|Year : 2016 | Volume
| Issue : 1 | Page : 13-17
Magnetic hyperthermia therapy: An emerging modality of cancer treatment in combination with radiotherapy
Neena Girish Shetake, Murali M.S Balla, Amit Kumar, Badri Narain Pandey
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India
|Date of Web Publication||23-Jun-2016|
Badri Narain Pandey
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Magnetic hyperthermia therapy (MHT) involves heat generation using magnetic nanoparticles (MNPs) in response to an externally applied alternating current magnetic field. These MNPs can be specifically targeted to the tumor site for homogenous heating. Compared to MHT, conventional methods of HT cause heterogeneous heating of tumor and thus poor efficacy of cancer treatment. MHT has also been shown to effectively eliminate the highly chemo- and radio-resistant cancer stem cells in the tumor mass. Due to their diagnostic capability as well as heat-induced cancer cell killing ability, extensive research has been carried out to develop MNPs as potential cancer theranostic agent. The major focus of MNP research has been to design MNPs formulations for efficient targeting, increased colloidal stability, effective heat generation, and minimal inherent toxicity. A few recent MNPs formulations meet some of the required features and showed promising results in preclinical and clinical studies. HT applied through conventional modes has been combined with chemo- and radiotherapy, owing to its ability to increase oxygenation and drug supply due to vasodilation but has shown a limited success in clinic. However, a great hope has arisen from the MNPs to make combinatorial therapies more successful, not only because of the many advantages of MNPs mentioned but also due to their potential for targeted delivery of a range of anti-cancer drugs and radiosensitizing agents.
Keywords: Cancer stem cells, combinatorial therapy, magnetic hyperthermia therapy, magnetic nanoparticles, radiotherapy
|How to cite this article:|
Shetake NG, Balla MM, Kumar A, Pandey BN. Magnetic hyperthermia therapy: An emerging modality of cancer treatment in combination with radiotherapy. J Radiat Cancer Res 2016;7:13-7
|How to cite this URL:|
Shetake NG, Balla MM, Kumar A, Pandey BN. Magnetic hyperthermia therapy: An emerging modality of cancer treatment in combination with radiotherapy. J Radiat Cancer Res [serial online] 2016 [cited 2018 Nov 22];7:13-7. Available from: http://www.journalrcr.org/text.asp?2016/7/1/13/184606
| Introduction|| |
Nanoparticle research is currently an area of immense scientific interest due to a wide variety of applications in biomedical, optical, and electronic fields. This is mainly due to their properties (depending on the material they consist of) such as: (i) High electron density and strong optical absorption (e.g., metal particles, in particular Au), (ii) photoluminescence (semiconductor quantum dots, e.g., CdSe or CdTe) or phosphorescence (doped oxide materials, e.g. Y2O3), (iii) magnetic moment (e.g., iron-oxide, γFe2O3, La0.7 Sr0.3 MnO3, or cobalt nanoparticles),, and (iv) a high surface area-to-volume ratio as compared to their bulk counterparts. Moreover, it is their large surface area that makes them more amenable to functionalize with various targeting agents to deliver nanoparticles to the diseased site. Owing to their small size (1–100 nm), nanoparticles can penetrate the cell interior and even cross the blood-brain barrier when labeled with appropriate agents such as polysorbates and chitosan., Among nanoparticles, iron oxide nanoparticles (IONPs) have gained immense attention for various biomedical applications due to their biocompatibility and relatively economic and simple method of synthesis. IONPs are superparamagnetic in nature (i.e., they have high magnetic moment in the presence of an external magnetic field and zero coercivity at room temperature) as against the ferromagnetic property of their bulk counterparts at room temperature. This property makes IONPs as an excellent candidate for magnetic hyperthermia therapy (MHT) as heat generation can be controlled/modulated by an externally applied alternating current magnetic field (AMF). Moreover, IONPs formulations having high specific absorption rate value may be developed, thereby enabling the use of low concentrations of IONPs for MHT applications, and thus, minimizing the inherent toxicity of the formulations.
HT involves exposing the diseased site (here it is tumor tissue) or whole body to an elevated temperature (42–43°C), which either kills the tumor cells directly or sensitizes them to chemo-/radiation-therapy. However, conventional HT suffers from two major drawbacks: (i) Nonaccessibility of the deep-seated tumors and (ii) nonuniform heating of the tumor tissue due to the generation of a temperature gradient from the surface to the tumor core. These limitations cause insufficient killing of tumor cells and severe side effects such as skin burns, blisters, pain, and discomfort to the patients. These drawbacks can be significantly overcome by the application of MHT due to following reasons. IONPs can be specifically targeted to the tumor site and thus can heat the tumor from within and more uniformly. This feature minimizes the development of temperature gradients and thermoresistance in tumor, and thus enabling better tumor control. Although MHT alone is significantly effective, a combinatorial approach of MHT along with chemo-, radiotherapy, and other sensitization approaches may lead to a much better cancer treatment.
The tumor microenvironment characterized by leaky/disorganized vasculature, nutrient deprivation, hypoxic tumor cores, and acidosis leads to the development of radioresistance [Figure 1],,,, which can be largely overcome by the application of HT through the mechanism of vasodilation and subsequent increased blood (oxygen) supply to the hypoxic regions of the tumor. It may be noteworthy to mention that even though the combinatorial approach of chemotherapy (CT) with radiotherapy (RT) has been well practiced clinically, combining RT with HT has shown limited success in clinic. In the present review, an overview of the current status of MHT in clinics has been presented along with its emerging therapeutic potential in combination with RT [Figure 1].
| Hyperthermia as a Combinatorial Approach for Cancer Radiotherapy|| |
In clinics, HT has been used along with RT for the treatment of various tumor types such as head and neck, breast, prostate, and other superficial lesions., The radiosensitization ability of HT is known to be mainly due to heat induced-increased oxygenation of the tumor mass. In one study, HT was used to improve the tumor oxygenation along with RT for the treatment of soft tissue sarcomas. Results showed a positive correlation between the magnitude of improved tumor oxygenation after first HT fraction and percentage necrosis in the resection tumor specimen. Song et al. demonstrated a significant rise in tumor oxygenation in R3230 Ac adenocarcinoma tumors of Fischer rats after mild hyperthermia. Measurement of the oxygenation status using a polarographic oxygen electrode system showed that the tumor pO2 measured within 10–15 min after heating (for 30 min at 42.5°C) was about three-folds greater than that in the control tumors. In another study, HT was combined with radiation for the treatment of locally advanced prostate cancer. In these patients, at a median follow-up of 70 months (range: 18–110 months), the 7-year overall survival rate was 94% and out of that, 61% of patients showed no recurrence. Thus, HT seems to be a promising approach; however, its application in clinics is not well appreciated, probably due to the conventional mode (such as water bath and infra-red) of application of hyperthermia. This limitation is overcome by MHT, and hence, it may prove to be an effective alternative mode for HT of cancer.
| Magnetic Hyperthermia Therapy|| |
Compared to conventional HT, MHT has received immense attention due to several reasons such as (i) targeted, homogenous, and controlled heat generation capacity; (ii) the ability to access deep-seated tumor; and (iii) ability to specifically target the tumor vasculature/hypoxic tumor cells. In this direction, significant progress has been made to formulate IONPs for efficient targeting to tumor vasculature  and hypoxic regions, however, their application for MHT needs to be established. In addition, MHT may also be employed to co-deliver drugs (such as anti-cancer agents, angiogenesis inhibitors, and radiosensitizers) for efficient combination therapy. Current targeting approaches for nanoparticles include ligands such as antibodies, peptides, and porphyrins to improve tumor uptake and specificity of the desired drug, and thus lower the amount of drugs needed for cancer treatment., Many other novel strategies have been developed to target nanoparticles to the tumor site. In one such approach, Ohta et al. recently developed nanoparticles functionalized with folic acid (FA). The presentation of FA on the surface of the nano-assembly was controlled by changing its shape using DNA as molecular keys. This in turn changes the position of FA from hidden to exposed state, thereby making it available for interaction with tumor cells over-expressing FA receptors resulting in enhanced (2.5 folds) targeted delivery of the nanoformulation to the tumor site. Most of these targeting approaches are used for the delivery of anti-cancer agents along with nanoparticles. However, utilization of these targeting strategies for IONPs would enable increased accumulation of the IONPs as well as the drug at the tumor site, thus resulting in effective heating during magnetic hyperthermia-based cancer therapy.
Several studies for preclinical applications of MHT are reported in literature. Zhao et al. (2012) reported the application of magnetic nanoparticles (MNPs) for the treatment of head and neck cancers using a mouse xenograft model. Results showed that the temperature of the tumor center was dramatically elevated from body temperature to 40°C in 5–10 min. This hyperthermia treatment resulted in necrosis in the treated tumor tissue. Similarly, Hu et al. used MHT for the treatment of murine lung carcinoma models. Results showed inhibition of the tumor growth via induction of apoptosis. Shetake et al. recently demonstrated the efficacy of oleic acid coated IONPs for MHT of murine fibrosarcoma tumor models. Results showed significant inhibition of tumors after MHT by induction of apoptosis via modulation of heat shock protein 90 (HSP 90)/AKT pathway. It may be pertinent to emphasize that in these animal studies, MNPs were injected intratumorally, a mode of injection not suitable for deep-seated and metastatic tumors. Moreover, intratumoral injections may cause tumor incongruence, invasiveness, and recurrence, especially from under-treated tumor regions. Therefore, for targeting and systemic administration of MNPs, intravenous injection is the preferred route. However, so far, it has been difficult to achieve the effective concentrations in tumors when MNPs were administered through intravenous route. Huang and Hainfeld demonstrated intravenous administration of polyethylene glycol-coated IONPs, with a well-tolerated dose, achieving a tumor concentration of 1.9 mg Fe/g of tumor tissue in a subcutaneous squamous cell carcinoma mouse model, with a tumor-to-nontumor ratio of >16. With an applied field of 38 kA/m at 980 kHz, tumors could be heated to 60°C for 2 min ablating them with millimeter range.
Route of administration of MNPs may vary depending on the type of cancer. For example, in case of lung cancer, inhalation would be the preferred route of administration. Sadhukha et al. demonstrated the administration of inhalable epidermal growth factor receptor-targeted MNPs in a murine orthotopic model of nonsmall cell lung carcinoma, which showed significant enhancement in targeting and retention of MNPs in the lung tumors. Moreover, in combination with AMF, it showed a significant growth inhibition of these tumors. This study also demonstrated that pulmonary delivery of targeted IONPs can circumvent their nonspecific distribution into organs such as liver and spleen, which commonly receive the highest concentration when NPs were administered intravenously. Thus, (i) targeting by tumor cell-specific molecules (e.g., antibodies, receptors or ligands, etc.,), (ii) an appropriate choice of route of administration of MNPs, based on cancer type, and (iii) combination with other modalities such as CT  or RT may result in accomplishment of a better tumor control.
| Cancer Stem Cells and Magnetic Hyperthermia Therapy|| |
Cancer relapse and its metastatic spread is a major challenge for the clinicians. Cancer stem cells (CSCs) were found to contribute to these features of cancer in addition to the mechanism of chemo- and radio-resistance. Many molecular and cellular approaches have been developed to target and kill the CSCs. Strategies for the application of MHT to target and kill the cancer cells are quite nascent but could prove highly effective, if the challenging task of targeting the CSCs in the tumor mass with MNPs could be achieved. Recently, Burke et al. compared the effectiveness of breast CSCs killing by conventional and nanoparticle-mediated photothermal therapy. Their findings suggest that breast CSCs are resistant to conventional hyperthermia partly due to the higher basal expression of HSP 90. In contrast, when these breast CSCs were treated with multiwalled carbon nanotubes, they became sensitive to hyperthermia delivered using a low power 1064 nm near infrared laser. It has been inferred that the cell death after laser-based HT was proportional to the time of laser exposure. Further,in vivo evaluation of efficacy of nanoparticle-mediated hyperthermia showed 100% survival of the mice compared to 20% survival in control. Atkinson et al. showed that in combination therapy, i.e., radiation therapy followed by optically activated gold nanoshells-based MHT resulted in radiosensitization of breast CSCs. Forty-eight hours after treatment, cells derived from the tumors treated with ionizing radiation and hyperthermia showed a significant decrease in tumorigenicity as well as increased differentiated phenotype than individual treatments. In another study, Galanzha et al. selectively targeted the circulating breast CSCs by tagging MNPs to folate or anti-human CD44 antibodies. Cancer cells targeted with these conjugated antibodies showed higher photothermal-based ablation when treated with NIR light., Sadhukha et al. demonstrated the efficacy of IONPs-mediated MHT in human lung and breast CSCs. Results showed that MHT caused a significant decrease in the CSCs of lung (A549) and breast (MDA-MB-231) carcinoma cells. Moreover, MHT was found to be significantly effective to suppress the colony and mammosphere formation of these tumor cells inin vitro conditions, respectively. Thus, these studies suggest that nanoparticles-based MHT may be an effective modality to kill CSCs and suppression of tumor growth and recurrences, which however, need to be further validated in other tumor models and under the clinical scenario.
| Status of the Clinical Applications of Magnetic Hyperthermia Therapy|| |
The first step toward the application of MHT in clinics was the development of magnetic field therapy system for treatment of human patients. Gneveckow et al. developed the first clinical 100-kHz, ferrite core-based magnetic field applicator, magnetic fluid hyperthermia (MFH ®) 300F (MagForce Nanotechnologies AG, Berlin, Germany) with a magnetic field strength of up to 18 kA/m in a cylindrical treatment area (20 cm diameter and aperture height 300 mm). Johannsen et al. showed for the first time, the clinical application of MHT for prostate cancer in a 67-year-old patient, using aminosilane-coated MNPs and the MagForce MFH 300F applicator (100 kHz radio-frequency and variable field strength (0–18 kAm −1). Hyperthermia using MNPs was feasible and well tolerated in this pilot study, in previously irradiated and locally recurrent prostate carcinoma. In another study, Matsubara et al. reported a novel MHT system for the treatment of patients with bone metastases. They used a calcium phosphate cement containing MNPs for MHT and combined the therapy with acridine orange for photodynamic therapy. MHT was applied postoperatively by inserting the limb into a cylindrical coil of the electromagnetic field generator. This MHT treatment was performed in six patients with seven bone cancer metastasis locations. Their study showed that this combination therapy for bone metastasis can preserve the limb function without local recurrence. Thus, this clinical evidence signifies the potential of MHT as a promising and emerging modality for combinatorial cancer therapy.
| Conclusion and Future Directions|| |
The potential of MHT as an emerging modality for cancer treatment has been well evaluated in preclinical tumor models. Few pilot studies conducted on cancer patients, further corroborate the capability of MHT to be a considerable option for anti-cancer management. The merit of MHT can be enhanced many folds when combined with appropriate doses of radiation to minimize the side effects or systemic toxicity for improved therapeutic efficacy. Moreover, a combination of IONPs along with targeted liposomal-based co-delivery of IONPS and anti-cancer drugs may lead to the development of nanoformulations that may serve as excellent candidates for theranostics applications (simultaneous diagnosis and therapy) of cancer. To develop MHT as an effective combinatorial cancer therapeutic modality, following aspects need to be explored in future:
- Optimization of design of MNPs based on knowledge gained for efficient targeting to facilitate a uniform distribution of MNPs within the tumor, as well as their efficient uptake and retention inside the tumor cells
- Targeting of CSCs for MHT and understanding the underlying mechanism
- Understanding the development of thermo-resistance and radio-resistance, if any, after MNPs-based HT when combined with RT
- In addition, optimization of the treatment plans (combining MHT and RT or CT) needs to be carried out in order to acquire maximum therapeutic gain, with minimum side effects to the patients.
Financial support and sponsorship
Conflicts off interest
There are no conflicts of interest.
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