Dual role of magnetic nanoparticles as intracellular hotspots and extracellular matrix disruptors triggered by magnetic hyperthermia in 3D cell culture models

Magnetic hyperthermia is a promising therapy for the localized treatment of cancer based on the exposure of magnetic nanoparticles to an external alternating magnetic field. In order to evaluate some of the mechanisms involved in the cellular damage caused by this treatment, two different 3D cell culture models were prepared using collagen, which is the most abundant protein of the extracellular matrix. The same amount of nanoparticles was added to cells either before or after their incorporation into the 3D structure. Therefore, in one model, particles were located only inside cells (In model), while the other one had particles both inside and outside cells (In&Out model). In the In&Out model, the hyperthermia treatment facilitated the migration of the particles from the outer areas of the 3D structure to the inner parts, achieving a faster homogeneous distribution throughout the whole structure and allowing the particles to gain access to the inner cells. The cell death mechanism activated by the magnetic hyperthermia treatment was different in both models. Necrosis was observed in the In model and apoptosis in the In&Out model 24 h after the hyperthermia application. This was clearly correlated with the amount of nanoparticles located inside the cells. Thus, the combination of both 3D models allowed us to demonstrate two different roles of the magnetic particles during the hyperthermia treatment: (i) The modulation of the cell death mechanism depending on the amount of intracellular particles and (ii) the disruption of the collagen matrix caused by the extracellular nanoparticles.The present work was supported by grants from the Universidad de Zaragoza (UZ2018-CIE-03), Spanish MINECO (MAT2011-26851-CO2-01, SAF2014-54763-C2-2-R, and BIO2017-84246-C2-1-R), Fondo Social de la DGA (grupos DGA), COST Action TD1402 (Radiomag), and the European Commission through the M-ERA.NET COFUND project MagicCellGene (PCIN-2017-060). L.B. thanks Santander-Universidad Zaragoza Fellowship program for her PhD position. L.A. acknowledges financial support from the Juan de la Cierva program (JFC1-2014-20655). L.G. and R.M.F. acknowledge financial support from the Ramón y Cajal program (RYC-2014-15512 and RYC-2015-17640).Peer reviewe