In Silico Study on Tumor-Size-Dependent Thermal Profiles inside an Anthropomorphic Female Breast Phantom Subjected to Multi-Dipole Antenna Array

Electromagnetic hyperthermia as a potent adjuvant for conventional cancer therapies can be considered valuable in modern oncology, as its task is to thermally destroy cancer cells exposed to high-frequency electromagnetic fields. Hyperthermia treatment planning based on computer in silico simulations has the potential to improve the localized heating of breast tissues through the use of the phased-array dipole applicators. Herein, we intended to improve our understanding of temperature estimation in an anatomically accurate female breast phantom embedded with a tumor, particularly when it is exposed to an eight-element dipole antenna matrix surrounding the breast tissues. The Maxwell equations coupled with the modified Pennes’ bioheat equation was solved in the modelled breast tissues using the finite-difference time-domain (FDTD) engine. The microwave (MW) applicators around the object were modelled with shortened half-wavelength dipole antennas operating at the same 1 GHz frequency, but with different input power and phases for the dipole sources. The total input power of an eight-dipole antenna matrix was set at 8 W so that the temperature in the breast tumor did not exceed 42 °C. Finding the optimal setting for each dipole antenna from the matrix was our primary objective. Such a procedure should form the basis of any successful hyperthermia treatment planning. We applied the algorithm of multi for multi-objective optimization for the power and phases for the dipole sources in terms of maximizing the specific absorption rate (SAR) parameter inside the breast tumor while minimizing this parameter in the healthy tissues. Electro-thermal simulations were performed for tumors of different radii to confirm the reliable operation of the given optimization procedure. In the next step, thermal profiles for tumors of various sizes were calculated for the optimal parameters of dipole sources. The computed results showed that larger tumors heated better than smaller tumors; however, the procedure worked well regardless of the tumor size. This verifies the effectiveness of the applied optimization method, regardless of the various stages of breast tumor development.     

A Smart Hyperthermia Nanofiber-Platform-Enabled Sustained Release of Doxorubicin and 17AAG for Synergistic Cancer Therapy

This study demonstrates the rational fabrication of a magnetic composite nanofiber mesh that can achieve mutual synergy of hyperthermia, chemotherapy, and thermo-molecularly targeted therapy for highly potent therapeutic effects. The nanofiber is composed of biodegradable poly(ε-caprolactone) with doxorubicin, magnetic nanoparticles, and 17-allylamino-17-demethoxygeldanamycin. The nanofiber exhibits distinct hyperthermia, owing to the presence of magnetic nanoparticles upon exposure of the mesh to an alternating magnetic field, which causes heat-induced cell killing as well as enhanced chemotherapeutic efficiency of doxorubicin. The effectiveness of hyperthermia is further enhanced through the inhibition of heat shock protein activity after hyperthermia by releasing the inhibitor 17-allylamino-17-demethoxygeldanamycin. These findings represent a smart nanofiber system for potent cancer therapy and may provide a new approach for the development of localized medication delivery.     

Hyperthermia Induces Apoptosis through Endoplasmic Reticulum and Reactive Oxygen Species in Human Osteosarcoma Cells

Osteosarcoma (OS) is a relatively rare form of cancer, but OS is the most commonly diagnosed bone cancer in children and adolescents. Chemotherapy has side effects and induces drug resistance in OS. Since an effective adjuvant therapy was insufficient for treating OS, researching novel and adequate remedies is critical. Hyperthermia can induce cell death in various cancer cells, and thus, in this study, we investigated the anticancer method of hyperthermia in human OS (U-2 OS) cells. Treatment at 43 °C for 60 min induced apoptosis in human OS cell lines, but not in primary bone cells. Furthermore, hyperthermia was associated with increases of intracellular reactive oxygen species (ROS) and caspase-3 activation in U-2 OS cells. Mitochondrial dysfunction was followed by the release of cytochrome c from the mitochondria, and was accompanied by decreased anti-apoptotic Bcl-2 and Bcl-xL, and increased pro-apoptotic proteins Bak and Bax. Hyperthermia triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels, as well as increased calpain expression and activity. In addition, cells treated with calcium chelator (BAPTA-AM) blocked hyperthermia-induced cell apoptosis in U-2 OS cells. In conclusion, hyperthermia induced cell apoptosis substantially via the ROS, ER stress, mitochondria, and caspase pathways. Thus, hyperthermia may be a novel anticancer method for treating OS.     

Hydrophobic to hydrophilic surface transformation of nano-scale zinc ferrite via oleic acid coating: Magnetic hyperthermia study towards biomedical applications

Nanoscale spinel zinc ferrite (ZNF) was prepared by sol-gel auto-ignition route and subsequently its surface was modified by oleic-acid (OA) coating. The pristine and surface modified ZNF nanoparticles (UC-ZNF and OA-ZNF) were characterized by standard techniques. XRD patterns of both the samples ensured the nanocrystalline mono-phasic cubic-spinel lattice structure with ‘Fd-3m space-group’. FT-IR spectra revealed the presence of vibrational frequency-modes of spinel structure and successful coating of OA over ZNF. The nano-size spherical grains with some agglomeration and OA coating over ZNF were visualized in FE-SEM images. The hydrophobic-to-hydrophilic surface-transition of ZNF was confirmed by water contact-angle measurements. The BET surface-area and distribution of pore-radius was evaluated by recording N₂-isotherms. The M − H plots confirmed the superparamagnetic nature of both the samples. Optical properties were studied by UV–Vis and PL spectroscopy techniques. The colloidal-stability and distribution of particle-sizes were estimated by zeta-potential and DLS measurements. Magnetic hyperthermia studies were carried out for different concentrations (2, 4, 6, 8 and 10 mg/mL) of both the samples. The biocompatible nature of both the samples was studied by cell-viability studies. All these results ensure the implementation of OA-ZNF nanoparticles with minimum dose rate (8 mg/mL) in magnetic hyperthermia therapies for cancer treatment.     

pH‐ and NIR Light‐Responsive Micelles with Hyperthermia‐Triggered Tumor Penetration and Cytoplasm Drug Release to Reverse Doxorubicin Resistance in Breast Cancer

The acquisition of multidrug resistance (MDR) is a major hurdle for the successful chemotherapy of tumors. Herein, a novel hybrid micelle with pH and near‐infrared (NIR) light dual‐responsive property is reported for reversing doxorubicin (DOX) resistance in breast cancer. The hybrid micelles are designed to integrate the pH‐ and NIR light‐responsive property of an amphiphilic diblock polymer and the high DOX loading capacity of a polymeric prodrug into one single nanocomposite. At physiological condition (i.e., pH 7.4), the micelles form compact nanostructure with particle size around 30 nm to facilitate blood circulation and passive tumor targeting. Meanwhile, the micelles are quickly dissociated in weakly acidic environment (i.e., pH ≤ 6.2) to release DOX prodrug. When exposed to NIR laser irradiation, the hybrid micelles can trigger notable tumor penetration and cytosol release of DOX payload by inducing tunable hyperthermia effect. In combination with localized NIR laser irradiation, the hybrid micelles significantly inhibit the growth of DOX‐resistant MCF‐7/ADR breast cancer in an orthotopic tumor bearing mouse model. Taken together, this pH and NIR light‐responsive micelles with hyperthermia‐triggered tumor penetration and cytoplasm drug release can be an effective nanoplatform to combat cancer MDR.     

Intratumoral Thermal Reading During Photo‐Thermal Therapy by Multifunctional Fluorescent Nanoparticles

The tremendous development of nanotechnology is bringing us closer to the dream of clinical application of nanoparticles in photothermal therapies of tumors. This requires the use of specific nanoparticles that must be highly biocompatible, efficient light‐to‐heat converters and fluorescent markers. Temperature reading by the heating nanoparticles during therapy appears of paramount importance to keep at a minimum the collateral damage that could arise from undesirable excessive heating. In this work, this thermally controlled therapy is possible by using Nd³⁺ ion‐doped LaF₃ nanocrystals. Because of the particular optical features of Nd³⁺ ions at high doping concentrations, these nanoparticles are capable of in vivo photothermal heating, fluorescent tumor localization and intratumoral thermal sensing. The successful photothermal therapy experiments here presented highlight the importance of controlling therapy parameters based on intratumoral temperature measurements instead of on the traditionally used skin temperature measurements. In fact, significant differences between intratumoral and skin temperatures do exist and could lead to the appearance of excessive collateral damage. These results open a new avenue for the real application of nano­particle‐based photothermal therapy at clinical level.     

Rotary scanning wireless temperature measurement method for hyperthermia using ferromagnetic implants

Recently, the use of a ferromagnetic material in a soft‐heating method has garnered much attention as a novel method for cancer treatment. By concurrently using this material as a thermal probe, we are currently developing a minimally invasive heating and wireless temperature measurement system. To make the approach feasible in a clinical setting, it is vital to overcome the key challenge of heating the local tumor at a constant temperature. In previous conventional approaches, it was necessary to switch the induction‐heating power supply on/off after the target tumor temperature was reached. However, it cannot determine the temperature of the material during the power‐off period. Therefore, we changed this approach and found that by adjusting the distance between the heating coil and the material while maintaining a constant current flow in heating coil, the drift problem, which happened just after power is supplied during the on/off operation, did not occur any longer. Accordingly, it was not required to use multiple sensors to reduce the drift, thereby minimizing the cost. This study verifies the validity of our wireless thermometry approach while performing rotary scanning and proposes a technique for determining achievement of the target temperature. This knowledge complements other approaches for cancer treatment utilizing hyperthermia. © 2015 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.     

Position adjustment method and distance estimation method of magnetic field supply and detection unit for magnetic hyperthermia

In magnetic hyperthermia, the temperature and localization of a ferromagnetic implant in a tumor region is vital in determining the effectiveness of therapeutic heating. We have developed a noninvasive wireless temperature measurement method by utilizing the magnetic permeability property of a ferromagnetic implant with low Curie temperature (FILCT) that varies with the temperature. In clinical settings, when the FILCT is injected into a tumor region, the position of the FILCT is expected to deviate from the central axis of the heating coil (drive coil). When it deviates, the magnetic flux density applied to the FILCT decreases, thus causing difficulty in detecting the temperature of FILCT via a pickup coil and heating of the FILCT at a constant treatment temperature. Therefore, to adjust the magnetic field supply and detection (MFSD) unit to be directly above the FILCT, we propose a position adjustment method by referring to three voltages induced in three pickup coils symmetrically installed inside the drive coil. By using the average value of the three voltages, we also propose a method to estimate the distance between the MFSD unit and the FILCT, which is required for wireless thermometry and determination of the optimal energy applied. The proposed methods are experimentally examined by a verification system.