The potential synergism and benefit of combined hyperthermia and radiation for cancer treatment is well established, but has yet to be optimized clinically. Specifically, the delivery of heat via external arrays /applicators or interstitial antennas has not demonstrated the spatial precision or specificity necessary to achieve appropriate a highly positive therapeutic ratio. Recently, antibody directed and possibly even non-antibody directed iron oxide nanoparticle hyperthermia has shown significant promise as a tumor treatment modality. Our studies are designed to determine the effects (safety and efficacy) of iron oxide nanoparticle hyperthermia and external beam radiation in a murine breast cancer model. Methods: MTG-B murine breast cancer cells (1 x 106) were implanted subcutaneous in 7 week-old female C3H/HeJ mice and grown to a treatment size of 150 mm3 +/- 50 mm3. Tumors were then injected locally with iron oxide nanoparticles and heated via an alternating magnetic field (AMF) generator operated at approximately 160 kHz and 400 - 550 Oe. Tumor growth was monitored daily using standard 3-D caliper measurement technique and formula. specific Mouse tumors were heated using a cooled, 36 mm diameter square copper tube induction coil which provided optimal heating in a 1 cm wide region in the center of the coil. Double dextran coated 80 nm iron oxide nanoparticles (Triton Biosystems) were used in all studies. Intra-tumor, peri-tumor and rectal (core body) temperatures were continually measured throughout the treatment period. Results: Preliminary in vivo nanoparticle-AMF hyperthermia (167 KHz and 400 or 550 Oe) studies demonstrated dose responsive cytotoxicity which enhanced the effects of external beam radiation. AMF associated eddy currents resulted in nonspecific temperature increases in exposed tissues which did not contain nanoparticles, however these effects were minor and not injurious to the mice. These studies also suggest that iron oxide nanoparticle hyperthermia is more effective than non-nanoparticle tumor heating techniques when similar thermal doses are applied. Initial electron and light microscopy studies of iron oxide nanoparticle and AMF exposed tumor cells show a rapid uptake of particles and acute cytotoxicity following AMF exposure.
Fe/Fe oxide nanoparticles, in which the core consists of metallic Fe and the shell is composed of Fe oxides, were
obtained by reduction of an aqueous solution of FeCl3 within a NaBH4 solution, or, using a water-in-oil micro-emulsion
with CTAB as the surfactant. The reduction was performed either in an inert atmosphere or in air, and passivation with
air was performed to produce the Fe/Fe3O4 core/shell composite. Phase identification and particle size were determined
by X-ray diffraction and TEM. Thermal analysis was performed using a differential scanning calorimeter. The quasistatic
magnetic properties were measured using a VSM, and the specific absorption rates (SARs) of both Fe oxide and
Fe/Fe3O4 composite nanoparticles either dispersed in methanol or in an epoxy resin were measured by Luxtron fiber
temperature sensors in an alternating magnetic field of 150 Oe at 250 kHz. It was found that the preparation conditions,
including the concentrations of solutions, the mixing procedure and the heat treatment, influence the particle size, the
crystal structure and consequently the magnetic properties of the particles. Compared with Fe oxides, the saturation
magnetization (MS) of Fe/Fe3O4 particles (100-190 emu/g) can be twice as high, and the coercivity (HC) can be tunable
from several Oe to several hundred Oe. Hence, the SAR of Fe/Fe3O4 composite nanoparticles can be much higher than
that of Fe oxides, with a maximum SAR of 345 W/g. The heating behavior is related to the magnetic behavior of the
nanoparticles.
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