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Review

Magnetic Hyperthermia Therapy for High-Grade Glioma: A State-of-the-Art Review

by
Benjamin Rodriguez
1,2,*,
Daniel Rivera
1,
Jack Y. Zhang
1,
Cole Brown
1,
Tirone Young
1,2,
Tyree Williams
2,3,
Sakibul Huq
4,
Milena Mattioli
5,
Alexandros Bouras
5 and
Constantinos G. Hadjpanayis
4,5,6,*
1
Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2
Sinai BioDesign, Department of Neurosurgery, Mount Sinai, New York, NY 10029, USA
3
Rensselaer Polytechnic Institute, Troy, NY 12180, USA
4
Department of Neurological Surgery, UPMC, Pittsburgh, PA 15213, USA
5
Brain Tumor Nanotechnology Laboratory, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
6
Center for Image-Guided Neurosurgery, Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2024, 17(3), 300; https://doi.org/10.3390/ph17030300
Submission received: 24 January 2024 / Revised: 20 February 2024 / Accepted: 20 February 2024 / Published: 26 February 2024
(This article belongs to the Special Issue Magnetic Nanoparticles (MNPs) in Biomedical Applications)
Browse Figures
Review Reports Versions Notes

Abstract

:
Magnetic hyperthermia therapy (MHT) is a re-emerging treatment modality for brain tumors where magnetic nanoparticles (MNPs) are locally delivered to the brain and then activated with an external alternating magnetic field (AMF) to generate localized heat at a site of interest. Due to the recent advancements in technology and theory surrounding the intervention, clinical and pre-clinical trials have demonstrated that MHT may enhance the effectiveness of chemotherapy and radiation therapy (RT) for the treatment of brain tumors. The future clinical success of MHT relies heavily on designing MNPs optimized for both heating and imaging, developing reliable methods for the local delivery of MNPs, and designing AMF systems with integrated magnetic particle imaging (MPI) for use in humans. However, despite the progression of technological development, the clinical progress of MHT has been underwhelming. This review aims to summarize the current state-of-the-art of MHT and offers insight into the current barriers and potential solutions for moving MHT forward.

1. Introduction

High-grade glioma (HGG), the most prevalent primary brain malignancy, presents a formidable challenge due to its resistance to standard treatment regimens, namely, maximal safe resection supplemented by adjuvant temozolomide (TMZ) chemotherapy and fractionated radiotherapy (RT) [1,2]. The infiltrative nature of HGG prevents complete resection, and the presence of resistant tumor cells within the surrounding healthy brain is a major driver of recurrence [3,4]. In over 80% of cases, HGG recurs locally, typically within two centimeters of the resection cavity [4]. This local recurrence underscores the potential of therapies that target the affected area directly. Given the dire statistics—a median survival of 15 months and below a 5% five-year survival rate [2,5]—more effective treatment approaches are desperately needed.
Magnetic hyperthermia therapy (MHT) is a re-emerging treatment approach for HGGs consisting of local heat generation in the tumor region through the direct delivery of magnetic nanoparticles (MNPs), which are activated by exposure to an external alternating magnetic field (AMF) [6,7,8,9,10]. The major advantages of MHT are its ability to focus heating on a small volume of a tumor without damaging surrounding tissue and its lack of ionizing radiation. Magnetic hyperthermia therapy leverages the unique cellular responses to heat, as the 42–45 °C hyperthermia it induces selectively causes tumor cell death while preserving healthy cells. This effect is facilitated by the hyperthermic environment in the tumor, which activates heat shock proteins and stimulates a strong immune cell response, enhancing the antitumor effect [11,12].
Although MHT is not yet a standard treatment for HGGs, its potential integration into existing treatment protocols is promising, especially as an adjunct therapy. This review explores key aspects of MHT imaging and treatment through the lens of a proposed treatment workflow [13]. Additionally, we address the challenges in transitioning MHT to clinical use and the ongoing efforts to resolve these issues. Our goal is to provide a comprehensive overview of the latest advancements in MHT, aiming to stimulate the further development and integration of this emerging technology into clinical practice for the safe and effective treatment of HGGs.

2. MHT Workflow

The workflow used to guide this review was proposed by Healy et al. [13]. This workflow involves both a clinician and a medical physicist working in concert to (1) obtain imaging (CT, MRI) to direct initial treatment planning (tumor margin, anatomy for NP delivery), (2) select optimal nanoparticles for treatment, (3) deliver chosen nanoparticles, (4) obtain post-procedural imaging (MPI) to ensure proper implantation, and (5) implement MHT using AMF (Figure 1). This review will focus on steps seeing the most innovation: nanoparticle selection and delivery, MPI imaging, and AMF treatment.

2.1. Nanoparticles

MHT efficacy relies heavily upon designing MNP constructs capable of generating a significant thermal dose at non-toxic concentrations. The thermal dose is dependent on the temperature achieved within the lesion of interest and the time for which that temperature is sustained [14]. Specifically, the thermal dose is calculated based on the maximum temperature achieved across 90% of the lesion (T90). Antitumor effects have been well described when the T90 is between 40 and 45 °C (mild hyperthermia) and >50 °C (thermal ablation) [15]. MHT for HGG aims to heat tissues within the lower range, between 42 and 45 °C [16].
MNPs’ heating capacity derives from their magnetic properties, which are influenced by the composition, size, density, and shape [17] an overview of MNP properties is shown in Table 1. Specifically, MNPs are superparamagnetic, meaning that the torque of the AMF acts upon the coupled electron spins of the ferromagnetic nanoparticles. This leads to MNPs having a much higher susceptibility and therefore a higher heating efficiency [18]. MNP heating efficiency is often described in specific loss power (SLP), defined as the measured thermal loss normalized to the mass or volume of magnetic material [19,20]. However, SLP can be context-dependent and therefore inconsistently measured at different frequencies [21]. Although, according to Rosenweig’s model, at low frequencies (105–106 Hz) such as those used in MHT, the out-of-phase component of susceptibility can be held constant [22], allowing for the utilization of the parameter intrinsic loss power (ILP). ILP provides a system-independent measurement parameter to measure MNP heating efficiency. To date, the most common materials used for MNP synthesis include pure metals (e.g., iron, cobalt, nickel), alloys (e.g., FeCo, alnico), and oxides (e.g., Fe3O4, g-Fe2O3, CoFe2O4). Magnetic iron oxide nanoparticles (MIONPs) are used most often in treating glioma due to their superior biocompatibility, established heating profile, and relatively low production cost [23]. With regard to MNP design for MHT specifically, substantial research has been dedicated to optimizing the heating efficiency in terms of MNP size, with the most common and effective MNPs reported to have a diameter between 10 and 20 nm [24,25,26,27]. Other groups have studied the efficacy of various shapes and arrangements of MNPs, showing that both cubic [27] and chain-like arrangements of MNPs [28] heated more effectively compared to spherical and randomly arranged MNPs, respectively. An additional finding was that an MNP suspension solution’s viscosity also impacts heating, with a higher viscosity resulting in decreased SLP [28].
Another important consideration for MNP optimization is ensuring they do not aggregate and precipitate once introduced. To achieve this, MNPs are often conjugated with various compounds and polymers, such as polyethylene glycol (PEG) and chitosan, to increase their chemical stability and solubility [29,30,31]. Numerous other surface coatings have also been applied for similar reasons [32,33,34,35,36]. Carbon-coated MNPs, in particular, have attracted significant attention due to their improved thermal stability compared to uncoated counterparts [37]. Silica is also frequently used, due to its biocompatibility and ability to limit MNP aggregation [38,39,40]. However, it has been shown that interactions between silica and the MNP surface may result in a reduction in saturation magnetization by 32%, thus decreasing heating efficiency [41]. This effect may be variable, as others have recently demonstrated that silica coating may reduce saturation magnetization by as low as 8% and may even result in an increase of as much as 14% [42]. Similarly, organic compounds such as PEG, which are used to reduce non-specific interactions between MNPs and proteins, may affect MNP geometry and therefore their magnetic properties [43,44]. These two examples highlight the complexity of MNP design and the trade-offs between biological stability and magnetic properties that must occur to synthesize stable, non-toxic, and effective MNPs.
Lastly, it is important to address the growing biomedical application of multi-core MNP systems. Thus far, our discussion has focused on single-core systems in which each nanoparticle is composed of a single magnetic core. In contrast, multi-core systems fix multiple magnetic cores together within a single matrix, allowing for additional intra- and inter-particle magnetic dipolar interactions [45]. Numerous studies have found that these multi-core systems exhibit superior heating for magnetic hyperthermia [46,47,48]. Unsurprisingly, the process for synthesizing these multi-core MNPs is complex and depends on the precise control of numerous parameters ranging from temperature and stirring conditions to reagent and surfactant concentrations [49]. As a result, batch-to-batch reproducibility and the up-scaling of production is a major challenge. A significant amount of research is devoted to refining multi-core MNP synthesis methods [49].

2.2. MPI

Beyond their ability to serve as therapeutic heating agents, MNPs can serve as diagnostic agents as well. MNPs have been used as MRI contrast agents due to their exceptionally high relaxivity [58,59]. However, at the high MNP concentrations required for MHT, MRI is not possible due to signal saturation, which results in a “black hole” susceptibility artifact on MRI that obscures all relevant anatomy [13]. This problem could be addressed by magnetic particle imaging (MPI), an emerging tomographic technique that may enable the real-time 3D imaging of MNPs at high therapeutic concentrations [60,61,62]. Briefly, MPI systems operate by generating strong magnetic field gradients that contain a specific area of low field strength, known as the field-free region (FFR). Rapidly passing the FFR over MNPs causes their magnetization to flip, creating a detectable signal. Importantly, biological tissue does not produce a significant signal in response to the low-amplitude magnetic fields used in MPI, giving the MNPs ideal contrast independent of their depth within the tissue [63]. However, this also means that MPI is unable to visualize underlying tissue anatomy, necessitating anatomic coregistration with a CT scan or MRI. The unique benefits of MPI include improved imaging signal-to-noise ratios, high spatial and temporal resolutions, the linear quantification of the number of MIONPs regardless of the tissue depth, and the ability to image MNPs at concentrations typically used for MHT (50–100 mg of Fe per g of tissue) [62].
With regard to MHT, preliminary studies have used MPI for image-guided MHT in vivo [64] and have even designed dual MPI–MHT systems [65]. One current limitation of MHT is that it is not possible to focus the high-frequency fields needed for MHT (>300 kHz) to specific regions of the body, thus posing the risk of the off-target heating of MIONPs that may have unintentionally migrated elsewhere in the body, such as the liver. However, one group demonstrated that by employing an MPI gradient field, they were able to achieve highly localized heating to a region just a few millimeters in size, preventing the heating of MNPs outside of the FFR [64,65]. The underlying physics of MPI can further be applied to enable real-time, noninvasive magnetic nanothermometry (MNT) during MHT. To understand this first requires understanding that the magnetization vector of MNPs changes when they are exposed to an AMF and upon the subsequent removal of that AMF signal. The timing of these changes in the MNP magnetization state is influenced by the temperature of the sample. Therefore, it is thought that by comparing the timing differences of changes in MNP magnetization against the time scale of the MPI device, the temperature of the sample can be estimated [13]. In 2023, one group designed a prototype of such a system, with promising preliminary data showing the ability for combined MHT–MNT–MPI in situ [66]. This is a significant advancement, as previous clinical trials studying MHT in the brain have relied on the insertion of invasive intracranial thermal probes for thermometry, effectively negating a key advantage of MHT—its non-invasiveness.
To date, MPI has shown great promise in clinical applications ranging from angiography to cancer theranostics and molecular imaging [67,68]. Recently, there has been a significant effort to develop MNPs optimized for MPI [69,70]. Superparamagnetic iron oxide nanoparticles (SPIONs) are the most effective agents for MPI, since their superparamagnetism enables high-order harmonics of excitation frequencies required for MPI [71]. The current challenge remains customizing MNPs with properties that enable both effective hyperthermia and MPI in vivo. Additionally, the upscaling of MPI systems for human use is needed, although this is being actively pursued [67,71].

2.3. Nanoparticle Delivery

The blood–brain barrier (BBB) is an important consideration for intracranial MHT, as it limits the efficacy of systemic MNP delivery [72]. Intracranial lesions must therefore be accessed directly through local delivery [69] by way of: direct intracavitary implantation following surgical resection, convection-enhanced delivery (CED) using a stereotactically placed catheter, or direct stereotactic injection (Figure 2). The underlying principle is a balance between maximizing intratumoral MNP delivery while minimizing reflux and undesired off-site toxicities [69,70]. Reflux is the retrograde flow of fluid back up the catheter or cannula’ this can lead to MNPs localizing in healthy tissue and causing damage when heated [73]. A further consideration in the delivery of MNPs is to preferentially choose minimally invasive techniques or those that can already fit within the workflow of another vital intervention.
Direct implantation is a modality that completely avoids the risk of reflux and allows for direct visualization as the resection cavity is still open and MNPs are pasted directly within [74]. Once the resection is complete, the surgeon will “paste” a viscous solution of MNPs on the wall of the resection cavity either by directly applying the solution [74] or by utilizing hydroxycellulose mesh and fibrin glue to layer the MNPs and provide enhanced stability [75]. Residual tumor cells then take up the MNPs, most often via the clathrin- and caveolae-mediated endocytosis pathways [74,76,77]. This modality has already been studied in two human trials [74,75]. This can be an invasive approach; however, if it fits into the workflow of the resection, then there is no excess trauma being done to the patient. With all of the risks and benefits considered, direct implantation is an ideal adjuvant modality for treating primary HGGs, where maximum possible resection is the primary standard-of-care treatment [78]. However, given recent data suggesting that reoperation does not necessarily provide an improved EOR [79], resection may not be the most effective intervention for patients with rHGG [78]. This eliminates the opportunity to deliver nanoparticles via direct implantation, and a different technique is needed for these patients.
Direct stereotactic injection is the most minimally invasive choice; only a small cannula is stereotactically inserted into the lesion, often without a preceding debulking procedure [80]. In the two human studies performed using this technique [50,80], the cannula was placed stereotactically multiple times within the lesion, dispensing small volumes of MNPs throughout the lesion. The authors delivered 0.4–1.4 mL of NPs over a 30–40 s interval 8–10 mm apart; the slow delivery and small volumes are tactics for minimizing fluid flow to prevent reflux along the cannula [80]. Stereotactic injection provides an option for rHGG in that it does not require a preceding resection and it is minimally invasive. However, the tactic required to minimize reflux (small volume and slow infusions) is a limiting factor in the efficacy of this technique. Direct injection is a viable option, but the ideal modality would allow for higher-volume infusions at an increased rate.
CED infusion is currently the most effective technique for the infusion of MNPs in patients lacking a preceding resection. The modality utilizes a burr hole with the stereotactic insertion of one or more catheters into the target lesion. An infusion pump then generates a pressure gradient at the catheter tip, infusing MNPs directly into the brain [81]. This form of infusion relies on bulk flow rather than diffusion to displace extracellular fluid and prevent reflux. CED mitigates the need for small-volume, slow infusions that are common with stereotactic injection [82]. CED is the most common delivery technique to date; robust literature exists describing CED in both large animal models and humans [83]. In three reported canine studies [70,84,85] and three human studies [74,86,87], MNPs were infused via a stereotactically placed catheter. However, despite CED being an improvement over direct injection, there is still a need to improve delivery techniques to allow for faster delivery and larger infusions, and further preclinical research is required to optimize nanoparticle delivery and minimize reflux.

2.4. AMF

Following safe and accurate MNP delivery, exposure to an alternating magnetic field (AMF) is required to excite the MNPs and generate hyperthermia. AMF is a magnetic field (MF) with an amplitude that varies over time [88] and generates MNP heating primarily through hysteresis loss. Briefly, in this process, AMF exposure induces cycles of magnetization and demagnetization, as the magnetic domains present within the MNP continuously switch to reorient with the fluctuating magnetic field [89]. Thermal energy production then primarily occurs during the return to equilibrium (relaxation) of individual magnetic domains, which, in order to overcome a rotational energy barrier, experience energy loss in the form of heat [22,89]. In Néel relaxation, energy loss occurs as the magnetic vectors reorient against the atomic lattice of the magnetic core [89,90]. In Brownian relaxation, energy loss occurs as entire MNPs themselves experience friction from rotating within the surrounding medium [89,90].
AMF parameters are an essential consideration in MHT, as therapeutic heating only begins upon the exposure of MNPs to the AMF. In accordance with the model of AMF-induced MNP heat generation described by Rosensweig et al., the quantity of electromagnetic energy that can be converted into heat increases with the MF amplitude and frequency [22,91]. In theory, target lesion destruction is achieved by maximizing these two parameters. In clinical practice, however, safety considerations impose an upper limit on these parameters. AMF can generate electric current loops (known as eddy currents) which can cause the thermal injury of healthy tissue and negatively impact MHT efficacy [92,93]. In prior clinical studies, MHT tolerance has been shown to be limited by headaches, which could potentially be mediated by temporary, heat-related increases in intracranial pressure [50,93,94].
To date, no long-term adverse effects of AMF or MHT treatment have been reported, and much of the existing data suggest that MHT is an overall safe intervention [9,10,14,95]. Most AMF generators approved for use in MHT produce MFs with frequencies far below the dangerous radio frequency range [10,96] and orders of magnitude below the frequencies used in routine MRI [97]. Even so, no universal guidelines detailing the upper limits of safe AMF exposure currently exist. Atkinson and Brezovich were among the first to investigate safe frequencies in MHT [98,99]. Their clinical studies on healthy patients culminated in the Atkinson–Brezovich criterion, which established a maximum MF-frequency product (H × f) of 4.85 × 108 Am−1 s [100]. On the basis that MF strength could safely be increased given a compensatory decrease in the target region size (i.e., a smaller tumor), Hergt et al., in 2007, proposed the higher threshold of 5.00 × 109 Am−1 s−1 for a target region with a diameter less than the 30 cm tested by Brezovich [98,99,101]. Up to this point, no clinical studies on MHT in HGGs have surpassed this threshold; the maximum H × f used in two such trials was 1.50 × 109 Am−1 s [9,50,75]. Pulsed heating has been shown to minimize the non-specific eddy current heating [14,102,103]. While optimizing AMF parameters is crucial for effective MHT, it is equally important to balance these parameters within safe limits to avoid adverse effects, ensuring that the therapeutic benefits of MHT are maximized without compromising patient safety.

2.5. MHT-Mediated Enhancement of Chemotherapy and Radiation

Hyperthermia therapy (HT) has been repeatedly shown to enhance the cytotoxic effects of radiation therapy (RT) on tumor cells. Although the exact mechanism driving this enhancement remains uncertain, it is thought that HT initiates intracellular heat shock responses that disrupt the repair of RT-induced DNA double-strand breaks [104,105,106]. Specifically, it has been found that HT degrades the DNA repair pathway protein BRCA2 [107,108]. Moderate HT has also been shown to enhance perfusion, potentially enhancing the effects of RT by reducing the radioresistant hypoxic cell population. In terms of chemotherapy, hyperthermia has been shown to disrupt the BBB, potentially allowing for increased levels of systemically administered chemotherapeutics to reach the tumor [109,110,111,112]. In addition to enhancing the anticancer effects of chemotherapy and RT through heat, MHT possesses other unique features that further promote tumor sensitization. MIONPs conjugated with GBM-targeting antibodies were shown to radiosensitize and induce apoptosis in the highly therapy resistant stem-like cancer cell populations thought to mediate local GBM recurrence [113]. Additionally, MNPs have been extensively studied as drug carriers that are to deliver chemotherapy directly to the tumor. One group used TMZ-loaded SPIONs to deliver chemotherapy to cancer cells and found that the combination of MHT, chemotherapy, and RT had the greatest anticancer effect compared to any monotherapy or two-modality combination therapy [114]. Many other groups have also shown that MNPs can be effective drug carriers for chemotherapy and found an added anticancer effect when giving MHT in combination with chemotherapy [110,115,116,117,118].

2.6. MHT for Glioma Clinical Impact

Over the last three decades, a number of clinical trials have investigated the use of MHT in HGG. A comprehensive list of these is outlined in Table 2. The earliest of these trials was performed in Japan in 1991 by Kobayashi and collaborators [74]. The team conducted a trial implementing MHT on 25 patients with malignant brain tumors, 13 of which were HGGs. MNPs were implanted with either intracavitary implantation or CED, depending on the tumor size. MHT was associated with a positive response rate of 34.8% in HGG patients following treatment, consistent with a complete or partial response rate according to the Japanese Society for Cancer Therapy [119]. The response rate was positive for five of the thirteen patients with HGG (38.4%).
This study was directly followed by two American trials in 1992 and 1994 performed by Stea et al. [86,87]. The 1992 study was a feasibility trial performed in which 28 patients with HGG were treated with a CED infusion of MNPs followed by MHT [87]. The median survival was 20.6 months. The 1994 study compared outcomes in a group of patients treated with MHT plus brachytherapy versus the control group of brachytherapy alone [86]. The 25 patients in the MHT plus brachytherapy group were found to have a 0.53 hazard ratio of death compared to the 37 patients in the control group.
Maier-Hauff et al. published a feasibility study in 2007 [80] followed by an efficacy trial in 2011 [50] where patients with recurrent glioblastoma (GBM) had MNPs stereotactically infused and were then treated with combined MHT and stereotactic RT. The efficacy trial reported a median progression-free survival (PFS) of 13.4 in the 59 GBM (66 total) participants as well as an overall survival (OS) of 23.2 months, both higher than the reported standard-of-care averages (PFS = 6.9 months, OS = 14.6 months, respectively) [50,120]. The brain autopsy studies showed particle aggregation at the sites of installation and the tumor necrosis area. These studies served to catapult MHT into clinical practice in Germany.
Most recently, Grauer et al. [75] implanted MNPs into six recurrent HGG (rHGG) patients through the “NanoPaste” technique, by which the resection cavity wall is coated with layers of Nanotherm® using a hydroxycellulose mesh and fibrin glue. Histopathology specimens of MNP-adjacent tumor areas showed sustained necrosis. The study saw two patients (33%) that experienced a sustained response to treatment, with an overall survival of >23 months.
Overall, the human MHT studies to date have shown consistently positive results. However, there is still much investigation to be carried out to establish MHT as a clinical norm worldwide. In addition to research, increased financial backing and collaboration among academic institutions will be critical for the further development of MHT in the treatment of HGG patients.

3. Discussion

MHT provides a potential therapeutic solution for the challenges associated with rHGGs treatment and offers many advantages over other heat-based therapies commonly used to treat brain tumors (i.e., laser interstitial thermal therapy, photothermal therapy). This is in large part due to the fact that, following implantation, MNPs can be remotely activated by an external AMF. The penetration depth of the AMF exceeds that of other activation modalities commonly used in hyperthermia therapy (e.g., light or acoustic waves), allowing for the heating of deeply seated tumors without necessitating further invasive procedures [96]. Moreover, MNPs remain intracranially around the delivery site for weeks to months, potentially allowing for multiple MHT sessions following a single delivery of MNPs [75]. Thus, unlike other thermal therapies, which may only be performed intraoperatively, multiple noninvasive sessions of MHT can be performed after post-operative recovery and the initiation of chemotherapy and RT [121,122,123].
The promising potential of MHT has translated into encouraging preliminary results. Preclinically, MHT has been shown to induce profound antitumor effects and enhance the efficacy of chemotherapy and RT when used to treat HGGs. Furthermore, MNPs have been used as multifunctional theranostic agents in applications such as cancer-targeting drug carriers and MRI contrast agents. Clinically, multiple trials between 1988 and 2019 have shown that numerous sessions of MHT are possible in the brain following a single intracranial delivery of MNPs. Overall, these studies reported that MHT was safe, conferred a survival benefit, and potentially induced an antitumor immune response [9].
Despite these promising initial results and the unique advantages of MHT, clinical progress has slowed over the past decade, particularly in the United States, where the most recent clinical trial took place in 1994 [86]. Additionally, the most well-known European producer of MNPs and AMF generators for clinical use, MagForce, filed for insolvency in 2022. This disparity between the promising preliminary data and the diminishing clinical initiative is puzzling and begs the question of why such a discrepancy exists.
The answer is likely multifactorial. Just as MHT boasts many unique advantages, it faces similarly unique challenges on its path towards clinical application. As described here, the success of MHT depends on the optimization and proper implementation of many distinct and complex components. For instance, designing biocompatible MNPs that are effective for simultaneous MHT and MPI in the brain is a complex process that comprises an entirely separate field of research. The same is true of AMF and MPI device design, as well as the development of intracranial MNP delivery techniques. MHT research spans multiple disciplines and specialties, including physics, bioengineering, cancer biology, clinical medicine, and surgery. As such, researchers with different expertise may work in isolation, leading to slowed progress. In order for any new treatment modality to be effectively translated into a clinical application, interdisciplinary collaboration and cross-talk between these specialists are essential.
This challenge of facilitating such cross-talk is not exclusive to MHT—prior work in other medical specialties has demonstrated the importance of integrating the efforts of researchers and clinicians, who frequently function independently. One example is deep brain stimulation (DBS), a technique in the rapidly evolving subfield of functional neurosurgery that integrates aspects of neurology, psychiatry, neuroscience, and electrical engineering [124,125]. DBS has an established organizational framework for multidisciplinary communication that enables independent regional groups of experts in the aforementioned disciplines to communicate regularly and stay abreast of recent updates [126,127]. Another example is stereotactic radiosurgery (SRS), in which neurosurgeons work in concert with radiation oncologists and medical physicists to plan and provide precise, targeted RT [128,129]. Existing workflows for SRS involve close multidisciplinary collaboration enhanced by the presence of established registries, databases, and conferences that facilitate information sharing [130]. Efforts to advance MHT could benefit greatly from incorporating similar strategies to foster collaboration between the physicists, neurosurgeons, and engineers. The authors suggest organizing an MHT-specific symposium to kick-start crosstalk among neurosurgeons, medical physicists, and other researchers within the field. The goal of this symposium would be to generate connections amongst groups working towards the same goal, clinical adoption.
Beyond addressing this research disconnect, MHT will need to build academic momentum to push into the clinical trial phase. The recent advancement of the chemotherapeutics field may provide valuable precedence. Two technologies discussed above—the CED delivery of MNPs and magnetic MNP targeting—are both the subject of numerous clinical trials studying their compatibility with chemotherapy [131,132,133,134,135]. The favorable clinical trajectory of these shared technologies in the realm of chemotherapeutics can guide the translation of MHT.
Additionally, MHT will need to address shortcomings in federal, philanthropic, and industry funding. Primary brain cancer is rare compared to other types of cancers [136], resulting in relatively less funding. To address this, MHT may benefit by leveraging the steady growth of nanomedicine as a research area and market. At the national level, the National Nanotechnology Initiative (NNI) is an ongoing research and development initiative established by the United States government in 2000, with an initial funding of approximately USD 464 million [137] in 2001. Since then, the nanomedicine subfield has experienced steady growth, with the global nanomedicine sector—valued at USD 53 billion in 2009 [138]—more than tripling by 2022 to USD 170 billion [139]. This major financial investment the field of nanomedicine is projected to receive can potentially address many key obstacles hindering the development of MHT covered here, including the recruitment of experts (and, potentially, the formation of interdisciplinary teams of specialists), the design and production of specialized nanoparticles and AMF generators, and the experimental confirmation of treatment safety and efficacy [140].
Although there are certain challenges facing its clinical application, the future of MHT is bright. The strong body of preliminary pre-clinical and clinical research has repeatedly demonstrated that MHT may confer additional survival benefits, enhance the current standard of care for high-grade brain tumors, and induce cancer cell death through a variety of mechanisms. Significant work is currently being done to address many of the limitations addressed in this review. Previous clinical trials have reported certain therapy-related toxicities due to the amount of delivered magnetic material, the migration of magnetic material during heating, and/or the need to insert invasive temperature probes into the patient’s brain to monitor temperature. At present, numerous groups aim to address these issues by designing MNP constructs optimized for both MPI and MHT, potentially enabling the non-invasive real-time thermometry and imaging of MNPs and more homogenous heating at lower MNP doses. Moreover, human-scale MHT-MPI systems are in development, and trials of these machines are the logical next step in the road towards clinical application. Additional basic science studies are needed to further elucidate the underlying biological mechanisms driving the MHT treatment response and help clinicians to understand how best to integrate MHT into the current standard of care for refractory brain tumors. It is clear that effectively translating MHT from the bench to the clinic is a challenging problem that requires significant progress across multiple disciplines. Although it may appear as if progress has stalled, it is more likely that addressing the shortcomings discovered from previous clinical trials is complex and requires significant research. It is important to recognize that MHT is a highly technology-dependent therapy, and the development of these technologies to the level of clinical use understandably takes time.

4. Conclusions

MHT is a promising treatment for HGGs that has not yet realized its full potential despite encouraging preclinical and clinical results. In this review, we described the essential components of the MHT workflow (nanoparticle composition, nanoparticle delivery to areas of interest, and AMF properties and generation), discussing the current state of each, areas of ongoing work, as well as opportunities for future development. We identify multiple factors hindering the clinical translation of MHT, including limited interdisciplinary collaboration and insufficient funding. We propose solutions that draw parallels to other fields in medicine that have experienced rapid evolution in recent years. Efforts to advance MHT in the preclinical and clinical realms are promising and warrant further attention and financial support from academic and industrial stakeholders in order to improve the care and outcomes of patients with HGGs.

Author Contributions

Conceptualization, B.R., J.Y.Z., D.R. and C.G.H.; methodology, C.G.H.; investigation, B.R., J.Y.Z., D.R. and C.B.; writing—original draft preparation, B.R., J.Y.Z., D.R. and C.B.; writing—review and editing, T.Y., T.W., S.H., M.M., A.B. and C.G.H.; supervision, C.G.H.; project administration, C.G.H.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created for this research.

Conflicts of Interest

C.G.H. is a consultant for Synaptive Medical, Hemerion Therapeutics, Stryker Corporation, Integra, and True Digital Surgery.

References

  1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2020. CA Cancer J. Clin. 2020, 70, 7–30. [Google Scholar] [CrossRef]
  2. Francis, S.S.; Ostrom, Q.T.; Cote, D.J.; Smith, T.R.; Claus, E.; Barnholtz-Sloan, J.S. The Epidemiology of Central Nervous System Tumors. Hematol. Oncol. Clin. N. Am. 2022, 36, 23–42. [Google Scholar] [CrossRef]
  3. Gisina, A.; Kholodenko, I.; Kim, Y.; Abakumov, M.; Lupatov, A.; Yarygin, K. Glioma Stem Cells: Novel Data Obtained by Single-Cell Sequencing. Int. J. Mol. Sci. 2022, 23, 14224. [Google Scholar] [CrossRef]
  4. Barthel, L.; Hadamitzky, M.; Dammann, P.; Schedlowski, M.; Sure, U.; Thakur, B.K.; Hetze, S. Glioma: Molecular Signature and Crossroads with Tumor Microenvironment. Cancer Metastasis Rev. 2022, 41, 53–75. [Google Scholar] [CrossRef]
  5. Schaff, L.R.; Mellinghoff, I.K. Glioblastoma and Other Primary Brain Malignancies in Adults: A Review. JAMA 2023, 329, 574–587. [Google Scholar] [CrossRef]
  6. Schupper, A.J.; Hadjipanayis, C.G. Novel Approaches to Targeting Gliomas at the Leading/Cutting Edge. J. Neurosurg. 2023, 139, 760–768. [Google Scholar] [CrossRef]
  7. Skandalakis, G.P.; Rivera, D.R.; Rizea, C.D.; Bouras, A.; Jesu Raj, J.G.; Bozec, D.; Hadjipanayis, C.G. Hyperthermia Treatment Advances for Brain Tumors. Int. J. Hyperth. 2020, 37, 3–19. [Google Scholar] [CrossRef] [PubMed]
  8. Schupper, A.J.; Chanenchuk, T.; Racanelli, A.; Price, G.; Hadjipanayis, C.G. Laser Hyperthermia: Past, Present, and Future. Neuro. Oncol. 2022, 24, S42–S51. [Google Scholar] [CrossRef] [PubMed]
  9. Rivera, D.; Schupper, A.J.; Bouras, A.; Anastasiadou, M.; Kleinberg, L.; Kraitchman, D.L.; Attaluri, A.; Ivkov, R.; Hadjipanayis, C.G. Neurosurgical Applications of Magnetic Hyperthermia Therapy. Neurosurg. Clin. N. Am. 2023, 34, 269–283. [Google Scholar] [CrossRef] [PubMed]
  10. Mahmoudi, K.; Bouras, A.; Bozec, D.; Ivkov, R.; Hadjipanayis, C. Magnetic Hyperthermia Therapy for the Treatment of Glioblastoma: A Review of the Therapy’s History, Efficacy and Application in Humans. Int. J. Hyperth. 2018, 34, 1316–1328. [Google Scholar] [CrossRef]
  11. Gupta, R.; Sharma, D. Evolution of Magnetic Hyperthermia for Glioblastoma Multiforme Therapy. ACS Chem. Neurosci. 2019, 10, 1157–1172. [Google Scholar] [CrossRef]
  12. Li, Z.; Deng, J.; Sun, J.; Ma, Y. Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors. Front. Immunol. 2020, 11, 595207. [Google Scholar] [CrossRef]
  13. Healy, S.; Bakuzis, A.F.; Goodwill, P.W.; Attaluri, A.; Bulte, J.W.M.; Ivkov, R. Clinical Magnetic Hyperthermia Requires Integrated Magnetic Particle Imaging. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2022, 14, e1779. [Google Scholar] [CrossRef]
  14. Attaluri, A.; Kandala, S.K.; Zhou, H.; Wabler, M.; DeWeese, T.L.; Ivkov, R. Magnetic Nanoparticle Hyperthermia for Treating Locally Advanced Unresectable and Borderline Resectable Pancreatic Cancers: The Role of Tumor Size and Eddy-Current Heating. Int. J. Hyperth. 2020, 37, 108–119. [Google Scholar] [CrossRef] [PubMed]
  15. Garanina, A.S.; Naumenko, V.A.; Nikitin, A.A.; Myrovali, E.; Petukhova, A.Y.; Klimyuk, S.V.; Nalench, Y.A.; Ilyasov, A.R.; Vodopyanov, S.S.; Erofeev, A.S.; et al. Temperature-Controlled Magnetic Nanoparticles Hyperthermia Inhibits Primary Tumor Growth and Metastases Dissemination. Nanomedicine 2020, 25, 102171. [Google Scholar] [CrossRef] [PubMed]
  16. Shirvalilou, S.; Khoei, S.; Esfahani, A.J.; Kamali, M.; Shirvaliloo, M.; Sheervalilou, R.; Mirzaghavami, P. Magnetic Hyperthermia as an Adjuvant Cancer Therapy in Combination with Radiotherapy versus Radiotherapy Alone for Recurrent/Progressive Glioblastoma: A Systematic Review. J. Neurooncol. 2021, 152, 419–428. [Google Scholar] [CrossRef] [PubMed]
  17. Wu, K.; Su, D.; Liu, J.; Saha, R.; Wang, J.-P. Magnetic Nanoparticles in Nanomedicine: A Review of Recent Advances. Nanotechnology 2019, 30, 502003. [Google Scholar] [CrossRef] [PubMed]
  18. Savliwala, S.; Chiu-Lam, A.; Unni, M.; Rivera-Rodriguez, A.; Fuller, E.; Sen, K.; Threadcraft, M.; Rinaldi, C. Chapter 13—Magnetic Nanoparticles. In Nanoparticles for Biomedical Applications; Chung, E.J., Leon, L., Rinaldi, C., Eds.; Elsevier: Amsterdam, The Netherlands, 2020; pp. 195–221. ISBN 9780128166628. [Google Scholar]
  19. Lanier, O.L.; Korotych, O.I.; Monsalve, A.G.; Wable, D.; Savliwala, S.; Grooms, N.W.F.; Nacea, C.; Tuitt, O.R.; Dobson, J. Evaluation of Magnetic Nanoparticles for Magnetic Fluid Hyperthermia. Int. J. Hyperth. 2019, 36, 687–701. [Google Scholar] [CrossRef]
  20. Soetaert, F.; Kandala, S.K.; Bakuzis, A.; Ivkov, R. Experimental Estimation and Analysis of Variance of the Measured Loss Power of Magnetic Nanoparticles. Sci. Rep. 2017, 7, 6661. [Google Scholar] [CrossRef]
  21. Kallumadil, M.; Tada, M.; Nakagawa, T.; Abe, M.; Pankhurst, Q.A. Suitability of Commercial Colloids for Magnetic Hyperthermia. J. Magn. Magn. Mater. 2009, 321, 1509–1513. [Google Scholar] [CrossRef]
  22. Rosensweig, R.E. Heating Magnetic Fluid with Alternating Magnetic Field. J. Magn. Magn. Mater. 2002, 252, 370–374. [Google Scholar] [CrossRef]
  23. Dutta, P.; Pal, S.; Seehra, M.S.; Shah, N.; Huffman, G.P. Size Dependence of Magnetic Parameters and Surface Disorder in Magnetite Nanoparticles. J. Appl. Phys. 2009, 105, 07B501. [Google Scholar] [CrossRef]
  24. Hergt, R.; Dutz, S.; Müller, R.; Zeisberger, M. Magnetic Particle Hyperthermia: Nanoparticle Magnetism and Materials Development for Cancer Therapy. J. Phys. Condens. Matter 2006, 18, S2919. [Google Scholar] [CrossRef]
  25. Verde, E.L.; Landi, G.T.; Gomes, J.A.; Sousa, M.H.; Bakuzis, A.F. Magnetic Hyperthermia Investigation of Cobalt Ferrite Nanoparticles: Comparison between Experiment, Linear Response Theory, and Dynamic Hysteresis Simulations. J. Appl. Phys. 2012, 111, 123902. [Google Scholar] [CrossRef]
  26. Mehdaoui, B.; Meffre, A.; Carrey, J.; Lachaize, S.; Lacroix, L.-M.; Gougeon, M.; Chaudret, B.; Respaud, M. Optimal Size of Nanoparticles for Magnetic Hyperthermia: A Combined Theoretical and Experimental Study. Adv. Funct. Mater. 2011, 21, 4573–4581. [Google Scholar] [CrossRef]
  27. Martinez-Boubeta, C.; Simeonidis, K.; Makridis, A.; Angelakeris, M.; Iglesias, O.; Guardia, P.; Cabot, A.; Yedra, L.; Estradé, S.; Peiró, F.; et al. Learning from Nature to Improve the Heat Generation of Iron-Oxide Nanoparticles for Magnetic Hyperthermia Applications. Sci. Rep. 2013, 3, 1652. [Google Scholar] [CrossRef] [PubMed]
  28. Serantes, D.; Simeonidis, K.; Angelakeris, M.; Chubykalo-Fesenko, O.; Marciello, M.; Morales, M.d.P.; Baldomir, D.; Martinez-Boubeta, C. Multiplying Magnetic Hyperthermia Response by Nanoparticle Assembling. J. Phys. Chem. C 2014, 118, 5927–5934. [Google Scholar] [CrossRef]
  29. Li, X.; Wei, J.; Aifantis, K.E.; Fan, Y.; Feng, Q.; Cui, F.-Z.; Watari, F. Current Investigations into Magnetic Nanoparticles for Biomedical Applications. J. Biomed. Mater. Res. A 2016, 104, 1285–1296. [Google Scholar] [CrossRef]
  30. Zavisova, V.; Koneracka, M.; Gabelova, A.; Svitkova, B.; Ursinyova, M.; Kubovcikova, M.; Antal, I.; Khmara, I.; Jurikova, A.; Molcan, M.; et al. Effect of Magnetic Nanoparticles Coating on Cell Proliferation and Uptake. J. Magn. Magn. Mater. 2019, 472, 66–73. [Google Scholar] [CrossRef]
  31. Gupta, A.K.; Gupta, M. Cytotoxicity Suppression and Cellular Uptake Enhancement of Surface Modified Magnetic Nanoparticles. Biomaterials 2005, 26, 1565–1573. [Google Scholar] [CrossRef] [PubMed]
  32. Biehl, P.; Von der Lühe, M.; Dutz, S.; Schacher, F.H. Synthesis, Characterization, and Applications of Magnetic Nanoparticles Featuring Polyzwitterionic Coatings. Polymers 2018, 10, 91. [Google Scholar] [CrossRef]
  33. Strable, E.; Bulte, J.W.M.; Moskowitz, B.; Vivekanandan, K.; Allen, M.; Douglas, T. Synthesis and Characterization of Soluble Iron Oxide−Dendrimer Composites. Chem. Mater. 2001, 13, 2201–2209. [Google Scholar] [CrossRef]
  34. Quaglia, F.; Ostacolo, L.; Nese, G.; Canciello, M.; De Rosa, G.; Ungaro, F.; Palumbo, R.; La Rotonda, M.I.; Maglio, G. Micelles Based on Amphiphilic PCL-PEO Triblock and Star-Shaped Diblock Copolymers: Potential in Drug Delivery Applications. J. Biomed. Mater. Res. A 2008, 87, 563–574. [Google Scholar] [CrossRef]
  35. Lacava, L.M.; Lacava, Z.G.; Da Silva, M.F.; Silva, O.; Chaves, S.B.; Azevedo, R.B.; Pelegrini, F.; Gansau, C.; Buske, N.; Sabolovic, D.; et al. Magnetic Resonance of a Dextran-Coated Magnetic Fluid Intravenously Administered in Mice. Biophys. J. 2001, 80, 2483–2486. [Google Scholar] [CrossRef]
  36. Gupta, A.K.; Curtis, A.S.G. Lactoferrin and Ceruloplasmin Derivatized Superparamagnetic Iron Oxide Nanoparticles for Targeting Cell Surface Receptors. Biomaterials 2004, 25, 3029–3040. [Google Scholar] [CrossRef]
  37. Albert, E.L.; Che Abdullah, C.A.; Shiroshaki, Y. Synthesis and Characterization of Graphene Oxide Functionalized with Magnetic Nanoparticle via Simple Emulsion Method. Results Phys. 2018, 11, 944–950. [Google Scholar] [CrossRef]
  38. Venkatesha, N.; Poojar, P.; Ashwini, R.; Qurishi, Y.; Geethanath, S.; Srivastava, C. Ultrafine Graphene Oxide–CoFe2O4 Nanoparticle Composite as T1 and T2 Contrast Agent for Magnetic Resonance Imaging. RSC Adv. 2016, 6, 17423–17429. [Google Scholar] [CrossRef]
  39. Crespo, P.; de la Presa, P.; Marín, P.; Multigner, M.; Alonso, J.M.; Rivero, G.; Yndurain, F.; González-Calbet, J.M.; Hernando, A. Magnetism in Nanoparticles: Tuning Properties with Coatings. J. Phys. Condens. Matter 2013, 25, 484006. [Google Scholar] [CrossRef] [PubMed]
  40. Chen, S.; Wang, L.; Duce, S.L.; Brown, S.; Lee, S.; Melzer, A.; Cuschieri, A.; André, P. Engineered Biocompatible Nanoparticles for in Vivo Imaging Applications. J. Am. Chem. Soc. 2010, 132, 15022–15029. [Google Scholar] [CrossRef] [PubMed]
  41. Villanueva, A.; de la Presa, P.; Alonso, J.M.; Rueda, T.; Martínez, A.; Crespo, P.; Morales, M.P.; Gonzalez-Fernandez, M.A.; Valdés, J.; Rivero, G. Hyperthermia HeLa Cell Treatment with Silica-Coated Manganese Oxide Nanoparticles. J. Phys. Chem. C 2010, 114, 1976–1981. [Google Scholar] [CrossRef]
  42. Fernandes, T.; Nogueira, H.I.S.; Amorim, C.O.; Amaral, J.S.; Daniel-da-Silva, A.L.; Trindade, T. Chemical Strategies for Dendritic Magneto-Plasmonic Nanostructures Applied to Surface-Enhanced Raman Spectroscopy. Chemistry 2022, 28, e202202382. [Google Scholar] [CrossRef] [PubMed]
  43. Torchilin, V.P.; Trubetskoy, V.S. Which Polymers Can Make Nanoparticulate Drug Carriers Long-Circulating? Adv. Drug Deliv. Rev. 1995, 16, 141–155. [Google Scholar] [CrossRef]
  44. Xie, J.; Xu, C.; Kohler, N.; Hou, Y.; Sun, S. Controlled PEGylation of Monodisperse Fe3O4 Nanoparticles for Reduced Non-specific Uptake by Macrophage Cells. Adv. Mater. 2007, 19, 3163–3166. [Google Scholar] [CrossRef]
  45. Bender, P.; Bogart, L.K.; Posth, O.; Szczerba, W.; Rogers, S.E.; Castro, A.; Nilsson, L.; Zeng, L.J.; Sugunan, A.; Sommertune, J.; et al. Structural and Magnetic Properties of Multi-Core Nanoparticles Analysed Using a Generalised Numerical Inversion Method. Sci. Rep. 2017, 7, 45990. [Google Scholar] [CrossRef]
  46. Sakellari, D.; Brintakis, K.; Kostopoulou, A.; Myrovali, E.; Simeonidis, K.; Lappas, A.; Angelakeris, M. Ferrimagnetic Nanocrystal Assemblies as Versatile Magnetic Particle Hyperthermia Mediators. Mater. Sci. Eng. C Mater. Biol. Appl. 2016, 58, 187–193. [Google Scholar] [CrossRef] [PubMed]
  47. Coral, D.F.; Zélis, P.M.; Marciello, M.; Morales, M.d.P.; Craievich, A.; Sánchez, F.H.; van Raap, M.B.F. Effect of Nanoclustering and Dipolar Interactions in Heat Generation for Magnetic Hyperthermia. Langmuir 2016, 32, 1201–1213. [Google Scholar] [CrossRef] [PubMed]
  48. Blanco-Andujar, C.; Ortega, D.; Southern, P.; Pankhurst, Q.A.; Thanh, N.T.K. High Performance Multi-Core Iron Oxide Nanoparticles for Magnetic Hyperthermia: Microwave Synthesis, and the Role of Core-to-Core Interactions. Nanoscale 2015, 7, 1768–1775. [Google Scholar] [CrossRef] [PubMed]
  49. Gutiérrez, L.; Costo, R.; Grüttner, C.; Westphal, F.; Gehrke, N.; Heinke, D.; Fornara, A.; Pankhurst, Q.A.; Johansson, C.; Veintemillas-Verdaguer, S.; et al. Synthesis Methods to Prepare Single- and Multi-Core Iron Oxide Nanoparticles for Biomedical Applications. Dalton Trans. 2015, 44, 2943–2952. [Google Scholar] [CrossRef]
  50. Maier-Hauff, K.; Ulrich, F.; Nestler, D.; Niehoff, H.; Wust, P.; Thiesen, B.; Orawa, H.; Budach, V.; Jordan, A. Efficacy and Safety of Intratumoral Thermotherapy Using Magnetic Iron-Oxide Nanoparticles Combined with External Beam Radiotherapy on Patients with Recurrent Glioblastoma Multiforme. J. Neurooncol. 2011, 103, 317–324. [Google Scholar] [CrossRef]
  51. Paez-Muñoz, J.M.; Gámez, F.; Fernández-Afonso, Y.; Gallardo, R.; Pernia Leal, M.; Gutiérrez, L.; de la Fuente, J.M.; Caro, C.; García-Martín, M.L. Optimization of Iron Oxide Nanoparticles for MRI-Guided Magnetic Hyperthermia Tumor Therapy: Reassessing the Role of Shape in Their Magnetocaloric Effect. J. Mater. Chem. B Mater. Biol. Med. 2023, 11, 11110–11120. [Google Scholar] [CrossRef]
  52. Fink, C.; Gevaert, J.J.; Barrett, J.W.; Dikeakos, J.D.; Foster, P.J.; Dekaban, G.A. In Vivo Tracking of Adenoviral-Transduced Iron Oxide-Labeled Bone Marrow-Derived Dendritic Cells Using Magnetic Particle Imaging. Eur. Radiol. Exp. 2023, 7, 42. [Google Scholar] [CrossRef]
  53. Israel, L.L.; Galstyan, A.; Holler, E.; Ljubimova, J.Y. Magnetic Iron Oxide Nanoparticles for Imaging, Targeting and Treatment of Primary and Metastatic Tumors of the Brain. J. Control. Release 2020, 320, 45–62. [Google Scholar] [CrossRef]
  54. Cheng, J.; Zhu, Y.; Xing, X.; Xiao, J.; Chen, H.; Zhang, H.; Wang, D.; Zhang, Y.; Zhang, G.; Wu, Z.; et al. Manganese-Deposited Iron Oxide Promotes Tumor-Responsive Ferroptosis That Synergizes the Apoptosis of Cisplatin. Theranostics 2021, 11, 5418–5429. [Google Scholar] [CrossRef]
  55. Hanini, A.; Lartigue, L.; Gavard, J.; Kacem, K.; Wilhelm, C.; Gazeau, F.; Chau, F.; Ammar, S. Zinc Substituted Ferrite Nanoparticles with Zn0.9Fe2.1O4 Formula Used as Heating Agents for in Vitro Hyperthermia Assay on Glioma Cells. J. Magn. Magn. Mater. 2016, 416, 315–320. [Google Scholar] [CrossRef]
  56. Wang, C.; Zhao, N.; Huang, Y.; He, R.; Xu, S.; Yuan, W. Coordination of Injectable Self-Healing Hydrogel with Mn-Zn Ferrite@mesoporous Silica Nanospheres for Tumor MR Imaging and Efficient Synergistic Magnetothermal-Chemo-Chemodynamic Therapy. Chem. Eng. J. 2020, 401, 126100. [Google Scholar] [CrossRef]
  57. Razumov, I.A.; Zav’yalov, E.L.; Troitskii, S.Y.; Romashchenko, A.V.; Petrovskii, D.V.; Kuper, K.E.; Moshkin, M.P. Selective Cytotoxicity of Manganese Nanoparticles against Human Glioblastoma Cells. Bull. Exp. Biol. Med. 2017, 163, 561–565. [Google Scholar] [CrossRef]
  58. Wang, Y.-X.J. Superparamagnetic Iron Oxide Based MRI Contrast Agents: Current Status of Clinical Application. Quant. Imaging Med. Surg. 2011, 1, 35–40. [Google Scholar]
  59. Mohapatra, J.; Mitra, A.; Tyagi, H.; Bahadur, D.; Aslam, M. Iron Oxide Nanorods as High-Performance Magnetic Resonance Imaging Contrast Agents. Nanoscale 2015, 7, 9174–9184. [Google Scholar] [CrossRef]
  60. Gleich, B.; Weizenecker, J. Tomographic Imaging Using the Nonlinear Response of Magnetic Particles. Nature 2005, 435, 1214–1217. [Google Scholar] [CrossRef] [PubMed]
  61. Gleich, B.; Weizenecker, J.; Borgert, J. Experimental Results on Fast 2D-Encoded Magnetic Particle Imaging. Phys. Med. Biol. 2008, 53, N81. [Google Scholar] [CrossRef]
  62. Billings, C.; Langley, M.; Warrington, G.; Mashali, F.; Johnson, J.A. Magnetic Particle Imaging: Current and Future Applications, Magnetic Nanoparticle Synthesis Methods and Safety Measures. Int. J. Mol. Sci. 2021, 22, 7651. [Google Scholar] [CrossRef]
  63. Wu, L.C.; Zhang, Y.; Steinberg, G.; Qu, H.; Huang, S.; Cheng, M.; Bliss, T.; Du, F.; Rao, J.; Song, G.; et al. A Review of Magnetic Particle Imaging and Perspectives on Neuroimaging. AJNR Am. J. Neuroradiol. 2019, 40, 206–212. [Google Scholar] [CrossRef]
  64. Tay, Z.W.; Chandrasekharan, P.; Chiu-Lam, A.; Hensley, D.W.; Dhavalikar, R.; Zhou, X.Y.; Yu, E.Y.; Goodwill, P.W.; Zheng, B.; Rinaldi, C.; et al. Magnetic Particle Imaging-Guided Heating in Vivo Using Gradient Fields for Arbitrary Localization of Magnetic Hyperthermia Therapy. ACS Nano 2018, 12, 3699–3713. [Google Scholar] [CrossRef]
  65. Hensley, D.; Tay, Z.W.; Dhavalikar, R.; Zheng, B.; Goodwill, P.; Rinaldi, C.; Conolly, S. Combining Magnetic Particle Imaging and Magnetic Fluid Hyperthermia in a Theranostic Platform. Phys. Med. Biol. 2017, 62, 3483–3500. [Google Scholar] [CrossRef] [PubMed]
  66. Buchholz, O.; Sajjamark, K.; Franke, J.; Wei, H.; Behrends, A.; Münkel, C.; Grüttner, C.; Levan, P.; von Elverfeldt, D.; Graeser, M.; et al. In Situ Theranostic Platform Combining Highly Localized Magnetic Fluid Hyperthermia, Magnetic Particle Imaging, and Thermometry in 3D. Theranostics 2024, 14, 324–340. [Google Scholar] [CrossRef] [PubMed]
  67. Goodwill, P.W.; Saritas, E.U.; Croft, L.R.; Kim, T.N.; Krishnan, K.M.; Schaffer, D.V.; Conolly, S.M. X-Space MPI: Magnetic Nanoparticles for Safe Medical Imaging. Adv. Mater. 2012, 24, 3870–3877. [Google Scholar] [CrossRef] [PubMed]
  68. Daneman, R.; Prat, A. The Blood-Brain Barrier. Cold Spring Harb. Perspect. Biol. 2015, 7, a020412. [Google Scholar] [CrossRef] [PubMed]
  69. Cha, G.D.; Jung, S.; Choi, S.H.; Kim, D.-H. Local Drug Delivery Strategies for Glioblastoma Treatment. Brain Tumor Res. Treat. 2022, 10, 151–157. [Google Scholar] [CrossRef] [PubMed]
  70. Freeman, A.C.; Platt, S.R.; Holmes, S.; Kent, M.; Robinson, K.; Howerth, E.; Eagleson, J.; Bouras, A.; Kaluzova, M.; Hadjipanayis, C.G. Convection-Enhanced Delivery of Cetuximab Conjugated Iron-Oxide Nanoparticles for Treatment of Spontaneous Canine Intracranial Gliomas. J. Neurooncol. 2018, 137, 653–663. [Google Scholar] [CrossRef]
  71. Pablico-Lansigan, M.H.; Situ, S.F.; Samia, A.C.S. Magnetic Particle Imaging: Advancements and Perspectives for Real-Time in Vivo Monitoring and Image-Guided Therapy. Nanoscale 2013, 5, 4040–4055. [Google Scholar] [CrossRef] [PubMed]
  72. Pardridge, W.M. A Historical Review of Brain Drug Delivery. Pharmaceutics 2022, 14, 1283. [Google Scholar] [CrossRef]
  73. Gill, T.; Barua, N.U.; Woolley, M.; Bienemann, A.S.; Johnson, D.E.; O’Sullivan, S.; Murray, G.; Fennelly, C.; Lewis, O.; Irving, C.; et al. In Vitro and in Vivo Testing of a Novel Recessed-Step Catheter for Reflux-Free Convection-Enhanced Drug Delivery to the Brain. J. Neurosci. Methods 2013, 219, 1–9. [Google Scholar] [CrossRef]
  74. Kobayashi, T.; Kida, Y.; Tanaka, T.; Hattori, K.; Matsui, M.; Amemiya, Y. Interstitial Hyperthermia of Malignant Brain Tumors by Implant Heating System: Clinical Experience. J. Neurooncol. 1991, 10, 153–163. [Google Scholar] [CrossRef]
  75. Grauer, O.; Jaber, M.; Hess, K.; Weckesser, M.; Schwindt, W.; Maring, S.; Wölfer, J.; Stummer, W. Combined Intracavitary Thermotherapy with Iron Oxide Nanoparticles and Radiotherapy as Local Treatment Modality in Recurrent Glioblastoma Patients. J. Neurooncol. 2019, 141, 83–94. [Google Scholar] [CrossRef] [PubMed]
  76. Oh, N.; Park, J.-H. Endocytosis and Exocytosis of Nanoparticles in Mammalian Cells. Int. J. Nanomed. 2014, 9 (Suppl. 1), 51–63. [Google Scholar]
  77. Hemery, G.; Genevois, C.; Couillaud, F.; Lacomme, S.; Gontier, E.; Ibarboure, E.; Lecommandoux, S.; Garanger, E.; Sandre, O. Monocore vs. Multicore Magnetic Iron Oxide Nanoparticles: Uptake by Glioblastoma Cells and Efficiency for Magnetic Hyperthermia. Mol. Syst. Des. Eng. 2017, 2, 629–639. [Google Scholar] [CrossRef]
  78. Fernandes, C.; Costa, A.; Osório, L.; Lago, R.C.; Linhares, P.; Carvalho, B.; Caeiro, C. Current Standards of Care in Glioblastoma Therapy; Codon Publications: Singapore, 2017. [Google Scholar]
  79. Zhao, Y.-H.; Wang, Z.-F.; Pan, Z.-Y.; Péus, D.; Delgado-Fernandez, J.; Pallud, J.; Li, Z.-Q. A Meta-Analysis of Survival Outcomes Following Reoperation in Recurrent Glioblastoma: Time to Consider the Timing of Reoperation. Front. Neurol. 2019, 10, 286. [Google Scholar] [CrossRef]
  80. Maier-Hauff, K.; Rothe, R.; Scholz, R.; Gneveckow, U.; Wust, P.; Thiesen, B.; Feussner, A.; von Deimling, A.; Waldoefner, N.; Felix, R.; et al. Intracranial Thermotherapy Using Magnetic Nanoparticles Combined with External Beam Radiotherapy: Results of a Feasibility Study on Patients with Glioblastoma Multiforme. J. Neurooncol. 2007, 81, 53–60. [Google Scholar] [CrossRef] [PubMed]
  81. Mehta, A.M.; Sonabend, A.M.; Bruce, J.N. Convection-Enhanced Delivery. Neurotherapeutics 2017, 14, 358–371. [Google Scholar] [CrossRef]
  82. Lonser, R.R.; Sarntinoranont, M.; Morrison, P.F.; Oldfield, E.H. Convection-Enhanced Delivery to the Central Nervous System. J. Neurosurg. 2015, 122, 697–706. [Google Scholar] [CrossRef] [PubMed]
  83. Kang, J.H.; Desjardins, A. Convection-Enhanced Delivery for High-Grade Glioma. Neurooncol. Pract. 2022, 9, 24–34. [Google Scholar] [CrossRef]
  84. Sharma, A.; Jangam, A.; Shen, J.L.Y.; Ahmad, A.; Arepally, N.; Rodriguez, B.; Borrello, J.; Bouras, A.; Kleinberg, L.; Ding, K.; et al. Validation of a Temperature-Feedback Controlled Automated Magnetic Hyperthermia Therapy Device. Cancers 2023, 15, 327. [Google Scholar] [CrossRef]
  85. Young, J.S.; Bernal, G.; Polster, S.P.; Nunez, L.; Larsen, G.F.; Mansour, N.; Podell, M.; Yamini, B. Convection-Enhanced Delivery of Polymeric Nanoparticles Encapsulating Chemotherapy in Canines with Spontaneous Supratentorial Tumors. World Neurosurg. 2018, 117, e698–e704. [Google Scholar] [CrossRef]
  86. Stea, B.; Rossman, K.; Kittelson, J.; Shetter, A.; Hamilton, A.; Cassady, J.R. Interstitial Irradiation versus Interstitial Thermoradiotherapy for Supratentorial Malignant Gliomas: A Comparative Survival Analysis. Int. J. Radiat. Oncol. Biol. Phys. 1994, 30, 591–600. [Google Scholar] [CrossRef]
  87. Stea, B.; Kittelson, J.; Cassady, J.R.; Hamilton, A.; Guthkelch, N.; Lulu, B.; Obbens, E.; Rossman, K.; Shapiro, W.; Shetter, A. Treatment of Malignant Gliomas with Interstitial Irradiation and Hyperthermia. Int. J. Radiat. Oncol. Biol. Phys. 1992, 24, 657–667. [Google Scholar] [CrossRef]
  88. Belova, N.A.; Acosta-Avalos, D. The Effect of Extremely Low Frequency Alternating Magnetic Field on the Behavior of Animals in the Presence of the Geomagnetic Field. J. Biophys. 2015, 2015, 423838. [Google Scholar] [CrossRef]
  89. Liu, X.; Zhang, Y.; Wang, Y.; Zhu, W.; Li, G.; Ma, X.; Zhang, Y.; Chen, S.; Tiwari, S.; Shi, K.; et al. Comprehensive Understanding of Magnetic Hyperthermia for Improving Antitumor Therapeutic Efficacy. Theranostics 2020, 10, 3793–3815. [Google Scholar] [CrossRef]
  90. Kötitz, R.; Weitschies, W.; Trahms, L.; Semmler, W. Investigation of Brownian and Néel Relaxation in Magnetic Fluids. J. Magn. Magn. Mater. 1999, 201, 102–104. [Google Scholar] [CrossRef]
  91. Kozissnik, B.; Bohorquez, A.C.; Dobson, J.; Rinaldi, C. Magnetic Fluid Hyperthermia: Advances, Challenges, and Opportunity. Int. J. Hyperth. 2013, 29, 706–714. [Google Scholar] [CrossRef]
  92. Dennis, C.L.; Ivkov, R. Physics of Heat Generation Using Magnetic Nanoparticles for Hyperthermia. Int. J. Hyperth. 2013, 29, 715–729. [Google Scholar] [CrossRef]
  93. Stigliano, R.V.; Shubitidze, F.; Petryk, J.D.; Shoshiashvili, L.; Petryk, A.A.; Hoopes, P.J. Mitigation of Eddy Current Heating during Magnetic Nanoparticle Hyperthermia Therapy. Int. J. Hyperth. 2016, 32, 735–748. [Google Scholar] [CrossRef]
  94. Wust, P.; Gneveckow, U.; Johannsen, M.; Böhmer, D.; Henkel, T.; Kahmann, F.; Sehouli, J.; Felix, R.; Ricke, J.; Jordan, A. Magnetic Nanoparticles for Interstitial Thermotherapy--Feasibility, Tolerance and Achieved Temperatures. Int. J. Hyperth. 2006, 22, 673–685. [Google Scholar] [CrossRef] [PubMed]
  95. Foo, C.Y.; Munir, N.; Kumaria, A.; Akhtar, Q.; Bullock, C.J.; Narayanan, A.; Fu, R.Z. Medical Device Advances in the Treatment of Glioblastoma. Cancers 2022, 14, 5341. [Google Scholar] [CrossRef] [PubMed]
  96. Périgo, E.A.; Hemery, G.; Sandre, O.; Ortega, D.; Garaio, E.; Plazaola, F.; Teran, F.J. Fundamentals and Advances in Magnetic Hyperthermia. Appl. Phys. Rev. 2015. [Google Scholar] [CrossRef]
  97. Hilschenz, I.; Körber, R.; Scheer, H.-J.; Fedele, T.; Albrecht, H.-H.; Mario Cassará, A.; Hartwig, S.; Trahms, L.; Haase, J.; Burghoff, M. Magnetic Resonance Imaging at Frequencies below 1 KHz. Magn. Reson. Imaging 2013, 31, 171–177. [Google Scholar] [CrossRef] [PubMed]
  98. Brezovich, I.A.; Meredith, R.F. Practical Aspects of Ferromagnetic Thermoseed Hyperthermia. Radiol. Clin. N. Am. 1989, 27, 589–602. [Google Scholar] [CrossRef] [PubMed]
  99. Atkinson, W.J.; Brezovich, I.A.; Chakraborty, D.P. Usable Frequencies in Hyperthermia with Thermal Seeds. IEEE Trans. Biomed. Eng. 1984, 31, 70–75. [Google Scholar] [CrossRef]
  100. Herrero de la Parte, B.; Rodrigo, I.; Gutiérrez-Basoa, J.; Iturrizaga Correcher, S.; Mar Medina, C.; Echevarría-Uraga, J.J.; Garcia, J.A.; Plazaola, F.; García-Alonso, I. Proposal of New Safety Limits for In Vivo Experiments of Magnetic Hyperthermia Antitumor Therapy. Cancers 2022, 14, 84. [Google Scholar] [CrossRef]
  101. Hergt, R.; Dutz, S. Magnetic Particle Hyperthermia—Biophysical Limitations of a Visionary Tumour Therapy. J. Magn. Magn. Mater. 2007, 311, 187–192. [Google Scholar] [CrossRef]
  102. Ivkov, R.; DeNardo, S.J.; Daum, W.; Foreman, A.R.; Goldstein, R.C.; Nemkov, V.S.; DeNardo, G.L. Application of High Amplitude Alternating Magnetic Fields for Heat Induction of Nanoparticles Localized in Cancer. Clin. Cancer Res. 2005, 11, 7093s–7103s. [Google Scholar] [CrossRef]
  103. Tansi, F.L.; Maduabuchi, W.O.; Hirsch, M.; Southern, P.; Hattersley, S.; Quaas, R.; Teichgräber, U.; Pankhurst, Q.A.; Hilger, I. Deep-Tissue Localization of Magnetic Field Hyperthermia Using Pulse Sequencing. Int. J. Hyperth. 2021, 38, 743–754. [Google Scholar] [CrossRef]
  104. Corry, P.M.; Robinson, S.; Getz, S. Hyperthermic Effects on DNA Repair Mechanisms. Radiology 1977, 123, 475–482. [Google Scholar] [CrossRef]
  105. Ihara, M.; Takeshita, S.; Okaichi, K.; Okumura, Y.; Ohnishi, T. Heat Exposure Enhances Radiosensitivity by Depressing DNA-PK Kinase Activity during Double Strand Break Repair. Int. J. Hyperth. 2014, 30, 102–109. [Google Scholar] [CrossRef]
  106. Khurana, N.; Laskar, S.; Bhattacharyya, M.K.; Bhattacharyya, S. Hsp90 Induces Increased Genomic Instability toward DNA-Damaging Agents by Tuning down RAD53 Transcription. Mol. Biol. Cell 2016, 27, 2463–2478. [Google Scholar] [CrossRef]
  107. van den Tempel, N.; Zelensky, A.N.; Odijk, H.; Laffeber, C.; Schmidt, C.K.; Brandsma, I.; Demmers, J.; Krawczyk, P.M.; Kanaar, R. On the Mechanism of Hyperthermia-Induced BRCA2 Protein Degradation. Cancers 2019, 11, 97. [Google Scholar] [CrossRef]
  108. Krawczyk, P.M.; Eppink, B.; Essers, J.; Stap, J.; Rodermond, H.; Odijk, H.; Zelensky, A.; van Bree, C.; Stalpers, L.J.; Buist, M.R.; et al. Mild Hyperthermia Inhibits Homologous Recombination, Induces BRCA2 Degradation, and Sensitizes Cancer Cells to Poly (ADP-Ribose) Polymerase-1 Inhibition. Proc. Natl. Acad. Sci. USA 2011, 108, 9851–9856. [Google Scholar] [CrossRef]
  109. Ko, S.H.; Ueno, T.; Yoshimoto, Y.; Yoo, J.S.; Abdel-Wahab, O.I.; Abdel-Wahab, Z.; Chu, E.; Pruitt, S.K.; Friedman, H.S.; Dewhirst, M.W.; et al. Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity. Clin. Cancer Res. 2006, 12, 289–297. [Google Scholar] [CrossRef]
  110. Marino, A.; Camponovo, A.; Degl’Innocenti, A.; Bartolucci, M.; Tapeinos, C.; Martinelli, C.; De Pasquale, D.; Santoro, F.; Mollo, V.; Arai, S.; et al. Multifunctional Temozolomide-Loaded Lipid Superparamagnetic Nanovectors: Dual Targeting and Disintegration of Glioblastoma Spheroids by Synergic Chemotherapy and Hyperthermia Treatment. Nanoscale 2019, 11, 21227–21248. [Google Scholar] [CrossRef]
  111. Tabatabaei, S.N.; Girouard, H.; Carret, A.-S.; Martel, S. Remote Control of the Permeability of the Blood-Brain Barrier by Magnetic Heating of Nanoparticles: A Proof of Concept for Brain Drug Delivery. J. Control. Release 2015, 206, 49–57. [Google Scholar] [CrossRef]
  112. Salehi, A.; Paturu, M.R.; Patel, B.; Cain, M.D.; Mahlokozera, T.; Yang, A.B.; Lin, T.-H.; Leuthardt, E.C.; Yano, H.; Song, S.-K.; et al. Therapeutic Enhancement of Blood-Brain and Blood-Tumor Barriers Permeability by Laser Interstitial Thermal Therapy. Neurooncol. Adv. 2020, 2, vdaa071. [Google Scholar] [CrossRef]
  113. Bouras, A.; Kaluzova, M.; Hadjipanayis, C.G. Radiosensitivity Enhancement of Radioresistant Glioblastoma by Epidermal Growth Factor Receptor Antibody-Conjugated Iron-Oxide Nanoparticles. J. Neurooncol. 2015, 124, 13–22. [Google Scholar] [CrossRef]
  114. Minaei, S.E.; Khoei, S.; Khoee, S.; Mahdavi, S.R. Sensitization of Glioblastoma Cancer Cells to Radiotherapy and Magnetic Hyperthermia by Targeted Temozolomide-Loaded Magnetite Tri-Block Copolymer Nanoparticles as a Nanotheranostic Agent. Life Sci. 2022, 306, 120729. [Google Scholar] [CrossRef] [PubMed]
  115. Liu, F.; Wu, H.; Peng, B.; Zhang, S.; Ma, J.; Deng, G.; Zou, P.; Liu, J.; Chen, A.T.; Li, D.; et al. Vessel-Targeting Nanoclovers Enable Noninvasive Delivery of Magnetic Hyperthermia-Chemotherapy Combination for Brain Cancer Treatment. Nano Lett. 2021, 21, 8111–8118. [Google Scholar] [CrossRef] [PubMed]
  116. Zamora-Mora, V.; Fernández-Gutiérrez, M.; González-Gómez, Á.; Sanz, B.; Román, J.S.; Goya, G.F.; Hernández, R.; Mijangos, C. Chitosan Nanoparticles for Combined Drug Delivery and Magnetic Hyperthermia: From Preparation to in Vitro Studies. Carbohydr. Polym. 2017, 157, 361–370. [Google Scholar] [CrossRef] [PubMed]
  117. Zhao, L.; Yang, B.; Wang, Y.; Yao, Z.; Wang, X.; Feng, S.-S.; Tang, J. Thermochemotherapy Mediated by Novel Solar-Planet Structured Magnetic Nanocomposites for Glioma Treatment. J. Nanosci. Nanotechnol. 2012, 12, 1024–1031. [Google Scholar] [CrossRef] [PubMed]
  118. Arriaga, M.A.; Enriquez, D.M.; Salinas, A.D.; Garcia, R., Jr.; Trevino De Leo, C.; Lopez, S.A.; Martirosyan, K.S.; Chew, S.A. Application of Iron Oxide Nanoparticles to Control the Release of Minocycline for the Treatment of Glioblastoma. Future Med. Chem. 2021, 13, 1833–1843. [Google Scholar] [CrossRef]
  119. Koyama, Y.S.T. Standarlized Evaluation of Direct Effect of Chemotherapy for Solid Tumor. J. Jpn. Soc. Cancer Ther. Ed. 1989, 929. [Google Scholar]
  120. Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.B.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med. 2005, 352, 987–996. [Google Scholar] [CrossRef] [PubMed]
  121. Kaluzova, M.; Bouras, A.; Machaidze, R.; Hadjipanayis, C.G. Targeted Therapy of Glioblastoma Stem-like Cells and Tumor Non-Stem Cells Using Cetuximab-Conjugated Iron-Oxide Nanoparticles. Oncotarget 2015, 6, 8788–8806. [Google Scholar] [CrossRef]
  122. Platt, S.; Nduom, E.; Kent, M.; Freeman, C.; Machaidze, R.; Kaluzova, M.; Wang, L.; Mao, H.; Hadjipanayis, C.G. Canine Model of Convection-Enhanced Delivery of Cetuximab-Conjugated Iron-Oxide Nanoparticles Monitored with Magnetic Resonance Imaging. Clin. Neurosurg. 2012, 59, 107–113. [Google Scholar] [CrossRef]
  123. Jordan, A.; Wust, P.; Fähling, H.; John, W.; Hinz, A.; Felix, R. Inductive Heating of Ferrimagnetic Particles and Magnetic Fluids: Physical Evaluation of Their Potential for Hyperthermia. Int. J. Hyperth. 1993, 9, 51–68. [Google Scholar] [CrossRef] [PubMed]
  124. Yim, R.L.H.; Leung, K.M.M.; Poon, C.C.M.; Irwin, M.G. Peri-Operative Management of Patients with Parkinson’s Disease. Anaesthesia 2022, 77 (Suppl 1), 123–133. [Google Scholar] [CrossRef] [PubMed]
  125. Grossman, N.; Bono, D.; Dedic, N.; Kodandaramaiah, S.B.; Rudenko, A.; Suk, H.-J.; Cassara, A.M.; Neufeld, E.; Kuster, N.; Tsai, L.-H.; et al. Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields. Cell 2017, 169, 1029–1041.e16. [Google Scholar] [CrossRef]
  126. Nuttin, B.; Wu, H.; Mayberg, H.; Hariz, M.; Gabriëls, L.; Galert, T.; Merkel, R.; Kubu, C.; Vilela-Filho, O.; Matthews, K.; et al. Consensus on Guidelines for Stereotactic Neurosurgery for Psychiatric Disorders. J. Neurol. Neurosurg. Psychiatry 2014, 85, 1003–1008. [Google Scholar] [CrossRef] [PubMed]
  127. Bell, E.; Racine, E. Ethics Guidance for Neurological and Psychiatric Deep Brain Stimulation. Handb. Clin. Neurol. 2013, 116, 313–325. [Google Scholar]
  128. Kim, S.; Palta, J. The Physics of Stereotactic Radiosurgery. In Principles and Practice of Stereotactic Radiosurgery; Chin, L.S., Regine, W.F., Eds.; Springer: New York, NY, USA, 2015; pp. 35–56. ISBN 9781461483632. [Google Scholar]
  129. Verhey, L.J.; Smith, V. The Physics of Radiosurgery. Semin. Radiat. Oncol. 1995, 5, 175–191. [Google Scholar] [CrossRef]
  130. Sheehan, J.P.; Kavanagh, B.D.; Asher, A.; Harbaugh, R.E. Inception of a National Multidisciplinary Registry for Stereotactic Radiosurgery. J. Neurosurg. 2016, 124, 155–162. [Google Scholar] [CrossRef]
  131. Mueller, S. CED with Irinotecan Liposome Injection Using Real Time Imaging in Children with Diffuse Intrinsic Pontine Glioma (DIPG) (PNOC 009). Available online: https://clinicaltrials.gov/study/NCT03086616?cond=dipg&intr=CED&rank=1 (accessed on 20 December 2023).
  132. Gov, C. MTX110 by Convection-Enhanced Delivery in Treating Participants with Newly-Diagnosed Diffuse Intrinsic Pontine Glioma (PNOC015). Available online: https://clinicaltrials.gov/study/NCT03566199?cond=dipg&intr=CED&rank=2 (accessed on 20 December 2023).
  133. Therapeutics, Y.-M. 131I-Omburtamab Delivered by Convection-Enhanced Delivery in Patients with Diffuse Intrinsic Pontine Glioma. Available online: https://clinicaltrials.gov/study/NCT05063357?cond=dipg&intr=CED&rank=3 (accessed on 20 December 2023).
  134. Therapeutics, Y.-M. Convection-Enhanced Delivery of 124I-Omburtamab for Patients with Non-Progressive Diffuse Pontine Gliomas Previously Treated With External Beam Radiation Therapy. Available online: https://clinicaltrials.gov/study/NCT01502917?cond=dipg&intr=CED&rank=4 (accessed on 20 December 2023).
  135. Lemke, A.-J.; Senfft von Pilsach, M.-I.; Lübbe, A.; Bergemann, C.; Riess, H.; Felix, R. MRI after Magnetic Drug Targeting in Patients with Advanced Solid Malignant Tumors. Eur. Radiol. 2004, 14, 1949–1955. [Google Scholar] [CrossRef]
  136. de Robles, P.; Fiest, K.M.; Frolkis, A.D.; Pringsheim, T.; Atta, C.; St Germaine-Smith, C.; Day, L.; Lam, D.; Jette, N. The Worldwide Incidence and Prevalence of Primary Brain Tumors: A Systematic Review and Meta-Analysis. Neuro Oncol. 2015, 17, 776–783. [Google Scholar] [CrossRef]
  137. National Research Council (US) Committee for the Review of the National Nanotechnology Initiative. Small Wonders, Endless Frontiers: A Review of the National Nanotechnology Initiative; National Academies Press: Washington, DC, USA, 2002. [Google Scholar]
  138. Morigi, V.; Tocchio, A.; Bellavite Pellegrini, C.; Sakamoto, J.H.; Arnone, M.; Tasciotti, E. Nanotechnology in Medicine: From Inception to Market Domination. J. Drug Deliv. 2012, 2012, 389485. [Google Scholar] [CrossRef]
  139. Nanomedicine Market Size, Growth, Trends, Report 2023–2032. Available online: https://www.precedenceresearch.com/nanomedicine-market (accessed on 20 December 2023).
  140. Farjadian, F.; Ghasemi, A.; Gohari, O.; Roointan, A.; Karimi, M.; Hamblin, M.R. Nanopharmaceuticals and Nanomedicines Currently on the Market: Challenges and Opportunities. Nanomedicine 2019, 14, 93–126. [Google Scholar] [CrossRef] [PubMed]
Pharmaceuticals 17 00300 g001
Figure 1. Schematic representation of a proposed MHT clinical workflow: (1) MNP delivery to the targeted lesion, (2) MPI validation of accurate NP delivery, (3) AMF therapy.
Figure 1. Schematic representation of a proposed MHT clinical workflow: (1) MNP delivery to the targeted lesion, (2) MPI validation of accurate NP delivery, (3) AMF therapy.
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Figure 2. Schematic representation of various MNP delivery methods: (A) CED delivery, (B) Direct implantation, (C) Stereotactic injection.
Figure 2. Schematic representation of various MNP delivery methods: (A) CED delivery, (B) Direct implantation, (C) Stereotactic injection.
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Table 1. Magnetic nanoparticles implemented in MHT. Qualitative and quantitative descriptions of their shape, size, composition, and administration. MNPs studied in clinical and preclinical studies with experimental findings.
Table 1. Magnetic nanoparticles implemented in MHT. Qualitative and quantitative descriptions of their shape, size, composition, and administration. MNPs studied in clinical and preclinical studies with experimental findings.
MNP TypeMNP Shape IllustrationMNP Types Used in Glioma MHT StudiesCharacteristic
MNP Size		Study TypeComposition and AdministrationExperimental
Results
Iron OxidePharmaceuticals 17 00300 i001

Pharmaceuticals 17 00300 i002

Pharmaceuticals 17 00300 i003

Pharmaceuticals 17 00300 i004		Magnetite (Fe3O4) [50]~12 nm (MagForce, used in Maier-Hoff)Human (phase II clinical trial)Coated with aminosilane
AMF—100 kHz		Demonstrated an overall survival following a diagnosis of 23.2 months in human patients
Iron OxideMaghemite (γ-Fe2O3) [51]50 nm [52] (Synomag-D)In vitro and in vivo (mouse model)AMF—192 kHz
IV injection		Delayed tumor growth
Iron OxideHematite, Ferric Oxide (α-Fe2O3) [53]3–100 nmIn vivo (mouse model)PEGylated
IV injection		Improved survival
FerritePharmaceuticals 17 00300 i001Manganese ferrite [54]~90 nmIn vivo (mouse model)IV injectionTreatment effect and low systemic toxicity
FerriteZinc ferrite [55] ~11 nmIn vitro (U-87MG)AMF—700 kHzSustained heating at 41.5 °C to trigger tumor cell death
FerriteMn-Zn ferrite [56]55 nm In vitro and in vivo (mouse model)Rhodamin B isothiocyanate (RBITC)-labeled/mesoporous silica-coated
AMF—160 kHz		Inhibited tumor growth
Other Manganese oxide (MnO) [57]120–160 nmIn vitro (U-87MG and U-251 GBM cell lines) and in vivoIV injectionDemonstrated highly selective cytotoxicity in U-87MG cell lines
Table 2. Comprehensive summary of human MHT studies for glioma, presented with the treatment population, nanoparticle delivery modality, and study outcomes.
Table 2. Comprehensive summary of human MHT studies for glioma, presented with the treatment population, nanoparticle delivery modality, and study outcomes.
Study AuthorsTitleN
(#)		MNP Delivery ModalityMNPs UsedStudy Outcomes
Kobayashi et al., 1991 [74]Interstitial hyperthermia of malignant brain tumors by implant heating system: clinical experience25Direct Implantation + CEDFe-Pt AlloySuccessful treatment completion in 23 of 25 patients with a 34.8% overall response rate to treatment
Stea et al., 1992 [87]Treatment of malignant gliomas with interstitial irradiation and hyperthermia28CEDNi-S AlloyDemonstrated feasibility of the interstitial MHT of brain tumors with ferromagnetic implants, with a median patient survival of 20.6 months from diagnosis
Stea et al., 1994 [86]Interstitial irradiation versus interstitial thermoradiotherapy for supratentorial malignant gliomas: a comparative survival analysis62CEDNi-S AlloyThe hazard of dying when treated with hyperthermia plus brachytherapy was 0.53 times that of the control group treated with brachytherapy alone
Maier-Hauff et al., 2007 [80]Intracranial Thermotherapy using Magnetic Nanoparticles Combined with External Beam Radiotherapy: Results of a Feasibility Study on Patients with Glioblastoma Multiforme14Stereotactic InjectionAminosilane-coated
Fe3O4		Treatment with a median maximum intratumoral temperature of 44.6 degrees C was tolerated in all 14 patients
Maier-Hauff et al., 2011 [50]Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme66Stereotactic InjectionAminosilane coated
Fe3O4		An overall survival after a primary tumor diagnosis of 23.4 months and an overall survival following a diagnosis of first tumor recurrence of 13.4 months
Grauer et al., 2019 [75]Combined intracavitary thermotherapy with iron oxide nanoparticles and radiotherapy as local treatment modality in recurrent glioblastoma patients6Direct ImplantationAminosilane-coated
Fe3O4		Demonstrated inflammatory reaction surrounding the resection cavity following intracavitary MHT in combination with radiation therapy, potentially triggering a potent antitumor immune response
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Rodriguez, B.; Rivera, D.; Zhang, J.Y.; Brown, C.; Young, T.; Williams, T.; Huq, S.; Mattioli, M.; Bouras, A.; Hadjpanayis, C.G. Magnetic Hyperthermia Therapy for High-Grade Glioma: A State-of-the-Art Review. Pharmaceuticals 2024, 17, 300. https://doi.org/10.3390/ph17030300

AMA Style

Rodriguez B, Rivera D, Zhang JY, Brown C, Young T, Williams T, Huq S, Mattioli M, Bouras A, Hadjpanayis CG. Magnetic Hyperthermia Therapy for High-Grade Glioma: A State-of-the-Art Review. Pharmaceuticals. 2024; 17(3):300. https://doi.org/10.3390/ph17030300

Chicago/Turabian Style

Rodriguez, Benjamin, Daniel Rivera, Jack Y. Zhang, Cole Brown, Tirone Young, Tyree Williams, Sakibul Huq, Milena Mattioli, Alexandros Bouras, and Constantinos G. Hadjpanayis. 2024. "Magnetic Hyperthermia Therapy for High-Grade Glioma: A State-of-the-Art Review" Pharmaceuticals 17, no. 3: 300. https://doi.org/10.3390/ph17030300

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