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Julian Palzer,1,2 Benedikt Mues,2 Richard Goerg,1,2 Merel Aberle,3 Sander S Rensen,3 Steven WM Olde Damink,1,3 Rianne DW Vaes,3 Thorsten Cramer,1,3 Thomas Schmitz-Rode,2 Ulf P Neumann,1,3 Ioana Slabu,2 Anjali A Roeth1,3 1Department of General, Visceral and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany; 2Institute of Applied Medical Engineering, Helmholtz Institute Aachen, RWTH Aachen University Hospital, Aachen, Germany; 3Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the NetherlandsCorrespondence: Anjali A Roeth Email aroeth@ukaachen.deIntroduction: Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a meager prognosis due to its chemotherapy resistance. A new treatment method may be magnetic fluid hyperthermia (MFH). Magnetoliposomes (ML), consisting of superparamagnetic iron oxide nanoparticles (SPION) stabilized with a phospholipid-bilayer, are exposed to an alternating magnetic field (AMF) to generate heat. To optimize this therapy, we investigated the effects of MFH on human PDAC cell lines and 3D organoid cultures.Material and Methods: ML cytotoxicity was tested on Mia PaCa-2 and PANC-1 cells and on PDAC 3D organoid cultures, generated from resected tissue of patients. The MFH was achieved by AMF application with an amplitude of 40– 47 kA/m and a frequency of 270 kHz. The MFH effect on the cell viability of the cell lines and the organoid cultures was investigated at two different time points. Clonogenic assays evaluated the impairment of colony formation. Altering ML set-ups addressed differences arising from intra- vs extracellular ML locations.Results: Mia PaCa-2 and PANC-1 cells showed no cytotoxic effects at ML concentrations up to 300 μg(Fe)/mL and 225 μg(Fe)/mL, respectively. ML at a concentration of 225 μg(Fe)/mL were also non-toxic for PDAC organoid cultures. MFH treatment using exclusively extracellular ML presented the highest impact on cell viability. Clonogenic assays demonstrated remarkable impairment as long-term outcome in MFH-treated PDAC cell lines. Additionally, we successfully treated PDAC organoids with extracellular ML-derived MFH, resulting in notably reduced cell viabilities 2h and 24 h post treatment. Still, PDAC organoids seem to partly recover from MFH after 24 h as opposed to conventional 2D-cultures.Conclusion: Treatment with MFH strongly diminished pancreatic cancer cell viability in vitro, making it a promising treatment strategy. As organoids resemble the more advanced in vivo conditions better than conventional 2D cell lines, our organoid model holds great potential for further investigations.Keywords: magnetic nanoparticles, SPION, pancreatic cancer, PDAC, organoids, magnetic fluid hyperthermia