Computational and Experimental Investigation of Magnetic Nanoparticle Based Hyperthermia

Abstract

Magnetic hyperthermia cancer treatment, uses magnetic nano-particles as heating source. In this magnetic nanoparticle hyperthermia (MNPH), heat is generated locally through nanoparticles induced to the targeted tissue (tumor tissue) under the influence of external magnetic field. This hyperthermia applicator has higher spatial contol of heat generation thus targeted damage could be induced to tumor tissue while minimizing the thermal damage to the neighboring healthy tissue. However, this novel therapy has some limitations and challenges in its practical implementation. These challenges are in the form of magnetic nanoparticle (MNP) heating power enhancement, regulating their dose and distribution, achieving spatial control of tumor temperature by multisite injections, and ensuring the safe infusion of particles. The present study aims to address these challenges and limitations to make magnetic hyperthermia applicable to the future cancer treatment therapy. The important parameters for efficient heating in MNPH are the MNP’s properties, size, materials, and externally applied magnetic field parameters (amplitude and frequency). A numerical investigation is done to analyze the effects of these parameters on heat generation for three nanoparticle systems (CoFe2O4, Fe3O4, and MnFe2O4). The quantification of specific loss power (SLP) or heat generation of different nanoparticle systems, which is influenced by their size-dependent magnetization (M_S) and the anisotropy energy has been done. Correlations for magnetization (M_S) and the anisotropy energy based on the previously reported experimental data have been established. These correlations are introduced into the Rosensweig model of induction heating for considered MNP systems. The comparisons show that SLP estimation using MNP size-dependent saturation magnetization 〖(M〗_S) are much closer to the experimentally reported values of SLP for all three MNP systems in comparison to SLP estimated by fixed values of saturation magnetization on 〖(M〗_S) and anisotropy energy constant (K_eff). Results show that dissipated power reaches a peak at an specific nano-particle size 〖(D〗_O). However, the 〖(D〗_O) varies with the magnetic field frequency and amplitude. It is also concluded that a particular size of MNP at resonant amplitude and frequency generates the maximum SLP. Additionally, in In Intro study, the SLP of magnetite (Fe3O4) nanoparticles dispersed in agar gel has been measured using a hyperthermia applicator (NAN201003 Magnetherm Applicator). The experimental temperature profiles were compared with the computational profile obtained using the bioheat model. The numerical results are in good agreement with experimental results. This increases the confidence and applicability of the simulated results of MNPH for further computational investigation of MNPH. In the first computational investigation of MNPH, tumor tissue position (depth) with respect to the skin surface as well as clinical environment conditions have been changed. The three-dimensional (3D) breast tumor model, enclosed by the healthy tissue is used for MNPH simulations. The position and heat transfer rate through the skin are altered to evaluate their effect on MNPH. The embedded tumor tissue (of size 1.5 cm) is positioned at six different depths with respect to the top surface and three heat transfer coefficients (h_c=2.5,5,and 7.5 W⁄(m^2 K)) on the skin are considered to simulate a wide range of clinical environment conditions during MNPH. The values of h_c is calculated from the empirical relations for natural and forced convective heat transfer of different posturing and ambient conditions exposed on human mannequin in literature. MNPH is induced for 1 hour with two heating powers (10 kA/m and 12.5 kA/m at 130 kHz) to assess thermal damage (Arrhenius (Ω=4.6) and cumulative equivalent minutes (CEM43)60 in the tissue. Results show that a critical depth exists, which is nearly half of the tumor size, up to which the MNPH is influenced by the position of the tumor. Similarly, the effects of the ambient conditions during this thermotherapy on thermal dosimetry also cease beyond this critical depth. The estimation of the critical depth of the tumor will help in predicting the therapeutic effects of magnetic hyperthermia applicators for specifically positioned tumors in actual environmental conditions. Further, the computational investigations are carried out to determine the breast tumor size-dependent MNP dose ((mg of MNP)⁄(cm^3 of tumor tissue)) for MNPH. The investigation is done through the simulations on the tumor models generated from DCE_MRI DICOM images of the patient’s breast cancer from TCIA (‘The Cancer Imaging Archive’). Five tumor models are produced from MRI data using 3D slicer software, ranging from 3 cm3 to 15 cm3. The FEM-based solver (COMSOL multi-physics) is used to simulate bioheat transfer physics in all five extracted models. Single and multipoint injection strategies have been used to induce MNP in tumor tissues. The required MNP dose that may induce necessary therapeutic effects is evaluated by comparing the therapeutic effects produced by constant dose (CD) (5( mg)⁄(cm^3 )) and variable reduced dose (RD) (5.5-2.8 mg⁄(cm^3 )) methodologies. The current observation states that for the requisite therapeutic effects, injected MNP doses( (mg)⁄(cm^3 )) should not remain constant as the size of the tumor increases. In fact, MNP dose ((mg)⁄(cm^3 )) should be reduced as the size of the tumor increases. Results also show that RD works better with a multi-injection strategy than a single injection of MNP. It has been found that the effective MNP dose ((mg)⁄(cm^3 )) is reduced by 50% for the biggest tumor size (15 cm3) using multi-injection MNP delivery with respect to the smallest tumor (3 cm3) selected in this study. Using the DICOM database, a more realistic tumor model has been developed. A more accurate physical model for MNPH application has an artery embedded inside the tumor. The MNP particles are infused to the tumor tissue using a multipoint injection strategy to gain a homogenous temperature distribution. The thermal damage of the tumor region has been evaluated with two conditions, i.e., with the flow and without the flow of blood through the artery. It has been observed that arterial blood flow, transports a substantial amount of heat. This reduces the thermal damage to tumor tissue during hyperthermia. It was noticed that the thermal damage was reduced by 25% due to the arterial blood flow in the partially submerged artery in the tumor region. It is concluded that besides the MNP distribution, its dose, and injection sites, the therapeutic effects of MNPH is significantly influenced by the blood vessels and arteries surrounding the tumor. The investigations carried out in this thesis aim to generate knowledge domain for MNPH that may help to optimize this therapy for future clinical applications.