Combining Bulk Temperature and Nanoheating Enables Advanced Magnetic Fluid Hyperthermia Efficacy on Pancreatic Tumor Cells

Ulrich M Engelmann,Ulrich M Engelmann,Anjali A Roeth,Anjali A Roeth,Ulf P Neumann,Ulf P Neumann,Dietmar Eberbeck,Eva M Buhl,Eva M Buhl,Ioana Slabu,Thomas Schmitz-Rode,Thomas Schmitz-Rode

doi:10.1038/s41598-018-31553-9

Abstract

Many efforts are made worldwide to establish magnetic fluid hyperthermia (MFH) as a treatment for organ-confined tumors. However, translation to clinical application hardly succeeds as it still lacks of understanding the mechanisms determining MFH cytotoxic effects. Here, we investigate the intracellular MFH efficacy with respect to different parameters and assess the intracellular cytotoxic effects in detail. For this, MiaPaCa-2 human pancreatic tumor cells and L929 murine fibroblasts were loaded with iron-oxide magnetic nanoparticles (MNP) and exposed to MFH for either 30 min or 90 min. The resulting cytotoxic effects were assessed via clonogenic assay. Our results demonstrate that cell damage depends not only on the obvious parameters bulk temperature and duration of treatment, but most importantly on cell type and thermal energy deposited per cell during MFH treatment. Tumor cell death of 95% was achieved by depositing an intracellular total thermal energy with about 50% margin to damage of healthy cells. This is attributed to combined intracellular nanoheating and extracellular bulk heating. Tumor cell damage of up to 86% was observed for MFH treatment without perceptible bulk temperature rise. Effective heating decreased by up to 65% after MNP were internalized inside cells.

Highlights

Either injected into the tumor or administrated intravenously and accumulated at the tumor site by external magnetic fields[13,14,15]
For magnetic fluid hyperthermia (MFH) treatment of pancreatic tumor cells (MiaPaCa-2) as well as of healthy cells (L929 murine fibroblasts), this study presents the dependency of cell survival on different physical quantities
The heating efficiency of ML described by the specific loss power (SLP) value was shown to drop by up to 65% for intracellular particles, suggesting less heat dissipation due to immobilization of intracellular magnetic nanoparticles (MNP)

Summary

Introduction

Either injected into the tumor or administrated intravenously and accumulated at the tumor site by external magnetic fields (magnetic targeting)[13,14,15]. An intratumoral injection is an invasive procedure with high risks of developing metastasis These risks can be omitted when magnetic targeting of MNP is intravenously applied, at the cost of reaching comparatively low MNP concentrations of approx. For tumors that can be reached endoscopically, such as PDAC, the MNP concentration inside the tumor could be drastically enhanced in the future using magnetic targeting settings In this way, the local MNP concentration at disposal for MFH treatment would be much higher than the one for simple magnets mentioned above and the effective temperatures for treatment might be reached more . Other cell damaging effects can arise from mechanical rupture of the membrane due to the MNP rotation with the magnetic field[38] In this way, intracellular nanoheating and mechanical rupture could support the efficacy of MFH treatment especially for lower MNP concentrations at the tumor site. The influences of treatment duration, internalized MNP amount and thermal energy deposition on MFH treatment efficacy were analysed

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