In Vivo Imaging of Local Gene Expression Induced by Magnetic Hyperthermia.

Olivier Sandre,Stéphane Mornet,Franck Couillaud,Coralie Genevois,Laurent Adumeau,Eneko Garaio

doi:10.3390/genes8020061

Abstract

The present work aims to demonstrate that colloidal dispersions of magnetic iron oxide nanoparticles stabilized with dextran macromolecules placed in an alternating magnetic field can not only produce heat, but also that these particles could be used in vivo for local and noninvasive deposition of a thermal dose sufficient to trigger thermo-induced gene expression. Iron oxide nanoparticles were first characterized in vitro on a bio-inspired setup, and then they were assayed in vivo using a transgenic mouse strain expressing the luciferase reporter gene under transcriptional control of a thermosensitive promoter. Iron oxide nanoparticles dispersions were applied topically on the mouse skin or injected subcutaneously with Matrigel™ to generate so-called pseudotumors. Temperature was monitored continuously with a feedback loop to control the power of the magnetic field generator and to avoid overheating. Thermo-induced luciferase expression was followed by bioluminescence imaging 6 h after heating. We showed that dextran-coated magnetic iron oxide nanoparticle dispersions were able to induce in vivo mild hyperthermia compatible with thermo-induced gene expression in surrounding tissues and without impairing cell viability. These data open new therapeutic perspectives for using mild magnetic hyperthermia as noninvasive modulation of tumor microenvironment by local thermo-induced gene expression or drug release.

Highlights

Gene therapies are promising techniques for curing diseases either by repairing or replacing a defective gene or by expressing some therapeutic proteins or regulatory noncoding RNA
Magneto-activatable thermogenic nanoparticles (MTN) were mixed with MatrigelTM, a natural component of the tumor microenvironment, and the mixture was placed into a 20 mL agar gel to mimic a mouse weight of about 20 g
The tumor phantom model was designed with a volume of 100 μL in order to exceed the diameter of 1.1 mm proposed by Rabin as a minimum size of magnetic sample to exhibit macroscopic heating compared to environmental temperature [23]

Summary

Introduction

Gene therapies are promising techniques for curing diseases either by repairing or replacing a defective gene or by expressing some therapeutic proteins or regulatory noncoding RNA. Tight spatiotemporal regulation of gene expression, in the region where therapy is necessary and for the duration required to achieve a therapeutic effect, is very important for clinical applications. Temporal control of gene expression may be achieved by several externally controlled, inducible gene promoters which respond to antibiotics [3]. Spatial control is more frequently envisaged by using tissue-specific or disease-specific promoters, yet lacking features for both temporal and external controls. These specific promoters often exhibit a low level of therapeutic gene expression

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