HYPER: pre-clinical device for spatially-confined magnetic particle hyperthermia

Abstract

Purpose: Magnetic particle hyperthermia is an approved cancer treatment that harnesses thermal energy generated by magnetic nanoparticles when they are exposed to an alternating magnetic field (AMF). Thermal stress is either directly cytotoxic or increases the susceptibility of cancer cells to standard therapies, such as radiation. As with other thermal therapies, the challenge with nanoparticle hyperthermia is controlling energy delivery. Here, we describe the design and implementation of a prototype pre-clinical device, called HYPER, that achieves spatially confined nanoparticle heating within a user-selected volume and location.

Design: Spatial control of nanoparticle heating was achieved by placing an AMF generating coil (340 kHz, 0-15 mT), between two opposing permanent magnets. The relative positions between the magnets determined the magnetic field gradient (0.7 T/m-2.3 T/m), which in turn governed the volume of the field free region (FFR) between them (0.8-35 cm³). Both the gradient value and position of the FFR within the AMF ([-14, 14]_x, [-18, 18]_y, [-30, 30]_z) mm are values selected by the user via the graphical user interface (GUI). The software then controls linear actuators that move the static magnets to adjust the position of the FFR in 3D space based on user input. Within the FFR, the nanoparticles generate hysteresis heating; however, outside the FFR where the static field is non-negligible, the nanoparticles are unable to generate hysteresis loss power.

Verification: We verified the performance of the HYPER to design specifications by independently heating two nanoparticle-rich areas of a phantom placed within the volume occupied by the AMF heating coil.

Keywords: Magnetic particle hyperthermia; design verification; spatially confined heating.

Figure 1:. Opposing magnets create a strong magnetic field gradient containing a FFR that provides the basis for spatially-confined heating with the HYPER prototype.

The volume of the FFR depends on gradient strength, where a stronger gradient creates a smaller FFR. When and AMF is applied, the nanoparticles within the FFR (Region A) are free to generate thermal energy due to hysteresis losses; however, outside the FFR (Region B), the magnetic moments of the nanoparticles are fixed and contribute little to heating.

Figure 2:. Three-dimensional computer-aided design (CAD) models of the magnet and RF assembly of the HYPER system.

(a) Isometric view of the magnet assembly; (b) Top view (normal to y-axis) of the HYPER without exterior paneling. This view shows the permanent magnets along the x-axis, the RF coil assembly, the tuning circuitry, and the sample platform. (c) Front view (normal to z-axis) of the HYPER without exterior paneling. From this angle, the y-axis stage is visible.

Figure 3:. Heating sequence programming using the graphic user interface (GUI)

. (a) The GUI enables the user to execute a spatially-confined heating plan entered as command lines. The user first selects the ROIs in 3D space on the sample using the bi-planar camera views: AP and LAT, and the program generates a preset plan in the configuration editor; (b) Flow chart outlining the processes that occur during a measurement with the HYPER.

Figure 4:. Assembled HYPER prototype.

(a) In addition to the magnet and AMF assembly, the system includes a rack containing control systems, an RF amplifier, a water chiller, and animal heater. The chiller circulates water through the RF coil, with temperature that can be varied between 20°C and 40°C. The animal heater circulates water through the sample stage during in vivo experiments to maintain the core body temperature of the mouse models. (b) Diagram of the sample stage orientation within the HYPER, denoted by the dashed box.

Figure 5:. Thermal PSF at five gradient strengths along all three axes.

A nanoparticle sample was heated at varying positions along the x, y, and z-axis relative to the FFR, located at the isocenter. Thermal PSF at varying gradients along (a) x-axis; (b) y-axis; (c) z-axis. (d) Upon fitting the thermal PSFs to the derivative of the Langevin function, we calculated the FWHM in each dimension for the tested particles.

Figure 6:. Verification of spatially confined heating with mouse phantom.

Regions of interest ROI 0 (red) and ROI 1 (yellow) were selected in the HYPER GUI from both the top (a) and side (b) views. (c) Sequential heating of ROI 0 and ROI 1 is demonstrated. Despite both ROIs existing within the RF coil, the gradient field limits observed heating to the selected ROI.