"SMART" MEDIATORS FOR SELF-CONTROLLED INDUCTIVE HEATING

Abstract

INTRODUCTION: Hyperthermia is a rapidly developing technique in cancer therapy. It takes advantage of the higher sensitivity of tumor tissue to heat and typically involves heating of the affected organ to 43 – 45 °C. Magnetic fluid hyperthermia [1] attracts increasing attention, since it allows minimizing side effects by the localized heating of only desired parts of the organism, including tumors located deep inside the patient’s body. The method involves introduction of ferromagnetic particles (mediators) into the desired part of the organism and heating them with an alternating electromagnetic field of radio-frequency range (RF). Magnetic fluids based on nanocrystalline Fe3O4, stabilized by biocompatible surfactants [2-6], are typically used as mediators. Unfortunately, it is impossible to control the local temperature near the mediator particles, possibly causing local overheating and necrosis of normal tissue. This problem could be solved with ferromagnetic particles of high RF absorption and a Curie temperature (Tc) of ca. 42 45 °C. Thus, local temperature control can be ensured even with a nonuniform distribution of mediator particles throughout the tissue, variable RF intensity and uneven dissipation of the evolving heat. If Tc of this material can be purposefully varied, mediators could be adapted to the particular medical application. Similar approach is used in cancer thermal therapies, which utilize implantable “thermoseeds” with a particular Curie temperature [7,8]. These macroscopically sized solid units are surgically inserted in the affected organ and are heated by an external RF. The Tc of the “thermoseed” determines the temperature of the heating. Significant limitations of these methods are the necessity of a stressful surgical intervention and a relatively small volume around each “thermoseed” which can be effectively heated. The reduction of size of the heatproducing elements so that they can be delivered as a suspension via catheter into the bloodstream of the tumor and spread throughout its capillaries, is the obvious solution of these problems. Sato et al [9,10] reported using 50 μm flakes of an amorphous ferromagnetic metal alloy with Tc of ca. 45 °C for intratissue hyperthermia in dogs. However, these relatively large electrically conducting particles are heated in an RF field by eddy currents even above Tc. and do not penetrate into small capillaries. Numerous studies [1-6,12,13] have shown that submicron-sized non-conducting particles are most effective for hyperthermia. The goal of this work was to produce biologically compatible, electrically non-conductive nanoparticles with Tc in the range of 40-50°C. Individual ferromagnetic substances with Tc in this range do not exist, but by combining several elements and by varying the composition of the mixture it is possible to produce alloys, amorphous structures, ferrites and other multi-component systems consisting of metals and metalloids. We used several synthesis techniques to produce a variety of ultradisperse particles with suitable Tc and tested their behavior in an RF field.