Nanoparticle-based hyperthermia distinctly impacts production of ROS, expression of Ki-67, TOP2A, and TPX2, and induction of apoptosis in pancreatic cancer

Robert Ludwig,1 Francisco J Teran,2,3 Ulf Teichgraeber,1 Ingrid Hilger1 1Department of Experimental Radiology, Institute for Diagnostic and Interventional Radiology, Jena University Hospital – Friedrich Schiller University Jena, Jena, Germany; 2iMdea-Nanociencia, Campus Universitario de Cantoblanco, 3Nanobiotecnología (iMdea-Nanociencia), Unidad Asociada al Centro Nacional de Biotecnología (CSIC), Madrid, Spain Abstract: So far, the therapeutic outcome of hyperthermia has shown heterogeneous responses depending on how thermal stress is applied. We studied whether extrinsic heating (EH, hot air) and intrinsic heating (magnetic heating [MH] mediated by nanoparticles) induce distinct effects on pancreatic cancer cells (PANC-1 and BxPC-3 cells). The impact of MH (100 µg magnetic nanoparticles [MNP]/mL; H=23.9 kA/m; f=410 kHz) was always superior to that of EH. The thermal effects were confirmed by the following observations: 1) decreased number of vital cells, 2) altered expression of pro-caspases, and 3) production of reactive oxygen species, and 4) altered mRNA expression of Ki-67, TOP2A, and TPX2. The MH treatment of tumor xenografts significantly (P≤0.05) reduced tumor volumes. This means that different therapeutic outcomes of hyperthermia are related to the different responses cells exert to thermal stress. In particular, intratumoral MH is a valuable tool for the treatment of pancreatic cancers. Keywords: iron oxide nanoparticles, magnetic hyperthermia, heat dose, nanomedicine, proliferation marke