Recent Developments in the Use of Magnetic Fluid Hyperthermia on Glioblastoma Multiforme Disease

Phases and neck from 48-58% to 72–83% in primary cervical has reported. Magnetic Fluid Hyperthermia (MFH) is a quite recent kind of HT treatment based on the use of Magnetic Nanoparticles (MNPs) as agents able to release heat when activated by an alternating Electromagnetic (EM) field of appropriate frequency and amplitude. At this aim, generally stable colloidal suspensions of MNPs in liquid media [12] are commonly used. In principle, MFH offers advantages in comparison to the more traditional HT treatments. In fact, the huge number of MNPs present in the suspensions assures an excellent heat release power allowing MNPs to reach the tumor tissues directly by local injections or simply through the blood circulation surgery. ABSTRACT The first evidence of the efficacy in the cancer treatment of hyperthermia, therapy focused on the heating of tumor masses to kill cells and tissues, went back almost a century and a half. One of the most promising techniques for increasing the cells and tissues temperature is based on the use of magnetic nanoparticles dispersed in concentrated colloidal suspensions and stimulated by an external alternating electromagnetic field, known as Magnetic Fluid Hyperthermia. Recently this technique has been used as coadjutant treatment of the most applied chemo and radio therapies in a series of different tumors, but in particular for Glioblastoma Multiforme till to clinical trials level. In this work, we report some of most significant progresses regarding the use of Magnetic Fluid Hyperthermia on Glioblastoma Multiforme disease published in literature during the last year, describing the more interesting outcomes for potential future clinical applications.


Mini Review
Hyperthermia (HT) is a therapeutic technique based on the heating of tumor cells and tissues up to temperatures between 40 and 45 °C [1] in order to kill them. At those temperatures a number of serious cellular events like protein denaturation [2], damages to the cytoskeleton [3], impairment of certain DNA repair processes [4], changes in cell membrane permeability and stimulation of the immune system [5] occur. It is well-know that temperatures above 4 °C can cause coagulation and vessels may collapse resulting in necrosis or apoptosis [1,6]. These effects are quite different from cell to cell and appear more pronounced in tumor cells and tissues mainly owing to their acidic microenvironment. Generally, cellular cytotoxicity induced by HT results strongly increased when cells suffer additional damages caused by chemo (CT) and Radiotherapy (RT). The synergy between HT and the more traditional cancer treatments has been extensively reported in literature [1,7].
Phases II and III clinical trials proved significant outcomes when HT was combined with RT [8][9][10][11]. As an example, a complete response increased from 38.1% with RT alone to 60.2% with HT and RT in locally recurrent breast cancer [9], from 39.6% to 62.5% in head and neck cancers [10], and from 48-58% to 72-83% in primary cervical cancer [11] has been reported. Magnetic Fluid Hyperthermia (MFH) is a quite recent kind of HT treatment based on the use of Magnetic Nanoparticles (MNPs) as agents able to release heat when activated by an alternating Electromagnetic (EM) field of appropriate frequency and amplitude. At this aim, generally stable colloidal suspensions of MNPs in liquid media [12] are commonly used. In principle, MFH offers advantages in comparison to the more traditional HT treatments. In fact, the huge number of MNPs present in the suspensions assures an excellent heat release power allowing MNPs to reach the tumor tissues directly by local injections or simply through the blood circulation [13] without surgery.

ARTICLE INFO ABSTRACT
The first evidence of the efficacy in the cancer treatment of hyperthermia, therapy focused on the heating of tumor masses to kill cells and tissues, went back almost a century and a half. One of the most promising techniques for increasing the cells and tissues temperature is based on the use of magnetic nanoparticles dispersed in concentrated colloidal suspensions and stimulated by an external alternating electromagnetic field, known as Magnetic Fluid Hyperthermia. Recently this technique has been used as coadjutant treatment of the most applied chemo and radio therapies in a series of different tumors, but in particular for Glioblastoma Multiforme till to clinical trials level. In this work, we report some of most significant progresses regarding the use of Magnetic Fluid Hyperthermia on Glioblastoma Multiforme disease published in literature during the last year, describing the more interesting outcomes for potential future clinical applications.
In recent years, many MNPs differing for magnetic properties and structure have been studied and characterized for MFH applications [14]. In particular, iron oxide MNPs, of magnetite (Fe3O 4 ) and/or maghemite (γ-Fe 2 O 3 ), resulted very promising systems because of their biocompatibility, their heat release capability, their excellent magnetic properties and also the easily to be synthesized with sizes and shapes very well-controlled [15].
Here, we report on the more recent developments concerning the application of MFH therapy to the treatment of the Glioblastoma Multiforme (GM) disease, one of the most severe and dangerous cerebral tumor forms. In the past years, MFH has just been applied in clinical trials on GM suffering patients. Jordan and co-workers [16][17][18]  In these studies, significant benefits on GM suffering patients were reported only when MFH was applied in combination with RT according to a well-defined protocol. In phase I and II clinical trials, Maier-Hauff and co-worker [19] studied the efficacy and tolerability of the MFH and RT combined treatment on patients suffering of recurrent GM disease using the same protocol proposed by Jordan and co-worker. In these studies, a median overall survival of 13.4 months in 59 patients was obtained, substantially longer than the typical six months median survival noted in such patients [20].
Moreover, the therapy was well tolerated without serious sideeffects and post-mortem analyses noted that MNPs were mainly confined to areas of tumor necrosis [21].

Basics and Limitations of MFH
The MNPs capability to release heat, after their activation by an external alternating EM field, is exploited in MFH therapy to reach hyperthermic temperatures in tumor cells and tissues. The MNPs energy absorption processes and thus their heating essentially depend on their electric permittivity ε and magnetic permeability µ that result to be strongly dependent on the applied frequency f and the field amplitude H. As a consequence, the external EM field parameters must be carefully chosen in order to optimize the MNPs heating performances and, at the same time, to preserve healthy tissues and patient comfort during the MFH treatment. Biological It is worth noting that, as above described, MNPs energy absorption is strongly related to the external EM field parameters.
As a consequence, SAR values reported in literature often are hardly comparable to each other since they are calculated by experimental data obtained using different EM fields and frequencies.

Very Recent MFH Applications on GM Disease
In 2020, some interesting studies concerning the application of MFH therapy to the treatment of GM disease, at preclinical level but potentially promising for future clinical applications, have been reported in literature. The more significant outcomes described in these works have been briefly reported in the following. Benyettou

Conflict of Interest
The authors declare no conflict of interest.