER2-specific binding to spheroids and receptor-specific therapeutic effects, including reduced spheroid proliferation over time and impaired cell migration. These results highlight the platform potential to accelerate the development of targeted cancer therapeutics for biomedicine.