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Evolution of Magnetic Hyperthermia for Glioblastoma Multiforme Therapy
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive type of glial tumors, and despite many recent advances, its prognosis remains dismal. Hence, new therapeutic approaches for successful GBM treatment are urgently required. Magnetic hyperthermia-mediated cancer therapy (MHCT), which is based on heating the tumor tissues using magnetic nanoparticles on exposure to an alternating magnetic field (AMF), has shown promising results in the preclinical studies conducted so far. The aim of this review is to evaluate the progression of MHCT for GBM treatment and to determine its effectiveness on the treatment either alone or in combination with other adjuvant therapies. The preclinical studies presented MHCT as an effective treatment module for the reduction of tumor cell growth and increase in survival of the tumor models used. Over the years, much research has been done to prove MHCT alone as the missing notch for successful GBM therapy. However, very few combinatorial studies have been reported. Some of the clinical studies carried out so far depicted that MHCT could be applied safely possessing minimal side effects. Finally, we believe that in the future, the advancements in the magnetic nanosystems might contribute toward establishing MHCT as a potential treatment tool for glioma therapy.
... 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]. ...
... 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. ...
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.
... Besides the more obvious impact in tissue disruption or ablation, enhanced infiltration of natural killer (NK) cells, T cells, dendritic cells, and macrophages into necrotic areas has been observed in preclinical glioma models [141]. Hyperthermia was also seen to induce an immune response chaperoned by heat shock protein (HSP)-peptide complexes released by dying glioma cells [142] These proteins are overexpressed in gliomas and are possible targets of inhibitors for hyperthermia sensitization; moreover, their release by dying cells stimulates T cell responses [141][142][143]. As in PTT, particle characteristics such as core size, composition, shape, and surface shell can be tailored to the application, and, as such, there have been systems designed for synergistic strategies with radio-, chemo-, and immunotherapy [138,140,141,144]. ...
... Besides the more obvious impact in tissue disruption or ablation, enhanced infiltration of natural killer (NK) cells, T cells, dendritic cells, and macrophages into necrotic areas has been observed in preclinical glioma models [141]. Hyperthermia was also seen to induce an immune response chaperoned by heat shock protein (HSP)-peptide complexes released by dying glioma cells [142] These proteins are overexpressed in gliomas and are possible targets of inhibitors for hyperthermia sensitization; moreover, their release by dying cells stimulates T cell responses [141][142][143]. As in PTT, particle characteristics such as core size, composition, shape, and surface shell can be tailored to the application, and, as such, there have been systems designed for synergistic strategies with radio-, chemo-, and immunotherapy [138,140,141,144]. ...
Glioblastoma multiforme (GBM) remains a challenging disease, as it is the most common and deadly brain tumour in adults and has no curative solution and an overall short survival time. This incurability and short survival time means that, despite its rarity (average incidence of 3.2 per 100,000 persons), there has been an increased effort to try to treat this disease. Standard of care in newly diagnosed glioblastoma is maximal tumour resection followed by initial concomitant radiotherapy and temozolomide (TMZ) and then further chemotherapy with TMZ. Imaging techniques are key not only to diagnose the extent of the affected tissue but also for surgery planning and even for intraoperative use. Eligible patients may combine TMZ with tumour treating fields (TTF) therapy, which delivers low-intensity and intermediate-frequency electric fields to arrest tumour growth. Nonetheless, the blood–brain barrier (BBB) and systemic side effects are obstacles to successful chemotherapy in GBM; thus, more targeted, custom therapies such as immunotherapy and nanotechnological drug delivery systems have been undergoing research with varying degrees of success. This review proposes an overview of the pathophysiology, possible treatments, and the most (not all) representative examples of the latest advancements.
... This complex showed enhanced penetration ability and glioblastoma cell specificity as an siRNA carrier. During the last decades, nanoparticles with various compositions have been developed, such as polymeric nanoparticles (PPs), gold NPs, gadolinium NPs, selenium NPs, or protein-based NPs (Gupta and Sharma, 2019). ...
... Magnetothermal therapy-mediated cancer therapy (MHCT) consists in exposing magnetic nanomaterials to an alternating magnetic field to heat tumor tissue and alter cellular mechanisms. A temperature rise from 37°C to 42°C-45°C can induce tumor cell death by activating specific intracellular and extracellular degradation mechanisms (Krawczyk et al., 2011;Zhang and Calderwood, 2011;Gupta and Sharma, 2019). At 42°C, tumor cells undergo irreversible damage leading to apoptosis, while achieving the same effect in normal cells requires at least 55°C. ...
Diagnosing and treating glioblastoma patients is currently hindered by several obstacles, such as tumor heterogeneity, the blood-brain barrier, tumor complexity, drug efflux pumps, and tumor immune escape mechanisms. Combining multiple methods can increase benefits against these challenges. For example, nanomaterials can improve the curative effect of glioblastoma treatments, and the synergistic combination of different drugs can markedly reduce their side effects. In this review, we discuss the progression and main issues regarding glioblastoma diagnosis and treatment, the classification of nanomaterials, and the delivery mechanisms of nanomedicines. We also examine tumor targeting and promising nano-diagnosis or treatment principles based on nanomedicine. We also summarize the progress made on the advanced application of combined nanomaterial-based diagnosis and treatment tools and discuss their clinical prospects. This review aims to provide a better understanding of nano-drug combinations, nano-diagnosis, and treatment options for glioblastoma, as well as insights for developing new tools.
... In particular, novel phototherapeutic approaches [60], such as photodermal (therapeutic agents transform near infrared radiation into heat for ablation of hyperthermia-sensitive cancerous cells) and photodynamic (photosensitive agents generate oxidative species upon incidence of light leading to local cytotoxicity) as well as sonodynamic [61] therapeutic strategies for neuro-oncological applications, can benefit greatly from next-generation nanomaterials and nanocarriers. Advances in nanobiotechnology have also accelerated another novel line of therapeutic intervention, namely, the magnetic field-responsive or the magnetic hyperthermia therapy, which relies on the properties of magnetically functionalized NPs to convert magnetic energy into heat for the selective cytotoxicity of tumor cells [62][63][64][65]. While magnetic hyperthermia therapy offers greater tissue penetration, most of the current nanocarriers (such as commercially available Nanotherm® used for malignant gliomas) have to be injected intracranially for localization at the tumor site. ...
... In particular, the unique ability of MENPs for localized hyperthermia therapy harbors huge implications for brain cancer theranostics (reviewed in [62,64]). In fact, recent studies provide evidence for the huge potential of iron oxide NPs for theranostic delivery in neuro-oncology [197]. ...
Despite their low prevalence, brain tumors are among the most lethal cancers. They are extremely difficult to diagnose, monitor and treat. Conventional anti-cancer strategies such as radio- and chemotherapy have largely failed, and to date, the development of even a single effective therapeutic strategy against central nervous system (CNS) tumors has remained elusive. There are several factors responsible for this. Brain cancers are a heterogeneous group of diseases with variable origins, biochemical properties and degrees of invasiveness. High-grade gliomas are amongst the most metastatic and invasive cancers, which is another reason for therapeutic failure in their case. Moreover, crossing the blood brain and the blood brain tumor barriers has been a significant hindrance in the development of efficient CNS therapeutics. Cancer nanomedicine, which encompasses the application of nanotechnology for diagnosis, monitoring and therapy of cancers, is a rapidly evolving field of translational medicine. Nanoformulations, because of their extreme versatility and manipulative potential, are emerging candidates for tumor targeting, penetration and treatment in the brain. Moreover, suitable nanocarriers can be commissioned for theranostics, a combinatorial personalized approach for simultaneous imaging and therapy. This review first details the recent advances in novel bioengineering techniques that provide promising avenues for circumventing the hurdles of delivering the diagnostic/therapeutic agent to the CNS. The authors then describe in detail the tremendous potential of utilizing nanotechnology, particularly nano-theranostics for brain cancer imaging and therapy, and outline the different categories of recently developed next-generation smart nanoformulations that have exceptional potential for making a breakthrough in clinical neuro-oncology therapeutics.
... In mouse experiments, Albarqi et al. confirmed that nanoparticle clusters could significantly inhibit the growth of subcutaneous ovarian tumors, opening another door to cancer treatment ( Figure 3h). It is more effective in combination with chemotherapy and radiotherapy (Figure 3i,j) [37]. The GBM tumors are highlighted in yellow circles [32]. ...
... In mouse experiments, Albarqi et al. confirmed that nanoparticle clusters could significantly inhibit the growth of subcutaneous ovarian tumors, opening another door to cancer treatment (Figure 3h). It is more effective in combination with chemotherapy and radiotherapy (Figure 3i,j) [37]. ...
The most common malignant tumor of the brain is glioblastoma multiforme (GBM) in adults. Many patients die shortly after diagnosis, and only 6% of patients survive more than 5 years. Moreover, the current average survival of malignant brain tumors is only about 15 months, and the recurrence rate within 2 years is almost 100%. Brain diseases are complicated to treat. The reason for this is that drugs are challenging to deliver to the brain because there is a blood–brain barrier (BBB) protection mechanism in the brain, which only allows water, oxygen, and blood sugar to enter the brain through blood vessels. Other chemicals cannot enter the brain due to their large size or are considered harmful substances. As a result, the efficacy of drugs for treating brain diseases is only about 30%, which cannot satisfy treatment expectations. Therefore, researchers have designed many types of nanoparticles and nanocomposites to fight against the most common malignant tumors in the brain, and they have been successful in animal experiments. This review will discuss the application of various nanocomposites in diagnosing and treating GBM. The topics include (1) the efficient and long-term tracking of brain images (magnetic resonance imaging, MRI, and near-infrared light (NIR)); (2) breaking through BBB for drug delivery; and (3) natural and chemical drugs equipped with nanomaterials. These multifunctional nanoparticles can overcome current difficulties and achieve progressive GBM treatment and diagnosis results.
... The AMF application induces localized heat in the tumor tissues, raising the temperature to 42-45 C, at which cancer cells are killed specically, while healthy cells remain unaffected. 1,2 Besides this magneto-selectivity, the capability to penetrate deep inside the tumor mass forms another major advantage of the MHCT modality as compared to the other treatment regimens including chemotherapy, radiotherapy and surgery. 3 Magnetic hyperthermia-mediated cancer therapy (MHCT) was rst performed by Gilchrist et al., in 1957 (ref. ...
... Various studies have indicated the increased expression of HSPs to be involved in the establishment of the malignant phenotype, including programmed cell death inhibition, sustaining angiogenesis, and reducing chemosensitivity. 1,[81][82][83][84] HSPs are essential for the survival and progression of neoplastic cells and thus, represent potential targets for anti-cancer therapy. Understanding the mechanisms and the cellular signaling machinery involved to inhibit up-regulation of these self-defensive HSPs gene expression by cancer cells can widely enhance the long term efficacy of MHCT. ...
Magnetic hyperthermia-based cancer therapy (MHCT) has surfaced as one of the promising techniques for inaccessible solid tumors. It involves generation of localized heat in the tumor tissues on application of an alternating magnetic field in the presence of magnetic nanoparticles (MNPs). Unfortunately, lack of precise temperature and adequate MNP distribution at the tumor site under in vivo conditions has limited its application in the biomedical field. Evaluation of in vitro tumor models is an alternative for in vivo models. However, generally used in vitro two-dimensional (2D) models cannot mimic all the characteristics of a patient's tumor and hence, fail to establish or address the experimental variables and concerns. Considering that three-dimensional (3D) models have emerged as the best possible state to replicate the in vivo conditions successfully in the laboratory for most cell types, it is possible to conduct MHCT studies with higher clinical relevance for the analysis of the selection of magnetic parameters, MNP distribution, heat dissipation, action and acquired thermotolerance in cancer cells. In this review, various forms of 3D cultures have been considered and the successful implication of MHCT on them has been summarized, which includes tumor spheroids, and cultures grown in scaffolds, cell culture inserts and microfluidic devices. This review aims to summarize the contrast between 2D and 3D in vitro tumor models for pre-clinical MHCT studies. Furthermore, we have collated and discussed the usefulness, suitability, pros and cons of these tumor models. Even though numerous cell culture models have been established, further investigations on the new pre-clinical models and selection of best fit model for successful MHCT applications are still necessary to confer a better understanding for researchers.
... Among the numerous possibilities offered by MNPs in biomedicine, those that stand out include ( Figure 6) (1) the localized delivery of molecules with biological activity (drugs, cytokines, antibodies, etc.) by means of magnetic fields to minimize the secondary effects related to their systemic dissemination [181,182]; (2) magnetic hyperthermia, which offers an option for oncological treatment through the heating of MNPs exposed to an alternating magnetic field [183][184][185]; (3) the use of MNPs as contrast agents for MRI [186,187]; (4) the magnetic targeting of immune cells using external magnetic fields as a solution for the previously indicated obstacles to cell-based immunotherapies with Tregs and tolDCs. Magnetic Targeting for Cell-Based Therapies ...
The Helios protein (encoded by the IKZF2 gene) is a member of the Ikaros transcription family and it has recently been proposed as a promising biomarker for systemic lupus erythematosus (SLE) disease progression in both mouse models and patients. Helios is beginning to be studied extensively for its influence on the T regulatory (Treg) compartment, both CD4+ Tregs and KIR+/Ly49+ CD8+ Tregs, with alterations to the number and function of these cells correlated to the autoimmune phenomenon. This review analyzes the most recent research on Helios expression in relation to the main immune cell populations and its role in SLE immune homeostasis, specifically focusing on the interaction between T cells and tolerogenic dendritic cells (tolDCs). This information could be potentially useful in the design of new therapies, with a particular focus on transfer therapies using immunosuppressive cells. Finally, we will discuss the possibility of using nanotechnology for magnetic targeting to overcome some of the obstacles related to these therapeutic approaches.
... HSP72 and its family respond to cellular stressors in both normal and transformed cells [102] and can interact with other stress-responsive proteins, including HMGB1 [103]. HMGB1-HSP72 modulation via fisetin in GBM ( Figure 6) is relevant for therapeutic approaches, as HSP70 proteins contribute to drug resistance in many cancers [104][105][106][107]. ...
The tumor microenvironment (TME) has emerged as a valuable therapeutic target in glioblastoma (GBM), as it promotes tumorigenesis via an increased production of reactive oxygen species (ROS). Immune cells such as microglia accumulate near the tumor and its hypoxic core, fostering tumor proliferation and angiogenesis. In this study, we explored the therapeutic potential of natural polyphenols with antioxidant and anti-inflammatory properties. Notably, flavonoids, including fisetin and quercetin, can protect non-cancerous cells while eliminating transformed cells (2D cultures and 3D tumoroids). We tested the hypothesis that fisetin and quercetin are modulators of redox-responsive transcription factors, for which subcellular location plays a critical role. To investigate the sites of interaction between natural compounds and stress-responsive transcription factors, we combined molecular docking with experimental methods employing proximity ligation assays. Our findings reveal that fisetin decreased cytosolic acetylated high mobility group box 1 (acHMGB1) and increased transcription factor EB (TFEB) abundance in microglia but not in GBM. Moreover, our results suggest that the most powerful modulator of the Nrf2-KEAP1 complex is fisetin. This finding is in line with molecular modeling and calculated binding properties between fisetin and Nrf2-KEAP1, which indicated more sites of interactions and stronger binding affinities than quercetin.
... A magnetic field was used to initiate the diffusion of magnetic anti-GB medicines into GB cells [81,82]. Previously encountered obstacles included a lack of equipment capable of producing a sufficient and precise magnetic field and concerns about unintended effects on normal tissue [90,91]. However, direct intratumoral delivery of magnetic nanoparticles (MNPs) is now feasible for GB treatment due to the high accumulation of MNPs at the tumor site following the development of a magnetic platform driveable by an external magnetic field [92,93]. ...
Glioblastoma (GB) is the prevalent and malignant type of solid brain tumor, having 10,000 novel incidents recorded each year in the United States. Even though rigorous multi-modal treatment, the overall survival after diagnosis is reported to be less than 15 months, the surgical excision of the tumor, observed by radiotherapy and chemotherapy, is a widely utilized treatment strategy for GB. However, contemporary advances exhibit that exosomes, dendrimers, liposomes, and certain metallic nanoparticles in the form of prodrugs advance the infiltration of the drugs into the blood-brain barriers, consequently contributing to novel chances of combating the GB confrontation with chemotherapeutics. The Food and Drug Administration of the United States (FDA) has accepted numerous medications, and significant initiatives have been adopted for advanced novel chemotherapeutic agents for GB. This overview provides new insights into developing a strong platform likely to be used for exploring certain novel drugs as well as means to treat GB clinically.
... In recent years, much effort has been invested to fight GBM, especially using targeted therapies, immunotherapies, or more advanced nanotechnology-based therapies, such as magnetic hyperthermia. [33][34][35][36] GBM therapy remains focused on achieving maximal surgical resection followed by concurrent radiation therapy combined with intravenous and oral chemotherapy. Tumor heterogeneity of GBM, containing among others selfrenewing, tumorigenic CSCs, has been related to tumor initiation and therapeutic resistance. ...
Over the last few years it has been understood that the interface between living cells and the underlying materials can be a powerful tool to manipulate cell functions. In this study, we explore the hypothesis that the electrical cell/material interface can regulate the differentiation of cancer stem-like cells (CSCs). Electrospun polymer fibres, either polyamide 66 or poly(lactic acid), with embedded graphene nanoplatelets (GnPs), have been fabricated as CSC scaffolds, providing both the 3D microenvironment and a suitable electrical environment favorable for CSCs adhesion, growth and differentiation. We have investigated the impact of these scaffolds on the morphological, immunostaining and electrophysiological properties of CSCs extracted from human glioblastoma multiform (GBM) tumor cell line. Our data provide evidence in favor of the ability of GnP-incorporating scaffolds to promote CSC differentiation to the glial phenotype. Numerical simulations support the hypothesis that the electrical interface promotes the hyperpolarization of the cell membrane potential, thus triggering the CSC differentiation. We propose that the electrical cell/material interface can regulate endogenous bioelectrical cues, through the membrane potential manipulation, resulting in the differentiation of CSCs. Material-induced differentiation of stem cells and particularly of CSCs, can open new horizons in tissue engineering and new approaches to cancer treatment, especially GBM.
... 7 This alternative and complementary cancer treatment is currently applied to brain tumors. 8 However, some challenges still prevent SPIONs from expressing their full potential: a simple, reproducible, and inexpensive methodology allowing large-scale production with useful physicochemical features suitable for hyperthermia applications. 9 Nevertheless, the technological challenge lies in the surface engineering of SPIONS, concerning solving the problems of (i) injectability, colloidal stability, biocompatibility, and increase in circulation time; (ii) introduction of tissue targeting and recognition agents, improving the accumulation or internalization in tumor cells; and (iii) coatings that potentiate the loading and release of antiinflammatory and antineoplastic agents. ...
... Among the cellular effects upon treatment with MHT are decreased cell viability; cytoskeleton damage; the elevation of oxidative stress; cell cycle arrest; and cellular death by apoptosis [10]. After success in various pre-clinical models, MHT has already entered clinical trials by the direct injection of magnetic nanoparticles into solid tumors such as glioblastoma [11] and prostate carcinoma [12]. ...
With the development of nanotechnology, the emergence of new anti-tumor techniques using nanoparticles such as magnetic hyperthermia and magneto-mechanical activation have been the subject of much attention and study in recent years, as anticancer tools. Therefore, the purpose of the current in vitro study was to investigate the cumulative effect of a combination of these two techniques, using magnetic nanoparticles against breast cancer cells. After 24 h of incubation, human breast cancer (MCF-7) and non-cancerous (MCF-10A) cells with and without MNPs were treated (a) for 15 min with magnetic hyperthermia, (b) for 30 min with magneto-mechanical activation, and (c) by a successive treatment consisting of a 15-min magnetic hyperthermia cycle and 30 min of magneto-mechanical activation. The influence of treatments on cell survival and morphology was studied by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay and light microscopy. When applied, separately, magneto-mechanical and thermal (hyperthermia) treatment did not demonstrate strong reduction in cell viability. No morphological changes were observed in non-cancerous cells after treatments. On the other hand, the combination of magneto-mechanical and thermal treatment in the presence of MNPs had a synergistic effect on decreased cell viability, and apoptosis was demonstrated in the cancer cell line. Synergism is most evident in the cancer cell line, incubated for 120 h, while in the non-cancerous line after 120 h, an increase in proliferation is clearly observed. MCF-7 cells showed more rounded cell morphology, especially after 120 h of combined treatment.
... This approach could lead to important breakthroughs in the development of MHT technology from its current restricted status within clinical study to widespread clinical application. Moreover, regardless of the MHT protocol conditions, safe operation clearly requires the use of optimized biocompatible nanomagnets to deliver controlled heating outputs under low alternating magnetic field amplitudes [4,9]. Regarding heating control, different approaches have been reported in the literature, including the modulation of MNP concentrations within liquid media with varying viscosities [10], dipolar interaction via MNP clustering [11], the nonmagnetic metal doping of typical MNPs [12] and the use of core-shell magnetic nanostructures [13]. ...
This study investigated the fabrication of spherical gold shelled maghemite nanoparticles for use in magnetic hyperthermia (MHT) assays. A maghemite core (14 ± 3 nm) was used to fabricate two samples with different gold thicknesses, which presented gold (g)/maghemite (m) content ratios of 0.0376 and 0.0752. The samples were tested in MHT assays (temperature versus time) with varying frequencies (100–650 kHz) and field amplitudes (9–25 mT). The asymptotic temperatures (T∞) of the aqueous suspensions (40 mg Fe/mL) were found to be in the range of 59–77 °C (naked maghemite), 44–58 °C (g/m=0.0376) and 33–51 °C (g/m=0.0752). The MHT data revealed that T∞ could be successful controlled using the gold thickness and cover the range for cell apoptosis, thereby providing a new strategy for the safe use of MHT in practice. The highest SAR (specific absorption rate) value was achieved (75 kW/kg) using the thinner gold shell layer (334 kHz, 17 mT) and was roughly twenty times bigger than the best SAR value that has been reported for similar structures. Moreover, the time that was required to achieve T∞ could be modeled by changing the thermal conductivity of the shell layer and/or the shape/size of the structure. The MHT assays were pioneeringly modeled using a derived equation that was analytically identical to the Box–Lucas method (which was reported as phenomenological).
... MHT generally refers to the heat released by a specific inductive medium during exposure to an alternating magnetic field (AMF) with appropriate frequency and amplitude [111]. The magnetic field is highly selective to the human body, so it causes little harm to health and can effectively perform high-specific hyperthermia therapy on deep and inaccessible tumors [112,113]. In addition, hyperthermia enhances the effect of chemotherapy through surgery [114], achieving reliable tumor killing effect. ...
Surgical resection is a widely used method for the treatment of solid tumor cancers. However, the inhibition of tumor recurrence and metastasis are the main challenges of postoperative tumor therapy. Traditional intravenous or oral administration have poor chemotherapeutics bioavailability and undesirable systemic toxicity. Polymeric hydrogels with a three-dimensional network structure enable on-site delivery and controlled release of therapeutic drugs with reduced systemic toxicity and have been widely developed for postoperative adjuvant tumor therapy. Among them, because of the simple synthesis, good biocompatibility, biodegradability, injectability, and multifunctionality, iron-based hydrogels have received extensive attention. This review has summarized the general synthesis methods and construction principles of iron-based hydrogels, highlighted the latest progress of iron-based hydrogels in postoperative tumor therapy, including chemotherapy, photothermal therapy, photodynamic therapy, chemo-dynamic therapy, and magnetothermal-chemical combined therapy, etc. In addition, the challenges towards clinical application of iron-based hydrogels have also been discussed. This review is expected to show researchers broad perspectives of novel postoperative tumor therapy strategy and provide new ideas in the design and application of novel iron-based hydrogels to advance this sub field in cancer nanomedicine.
... In cancer therapy, it has now become more and more necessary to find new alternative methods to the conventional ones (chemo-and radiotherapy) such as magnetic hyperthermia [1][2][3][4][5], photothermal therapy [6][7][8][9], or theranostic [10][11][12][13], which would lead to an increase in efficacy, but especially to a reduction in toxicity and side effects on the human body such as those caused by the classic chemotherapy and/or radiation therapy, techniques currently used in the treatment of cancer. Magnetic hyperthermia or recently superparamagnetic [13][14][15] is one of the most promising alternative methods in this issue. ...
In this paper, we present a study by computer simulation on superparamagnetic hyperthermia with CoFe2O4 ferrimagnetic nanoparticles coated with biocompatible gamma-cyclodextrins (γ-CDs) to be used in alternative cancer therapy with increased efficacy and non-toxicity. The specific loss power that leads to the heating of nanoparticles in superparamagnetic hyperthermia using CoFe2O4–γ-CDs was analyzed in detail depending on the size of the nanoparticles, the thickness of the γ-CDs layer on the nanoparticle surface, the amplitude and frequency of the alternating magnetic field, and the packing fraction of nanoparticles, in order to find the proper conditions in which the specific loss power is maximal. We found that the maximum specific loss power was determined by the Brown magnetic relaxation processes, and the maximum power obtained was significantly higher than that which would be obtained by the Néel relaxation processes under the same conditions. Moreover, increasing the amplitude of the magnetic field led to a significant decrease in the optimal diameter at which the maximum specific loss power is obtained (e.g., for 500 kHz frequency the optimal diameter decreased from 13.6 nm to 9.8 nm when the field increased from 10 kA/m to 50 kA/m), constituting a major advantage in magnetic hyperthermia for its optimization, in contrast to the known results in the absence of cyclodextrins from the surface of immobilized nanoparticles of CoFe2O4, where the optimal diameter remained practically unchanged at ~6.2 nm.
... Despite the success of HT, it has not yet become one of the standard GBM therapies due to certain limitations. Among the therapeutic limitations are the unspecific drug uptake, delivery challenges, acute toxicity (convulsions, tachycardia, grade 3-4 leucopenia, motor convulsions, headaches), lack of knowledge on the sufficient dosage, issues with the distribution of heat and tumor specificity, and the lack of knowledge on the suitable route of administration (Maier-Hauff et al., 2011;Gupta and Sharma, 2019). Regardless the limitations, HT remains attractive and possesses great potential to be a promising platform for GBM treatment if the limitations could be addressed. ...
Glioblastoma multiforme (GBM) is one of the most common, most formidable, and deadliest malignant types of primary astrocytoma with a poor prognosis. At present, the standard of care includes surgical tumor resection, followed by radiation therapy concomitant with chemotherapy and temozolomide. New developments and significant advances in the treatment of GBM have been achieved in recent decades. However, despite the advances, recurrence is often inevitable, and the survival of patients remains low. Various factors contribute to the difficulty in identifying an effective therapeutic option, among which are tumor complexity, the presence of the blood-brain barrier (BBB), and the presence of GBM cancer stem cells, prompting the need for improving existing treatment approaches and investigating new treatment alternatives for ameliorating the treatment strategies of GBM. In this review, we outline some of the most recent literature on the various available treatment options such as surgery, radiotherapy, cytotoxic chemotherapy, gene therapy, immunotherapy, phototherapy, nanotherapy, and tumor treating fields in the treatment of GBM, and we list some of the potential future directions of GBM. The reviewed studies confirm that GBM is a sophisticated disease with several challenges for scientists to address. Hence, more studies and a multimodal therapeutic approach are crucial to yield an effective cure and prolong the survival of GBM patients.
... As a safe rule of thumb, the amplitude of a 100 kHz magnetic field should be below 16 kA/m to provide the required heating of the malignant tissue by raising the temperature to around 43 C. In their review on the evolution of magnetic hyperthermia for Glioblastoma Multiforme therapy, Gupta et al. figure out the range of alternating magnetic field parameters used in in vivo Glioma animal models [30]. For the functionalized iron oxide nanoparticles, the range of AMF frequency for different studies ranged from 100-200 kHz and the amplitude in most of the cases was about 384 Oe. ...
The advancements in magnetic nanoparticle mediated hyperthermia give so many optimistic and fruitful results that make it a promising and complementary approach for the existing treatment modalities of cancer. This thermotherapy is gaining wide acceptance among the medical community compared to the conventional treatment methods. The former provides a local heat generation in the malignant tumor cells and remains non-invasive to the adjacent healthy cells. The increased heating efficiency of magnetic nanoparticles and the control of local therapeutic temperature are the main challenges of hyperthermia. Superparamagnetic Iron Oxide nanoparticles have been intensively studied and dominating in magnetic hyperthermia. Recently many researchers successfully demonstrated high heating efficiency and biocompatibility of a wide variety of magnetic metal nanoparticles and proposed as the most promising alternative for traditional iron oxides, which opens up a new avenue for magnetic metal nanoparticles in magnetic hyperthermia. The review presents the recent advancements that occurred in the field of metal nanoparticle mediated magnetic hyperthermia. The theory underlying heat generation, synthesis methods, biofunctionalization, Specific Absorption Rate studies, challenges and future perspectives of magnetic metal nanoparticles are presented. This will inspire more in-depth research and advance practical applications of metal nanoparticles in magnetic hyperthermia.
... In particular, magnetic hyperthermia is a type of cancer treatment based on the heat generated by SPIONs under an alternate magnetic field, to increase the local temperature to 42-46 • C, which induces the death of tumor cells [3,8]. The therapy has been improved over the last decades especially by enhancing the capacity of the nanoparticles to produce heat [9], however, it is a challenge to target the particles at the tumor site through a non-invasive route of administration and treat it effectively [10,11]. ...
Composites of magnetite nanoparticles encapsulated with polymers attract interest for many applications, especially as theragnostic agents for magnetic hyperthermia, drug delivery, and magnetic resonance imaging. In this work, magnetite nanoparticles were synthesized by coprecipitation and encapsulated with different polymers (Eudragit S100, Pluronic F68, Maltodextrin, and surfactants) by nano spray drying technique, which can produce powders of nanoparticles from solutions or suspensions. Transmission and scanning electron microscopy images showed that the bare magnetite nanoparticles have 10.5 nm, and after encapsulation, the particles have approximately 1 μm, with size and shape depending on the material’s composition. The values of magnetic saturation by SQUID magnetometry and mass residues by thermogravimetric analysis were used to characterize the magnetic content in the materials, related to their magnetite/polymer ratios. Zero-field-cooling and field-cooling (ZFC/FC) measurements showed how blocking temperatures of the powders of the composites are lower than that of bare magnetite, possibly due to lower magnetic coupling, being an interesting system to study magnetic interactions of nanoparticles. Furthermore, studies of cytotoxic effect, hydrodynamic size, and heating capacity for hyperthermia (according to the application of an alternate magnetic field) show that these composites could be applied as a theragnostic material for a non-invasive administration such as nasal.
... 15 These phase I/II trials were conducted on patients with primarily glioblastoma or prostate carcinomas and showed a reduction in side effects in comparison to other conventional hyperthermia techniques. 108−113 The ethical guidelines on MFH treatment of glioblastoma were published in 2009, 115 and the efficiency and safety of NanoTherm on recurrent glioblastoma was reported in 2011. 111 The European Medicines Agency (EMA) and the German Federal Institute for drug and medical devices (BfArm) gave MagForce the approval to start treating glioblastoma using NanoTherm therapy in 2013. ...
... MNPs can penetrate biological tissues, since they easily cross many biological barriers and are considered relatively safe for humans [7]. Accordingly, MPH has been proposed in a clinical trial together with radiation therapy in patients with recurrent glioblastoma, reducing radiation session duration by 50% and increasing life expectancy by 100% [8,9]. ...
Objective: In magnetic particle hyperthermia, a promising least-invasive cancer treatment, malignant regions in proximity with magnetic nanoparticles undergo heat stress, while unavoidably surrounding healthy tissues may also suffer from heat either directly or indirectly by the induced eddy currents, due to the developed electric fields as well. Here, we propose a facile upgrade of a typical magnetic particle hyperthermia protocol, to selectively mitigate eddy currents' heating without compromising the beneficial role of heating in malignant regions.
Method: The key idea is to apply the external magnetic field intermittently (in an ON/OFF pulse mode), instead of the continuous field mode typically applied. The parameters of the intermittent field mode, such as time intervals (ON time: 25-100 s, OFF time: 50-200 s, Duty Cycle:16-100%) and field amplitude (30-70 mT) are optimized based on evaluation on healthy tissue and cancer tissue phantoms. The goal is to sustain in cancer tissue phantom the maximum temperature increase (preferably within 4-8°C above body temperature of 37°C), while in the healthy tissue phantom temperature variation is suppressed far below the 4°C dictating the eddy current mitigation.
Results: Optimum conditions of intermittent field (ON/OFF: 50/100 in s, Duty Cycle: 33%, magnetic field: 45mT) are then examined in ex-vivo samples verifying the successful suppression of eddy currents. Simultaneously, a well-elaborated theoretical approach provides a rapid calculation of temperature increase and, furthermore, the ability to quickly simulate a variety of duty cycle times and field controls may save experimental time.
Conclusion: Eventually, the application of an intermittent field mode in a magnetic particle hyperthermia protocol, succeeds in eddy current mitigation in surrounding tissues and allows for the application of larger field amplitudes that may augment hyperthermia efficiency without objecting typical biomedical applicability field constraints such as Brezovich criterion.
... Therefore, to explore an effective cancer therapy which could kill the cancer cells effectively without causing serious side effects is quite essential. Magnetic induction hyperthermia (MIH) has been considered as an effective "green" method for cancer therapy owing to its high safety and efficiency since it was proposed by Gilchrist firstly in 1957 [20][21][22][23][24][25][26][27][28][29][30]. The schematic mechanism of MIH is displayed in Fig. 2 [31]. ...
In the past decades, cancer has become the most serious threat for people’s health. The traditional treating methods for cancer including chemotherapy and radiation therapy would cause severe side effects, which restrict the treating effectiveness for tumors. Recently, magnetic induction hyperthermia (MIH) was proved to have great potential for cancer therapy owing to their advantages including excellent targeting ability and high safety. With the development of nanotechnology, magnetic nanoparticles such as iron oxide and their composites have been widely applied for MIH, and improved treating effectiveness was obtained. Besides, great progress was also made for the combination of MIH and other treating methods. In this review, we firstly summarized the methods for improving the heating generation efficiency of magnetic NPs, which is the key to the treating effectiveness. Then we summarized recent development for MIH and their combination therapy based on the current reports. Finally, the current challenge and prospects were proposed.
Graphical abstract
... The incorporation of magnetic nanoparticles (MNP) in living cells is a topic of increasing interest in biomedical research [1]. Examples, among others, are molecular separation [2], fieldassisted gene [3], drug [4] or cell delivery [5] and magnetic energy to heat transduction [6] for tissue engineering [7] and regeneration [8] and cancer treatment [9]. Of importance, magnetic hyperthermia sensitized chemo and radio oncologic therapies [10] and can be combined with imaging [11]. ...
Access to detailed information on cells loaded with nanoparticles with nanoscale precision is of a long-standing interest in many areas of nanomedicine. In this context, designing a single experiment able to provide statistical mean data from a large number of living unsectioned cells concerning information on the nanoparticle size and aggregation inside cell endosomes and accurate nanoparticle cell up-take is of paramount importance. Small-angle X-ray scattering (SAXS) is presented here as a tool to achieve such relevant data. Experiments were carried out in cultures of B16F0 murine melanoma and A549 human lung adenocarcinoma cell lines loaded with various iron oxide nanostructures displaying distinctive structural characteristics. Five systems of water-dispersible magnetic nanoparticles (MNP) of different size, polydispersity and morphology were analyzed, namely, nearly monodisperse MNP with 11 and 13 nm mean size coated with meso-2,3-dimercaptosuccinic acid, more polydisperse 6 nm colloids coated with citric acid and two nanoflowers (NF) systems of 24 and 27 nm in size resulting from the aggregation of 8 nm MNP. Up-take was determined for each system using B16F0 cells. Here we show that SAXS pattern provides high resolution information on nanoparticles disposition inside endosomes of the cytoplasm through the structure factor analysis, on nanoparticles size and dispersity after their incorporation by the cell and on up-take quantification from the extrapolation of the intensity in absolute scale to null scattering vector. We also report on the cell culture preparation to reach sensitivity for the observation of MNP inside cell endosomes using high brightness SAXS synchrotron source. Our results show that SAXS can become a valuable tool for analyzing MNP in cells and tissues.
... GMB represents 76% of all gliomas [3], with a high rate of patients deaths (15,000/year in the United States), and less than 10% of patients achieve a 5-year survival rate [4,5]. The main therapeutics approaches for GBM tumors include radiation therapy, chemotherapy, thermal therapy, and surgeries focusing on the best technique of tumor resection; these therapies can be used isolated or combined [6,7]. Regarding the low efficacy of the GBM therapies mentioned above, ...
This in vitro study aims to evaluate the magnetic hyperthermia (MHT) technique and the best strategy for internalization of magnetic nanoparticles coated with aminosilane (SPIONAmine) in glioblastoma tumor cells. SPIONAmine of 50 and 100 nm were used for specific absorption rate (SAR) analysis, performing the MHT with intensities of 50, 150, and 300 Gauss and frequencies varying between 305 and 557 kHz. The internalization strategy was performed using 100, 200, and 300 µgFe/mL of SPIONAmine, with or without Poly-L-Lysine (PLL) and filter, and with or without static or dynamic magnet field. The cell viability was evaluated after determination of MHT best condition of SPIONAmine internalization. The maximum SAR values of SPIONAmine (50 nm) and SPIONAmine (100 nm) identified were 184.41 W/g and 337.83 W/g, respectively, using a frequency of 557 kHz and intensity of 300 Gauss (≈23.93 kA/m). The best internalization strategy was 100 µgFe/mL of SPIONAmine (100 nm) using PLL with filter and dynamic magnet field, submitted to MHT for 40 min at 44 °C. This condition displayed 70.0% decreased in cell viability by flow cytometry and 68.1% by BLI. We can conclude that our study is promising as an antitumor treatment, based on intra- and extracellular MHT effects. The optimization of the nanoparticles internalization process associated with their magnetic characteristics potentiates the extracellular acute and late intracellular effect of MHT achieving greater efficiency in the therapeutic process.
... Hyperthermia derived from the magnetic excitation of nanoparticles has demonstrated relevant but reversible opening of the BBB in the absence of inflammation processes [91,92]. This heat-driven transient BBB disruption has allowed higher delivery of bioactive therapeutic compounds into the brain parenchyma [93]. However, to our knowledge, nanoparticles have been used as shuttles of nanobodies through the BBB, instead of facilitating their passage upon magnetic hyperthermia in a two-step (first nanoparticles, later nanobodies) administration approach [66,94]. ...
Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies.
... Furthermore, magnetic hyperthermia-mediated cancer therapy (MHCT) has shown promising results in the preclinical studies. MHCT has applied magnetic nanoparticles to heat tumor tissues, which is based on an alternating magnetic field (AMF) [367,368]. Gupta et al. have developed manganese-doped magnetic nanoclusters for hyperthermia and photothermal GBM therapy, they observed oxidative stress produced in the cellular environment and confirmed the ROS-dependent apoptosis of GBM cells via the mitochondrial pathway [369]. Mamani et al. found magnetic hyperthermia effectively decreased cell viability (about 20% and 100% after 10-and 30-minutes therapy) with a GBM 3D cells culture model [370]. ...
Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature, genetic heterogeneity, and protection by the blood brain barrier (BBB) have posed great treatment challenges. The standard treatment for GBMs is surgical resection followed by chemoradiotherapy. The robust DNA repair and self-renewing capabilities of glioblastoma cells and glioma initiating cells (GICs), respectively, promote resistance against all current treatment modalities. Thus, durable GBM management will require the invention of innovative treatment strategies. In this review, we will describe biological and molecular targets for GBM therapy, the current status of pharmacologic therapy, prominent mechanisms of resistance, and new treatment approaches. To date, medical imaging is primarily used to determine the location, size and macroscopic morphology of GBM before, during, and after therapy. In the future, molecular and cellular imaging approaches will more dynamically monitor the expression of molecular targets and/or immune responses in the tumor, thereby enabling more immediate adaptation of tumor-tailored, targeted therapies.
... Magnetically induced hyperthermia was shown by Gupta and Sharma [98] to enhance activity of chemotherapeutic agents by increasing permeability of the BBB, which increased drug concentrations within tumors. This increased synergy of magnetic hyperthermia with conventional cancer therapies is well confirmed [13]. ...
Magnetic nanoparticles (MNPs) have a wide range of applications; an area of particular interest is magnetic particle imaging (MPI). MPI is an imaging modality that utilizes superparamagnetic iron oxide particles (SPIONs) as tracer particles to produce highly sensitive and specific images in a broad range of applications, including cardiovascular, neuroimaging, tumor imaging, magnetic hyperthermia and cellular tracking. While there are hurdles to overcome, including accessibility of products, and an understanding of safety and toxicity profiles, MPI has the potential to revolutionize research and clinical biomedical imaging. This review will explore a brief history of MPI, MNP synthesis methods, current and future applications, and safety concerns associated with this newly emerging imaging modality.
... Today, superparamagnetic hyperthermia is considered as the method of the future in cancer therapy due to the very promising results obtained so far both in vitro, in vivo and in clinical trials [7,10,11,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. However, the effectiveness and efficiency of superparamagnetic hyperthermia in destroying tumor cells depends very much on the magnetic nanoparticles used for it. ...
In this paper, we present a theoretical study on the maximum specific loss power in the admissible biological limit (PsM)l for CoFe2O4 ferrimagnetic nanoparticles, as a possible candidate in alternative and non-invasive cancer therapy by superparamagnetic hyperthermia. The heating time of the nanoparticles (Δto) at the optimum temperature of approx. 43 °C for the efficient destruction of tumor cells in a short period of time, was also studied. We found the maximum specific loss power PsM (as a result of superparamegnetic relaxation in CoFe2O4 nanoparticles) for very small diameters of the nanoparticles (Do), situated in the range of 5.88–6.67 nm, and with the limit frequencies (fl) in the very wide range of values of 83–1000 kHz, respectively. Additionally, the optimal heating temperature (To) of 43 °C was obtained for a very wide range of values of the magnetic field H, of 5–60 kA/m, and the corresponding optimal heating times (Δto) were found in very short time intervals in the range of ~0.3–44 s, depending on the volume packing fraction (ε) of the nanoparticles. The obtained results, as well as the very wide range of values for the amplitude H and the frequency f of the external alternating magnetic field for which superparamagnetic hyperthermia can be obtained, which are great practical benefits in the case of hyperthermia, demonstrate that CoFe2O4 nanoparticles can be successfully used in the therapy of cancer by superaparamagnetic hyperthermia. In addition, the very small size of magnetic nanoparticles (only a few nm) will lead to two major benefits in cancer therapy via superparamagnetic hyperthermia, namely: (i) the possibility of intracellular therapy which is much more effective due to the ability to destroy tumor cells from within and (ii) the reduced cell toxicity.
... NP-based magnetically induced hyperthermia has been investigated in the treatment of glioblastoma multiforme [37], oral cancer [38], osteosarcoma [39], pancreatic cancer [40], breast cancer [41], melanoma [42], and prostate cancer [43]. In lung cancer, iron oxide MNPs were incorporated into magnetic nanocomposite microparticles through spray drying. ...
Background:
Worldwide, lung cancer is one of the leading causes of cancer death. Nevertheless, new therapeutic agents have been developed to treat lung cancer that could change this mortality-rate. Interestingly, incredible advances have occurred in recent years in the development and application of nanotechnology in the detection, diagnosis, and treatment of lung cancer.
Aim:
Nanoparticles (NPs) have the ability to incorporate multiple drugs and targeting agents and therefore lead to an improved bioavailability, sustained delivery, solubility, and intestinal absorption.
Relevance for patients:
This review briefly summarizes the latest innovations in therapeutic nanomedicine in lung cancer with examples on magnetic, lipid, and polymer NP. Emphasis will be placed on future studies and ongoing clinical trials in this field.
... Natural exosomes are very useful drug delivery carriers because drugs and ligands having different properties can be either encapsulated or attached on the surface. Because of the innate intracellular mobility, many kinds of research have progressed in the field of not only various cancers, but also neurological diseases such as Parkinson's disease [19,20]. In addition, since exosomes isolated from the respective cancer cell lines are known to have a homing effect, they have an improvised targeting ability towards cancer tissues, can deliver a therapeutic drug into cells while overcoming anticancer drug resistance, and show sufficient potential as a direct treatment [21][22][23]. ...
Recently, natural exosomes have attracted attention as an ideal drug carrier to overcome the limitations of existing drug delivery systems which are toxicity induction and low cancer-targeting performance. In this study, we propose an exosome-based hybrid nanostructure (EHN) with improved targeting ability and therapeutic efficacy against colorectal cancer by using exosomes isolated from the tumor cell line as a drug carrier. The proposed EHN can have high biocompatibility by using exosomes, a biologically derived material, and show improved targeting performance by adding a tumor-targeting ligand (folic acid). In addition, the proposed EHN is capable of chemotherapy because doxorubicin, an anticancer drug, is encapsulated by the exosome with high efficiency, and it can induce hyperthermia therapy because of the magnetic nanoparticles (MNPs) attached to the surface of exosomes. Through in vitro and in vivo experiments using a xenograft tumor mouse model, it was confirmed that the proposed EHN could exhibit increased apoptosis and excellent tumor growth inhibition ability. Therefore, the proposed EHN is expected to overcome the limitations of existing drug delivery systems and be utilized as an effective drug delivery system in cancer treatment.
... MNPs can penetrate biological tissues, since they easily cross many biological barriers and are considered relatively safe for humans [7]. Accordingly, MPH has been proposed in a clinical trial together with radiation therapy in patients with recurrent glioblastoma, reducing radiation session duration by 50% and increasing life expectancy by 100% [8,9]. ...
Aim: In this work, we study the eddy current evolution naturally occurring in magnetically driven treatments, such as MRI and magnetic particle hyperthermia (MPH), and propose the mitigation of eddy currents by careful control of field parameters. Materials & methods: We start by simulation of typical MRI and MPH experimental setups to witness eddy currents and then we examine experimentally how field parameters (frequency, amplitude and pulse duration) mitigate eddy currents in a typical MPH treatment. Results and conclusion: By tuning the frequency, the amplitude and by applying pulsed field mode, we successfully attenuate undesirable heating, due to eddy currents’ evolution, on surrounding healthy tissues without sparing beneficial effect within the malignant region, thus treatment remains reliable yet with milder side effects.
Driving immobilized, single-domain magnetic nanoparticles at high frequency by square wave fields instead of sinusoidal waveforms leads to qualitative and quantitative improvements in their performance both as point-like heat sources for magnetic hyperthermia and as sensing elements in frequency-resolved techniques such as magnetic particle imaging and magnetic particle spectroscopy. The time evolution and the frequency spectrum of the cyclic magnetization of magnetite nanoparticles with random easy axes are obtained by means of a rate-equation method able to describe time-dependent effects for the particle sizes and frequencies of interest in most applications to biomedicine. In the presence of a high-frequency square-wave field, the rate equations are shown to admit an analytical solution and the periodic magnetization can be therefore described with accuracy, allowing one to single out effects which take place on different timescales. Magnetic hysteresis effects arising from the specific features of the square-wave driving field results in a breakthrough improvement of both the magnetic power released as heat to an environment in magnetic hyperthermia treatments and the magnitude of the third harmonic of the frequency spectrum of the magnetization, which plays a central role in magnetic particle imaging.
There is considerable interest in developing anti-glioma nanoplatforms. They make the all-in-one combination of therapies possible. Here we show how the selective Glioblastoma multiforme (GBM) cell killing of the here-established nanoplatforms increased after each coating and how the here-established vibration-inducing Alternating magnetic field (AMF) decreased the treatment time from 72 h to 30 s. Thanks to their magnetite core, these nanoplatforms can be guided to the tumor's specific site by a Fixed magnetic field, they bypass the Blood–Brain Barrier (BBB) and accumulate at the tumor site thanks to the RVG29 bonding to the G-protein on the ion-gated channel receptor known as the nicotinic acetylcholine receptor (nAchR), which expresses on BBB cells and overexpresses on GBM cells, and thanks to the positive charge gained by both chitosan and RVG29's peptide. Both ZIF-8 and its mediate adherence, Chitosan increases the drug loading capacity that stimuli response to the tumor's acidic environment. The Zn ²⁺ ions generated from ZIF-8 sustained degradation in such an environment kill the GBM cells. Dynamic Light Scattering (DLS) evaluated these nanoplatform's mean size 155 nm indicating their almost optimum size for brain applications. Based on their elements' intrinsic properties, these nanoplatforms can enhance and combine other adjuvant therapies.
Magnetic hyperthermia-based cancer therapy (MHCT) holds great promise as a non-invasive approach utilizing heat generated by an alternating magnetic field for effective cancer treatment. For an efficacious therapeutic response, it...
ViSiON (visualization materials composed of silicon‐based optical nanodisks) is presented, which offers a unique optical combination of near‐infrared (NIR) optical properties and biodegradability. Initially, numerical simulations are conducted to calculate the total extinction and scattering effects of ViSiON by the diameter‐to‐thickness ratio, predicting precise control over its scattering properties in the NIR region. A top‐down patterning technique is employed to synthesize ViSiON with accurate diameter and thickness control. ViSiON with a 50 nm thickness exhibits scattering properties over 400 times higher than that of 30 nm, rendering it suitable as a contrast agent for optical coherence tomography (OCT), especially in ophthalmic applications. Furthermore, ViSiON possesses inherent biodegradability in media, with ≈95% degradation occurring after 48 h, and the degradation rate can be finely tuned based on the quantity of protein coating applied to the surface. Subsequently, the OCT imaging capability is validated even within vessels smaller than 300 µm, simulating retinal vasculature using a retinal phantom. Then, using an ex ovo chick embryo model, it is demonstrated that ViSiON enhances the strength of protein membranes by 6.17 times, thereby presenting the potential for ViSiON as an OCT imaging probe capable of diagnosing retinal diseases.
The Curie temperature is an important thermo-characteristic of magnetic materials, which causes a phase transition from ferromagnetic to paramagnetic by changing the spontaneous re-arrangement of their spins (intrinsic magnetic mechanism) due to an increase in temperature. The self-control temperature (SCT) leads to the conversion of ferro/ferrimagnetic materials to paramagnetic materials, which can extend the temperature-based applications of these materials from industrial nanotechnology
to the biomedical field. In this case, magnetic induction hyperthermia (MIH) with self-control temperature has been proposed as a physical thermo-therapeutic method for killing cancer tumors in a biologically safe environment. Specifically, the thermal source of MIH is magnetic nanoparticles (MNPs), and thus their biocompatibility and Curie temperature are two important properties, where the former is required for their clinical application, while the latter acts as a switch to automatically control the temperature of MIH. In this review, we focus on the Curie temperature of magnetic materials and provide a complete overview beginning with basic magnetism and its inevitable relation with Curie’s law, theoretical prediction and experimental measurement of the Curie temperature. Furthermore, we discuss the significance, evolution from different types of alloys to ferrites and impact of the shape, size, and concentration of particles on the Curie temperature considering the proposed SCT-based MIH together with their biocompatibility. Also, we highlight the thermal efficiency of MNPs in destroying
tumor cells and the significance of a low Curie temperature. Finally, the challenges, concluding remarks, and future perspectives in promoting self-control-temperature based MIH to clinical application are discussed.
High-grade gliomas (HGG) are the most common primary brain malignancy and continue to be associated with a dismal prognosis (median survival rate of 15-18 months) with standard of care therapy. Magnetic hyperthermia therapy (MHT) is an emerging intervention that leverages the ferromagnetic properties of magnetic iron-oxide nanoparticles (MIONPs) to target cancer cells that are otherwise left behind after resection. We report a novel port device to facilitate localization, delivery, and temperature measurement of MIONPs within a target lesion for MHT therapy. We conducted an in-depth literature and intellectual property review to define specifications of the conceived port device. After setting the design parameters, a thorough collaboration with neurological surgeons guided the iterative modeling process. A prototype was developed using Fusion 360 (Autodesk, San Rafael, CA) and printed on a Form 3 printer (Formlabs, Medford, MA) in Durable resin. The prototype was then tested in a phantom skull printed on a ProJet 660Pro 3D printer (3D Systems, Rock Hill, SC) and a brain model based on mechanical and electrochemical properties of native brain tissue. This phantom underwent MHT heating tests using an AMF sequence based on current MHT workflow. Successful localization, delivery, and temperature measurement were demonstrated. The purpose of this study was twofold: firstly, to create and validate the procedural framework for a novel device, providing the groundwork for an upcoming comprehensive animal trial, and secondly, to elucidate a cooperative approach between engineers and clinicians that propels advancements in medical innovation.
Spinel ferrite-based magnetic nanomaterials have been investigated for numerous biomedical applications, including targeted drug delivery, magnetic hyperthermia therapy (MHT), magnetic resonance imaging (MRI), and biosensors, among others. Recent studies have found that zinc ferrite-based nanomaterials are favorable candidates for cancer theranostics, particularly for magnetic hyperthermia applications. Zinc ferrite exhibits excellent biocompatibility, minimal toxicity, and more importantly, exciting magnetic properties. In addition, these materials demonstrate a Curie temperature much lower than other transition metal ferrites. By regulating synthesis protocols and/or introducing suitable dopants, the Curie temperature of zinc ferrite-based nanosystems can be tailored to the MHT therapeutic window, i.e., 43-46 °C, a range which is highly beneficial for clinical hyperthermia applications. Furthermore, zinc ferrite-based nanostructures have been extensively used in successful pre-clinical trials on mice models focusing on the synergistic killing of cancer cells involving magnetic hyperthermia and chemotherapy. This review provides a systematic and comprehensive understanding of the recent developments of zinc ferrite-based nanomaterials, including doped particles, shape-modified structures, and composites for magnetic hyperthermia applications. In addition, future research prospects involving pure ZnFe2O4 and its derivative nanostructures have also been proposed.
Glioblastoma (GBM) is the most invasive brain tumor and remains lack of effective treatment. The existence of blood-brain tumor barrier (BBTB) constitutes the greatest barrier to non-invasive delivery of therapeutic agents to tumors in the brain. Here, we propose a novel approach to specifically modulate BBTB and deliver magnetic hyperthermia in a systemic delivery mode for the treatment of GBM. BBTB modulation is achieved by targeted delivering fingolimod to brain tumor region via dual redox responsive PCL-SeSe-PEG (poly (ε-caprolactone)-diselenium-poly (ethylene glycol)) polymeric nanocarrier. As an antagonist of sphingosine 1-phosphate receptor-1 (S1P1), fingolimod potently inhibits the barrier function of BBB by blocking the binding of sphingosine 1-phosphate (S1P) to S1P1 in endothelial cells. We found that the modulated BBTB showed slight expression level of tight junction proteins, allowing efficient accumulation of zinc- and cobalt- doped iron oxide nanoclusters (ZnCoFe NCs) with enhanced magnetothermal conversion efficiency into tumor tissues through the paracellular pathway. As a result, the co-delivery of heat shock protein 70 inhibitor VER-155008 with ZnCoFe NCs could realize synergistic magnetic hyperthermia effects upon exposure to an alternating current magnetic field (ACMF) in both GL261 and U87 brain tumor models. This modulation approach brings new ideas for the treatment of central nervous system diseases that require delivery of therapeutic agents across the blood-brain barrier (BBB).
Despite advances in neurology, drug delivery to the central nervous system is considered a challenge due to the presence of blood brain barrier (BBB). In this study, the role of magnetic hyperthermia induced by exposure of magnetic nanoparticles (MNPs) to an alternating magnetic field (AMF) in synergy with an external magnetic field (EMF) was investigated to transiently increase the permeability of the MNPs across the BBB. A dual magnetic targeting approach was employed by first dragging the MNPs by EMF for an intended enhanced cellular association with the brain endothelial cells and then activating the MNPs by AMF for the temporary disruption of the tight junctions of BBB. The efficacy of the BBB permeability for the MNPs under the influence of dual magnetic targeting was evaluated in vitro using transwell models developed by co-culturing murine brain endothelial cells with astrocytes, as well as in vivo in mice models. The in vitro results revealed that the AMF exposure transiently opened the tight junctions at the BBB which after 3 h of treatment were observed to recover back to the comparable control levels. The nanoparticles biodistribution analysis confirmed targeted accumulation of MNPs in the brain following dual targeting. The dual targeting approach was observed to open the tight junctions thus, increasing the transport of the MNPs into the brain with higher specificity as compared to EMF targeting alone. Thus, suggesting dual magnetic targeting-induced transport of MNPs across the BBB to be an effective measure for delivery of therapeutics.
The poor permeability of therapeutic agents across the blood-brain barrier and blood-tumor barrier is a significant barrier in glioma treatment. Low-density lipoprotein receptor-related protein (LRP-1) recognises a dual-targeting ligand, angiopep-2, which is overexpressed in the BBB and gliomas. Here, we have synthesized Ti@FeAu core-shell nanoparticles conjugated with angiopep-2 (Ti@FeAu-Ang nanoparticles) to target glioma cells and treat brain cancer via hyperthermia produced by a magnetic field. Our results confirmed that Ti@FeAu core-shell nanoparticles were superparamagnetic, improved the negative contrast effect on glioma, and exhibited a temperature elevation of 12° C upon magnetic stimulation, which implies potential applications in magnetic resonance imaging (MRI) and hyperthermia-based cancer therapy. Angiopep-2-decorated nanoparticles exhibited higher cellular uptake by C6 glioma cells than by L929 fibroblasts, demonstrating selective glioma targeting and improved cytotoxicity up to 85% owing to hyperthermia produced by a magnetic field. The in vivo findings demonstrated that intravenous injection of Ti@FeAu-Ang nanoparticles exhibited a 10-fold decrement in tumor volume compared to the control group. Furthermore, immunohistochemical analysis of Ti@FeAu-Ang nanoparticles showed that coagulative necrosis of tumor tissues and preliminary safety analysis highlighted no toxicity to the haematological system, after Ti@FeAu-Ang nanoparticle-induced hyperthermia treatment.
Glioblastoma Multiforme (GBM) is a multifaceted and complex disease, which has experienced no changes in treatment for nearly two decades and has a 5-year survival rate of only 5.4%. Alongside challenges in delivering chemotherapeutic agents across the blood brain barrier (BBB) to the tumour, the immune microenvironment is also heavily influenced by tumour signalling. Immunosuppression is a major aspect of GBM; however, evidence remains conflicted as to whether pro-inflammatory or anti-inflammatory therapies are the key to improving GBM treatment. To address both of these issues, particle delivery systems can be designed to overcome BBB transport while delivering a wide variety of immune-stimulatory molecules to investigate their effect on GBM. This review explores literature from the past 3 years that combines particle delivery systems alongside immunotherapy for the effective treatment of GBM.
Development of multifunctional magnetic nanomaterials (MNPs) with improved heat-generating capabilities and effective combination with localized chemotherapy has emerged as a promising therapeutic regime for solid tumors like glioblastoma. In this regard, the shape-dependent hyperthermic and chemo-therapeutic potential of nanomaterials, has not been extensively explored. Here we present, development of various morphological designs of MNPs including spherical, clusters, rods and cubic; to compare the effect of shape on tuning the properties of MNPs that are relevant to many potential biomedical applications like drug delivery, cellular uptake and heat generation. The study includes extensive comparison of morpho-structural characteristics, size distributions, chemical composition, surface area measurements and magnetic properties of the variable shaped MNPs. Further the heating efficiencies in aqueous and cellular environments and heat triggered drug release profiles for successful magneto-chemotherapy were compared among all in-house synthesized MNPs. Under biosafety limit considerations given by Hergt's limit (H*f value <5 × 109 Am-1 s-1), cuboidal shaped MNPs demonstrated highest heating efficiency owing to magnetosome-like chain formation along with sustained drug release profile as compared to other synthesized MNPs. The mechanism of cancer cell death mediated via magneto-chemotherapy was elucidated to be the oxidative stress-mediated apoptotic cell death pathway. In vivo studies further demonstrated complete tumor regression only in the magneto-chemotherapy treated group. These findings suggest the potential of combinatorial therapy to overcome the clinical limitations of the independent therapies for advanced thermotherapy of glioblastoma.
Aims:
Recently, the development of new strategies in the treatment and diagnosis of cancer cells such as thermo-radiation-sensitizer and theranostic agents have received a great deal of attention. In this work, folic acid-conjugated temozolomide-loaded SPION@PEG-PBA-PEG nanoparticles (TMZ-MNP-FA NPs) were proposed for use as magnetic resonance imaging (MRI) contrast agents and to enhance the cytotoxic effects of hyperthermia and radiotherapy.
Main methods:
Nanoparticles were synthesized by the Nano-precipitation method and their characteristics were determined by dynamic light scattering (DLS), scanning electron microscopy (SEM) and X-ray powder diffraction (XRD). To evaluate the thermo-radio-sensitization effects of NPs, C6 cells were treated with nanoparticles for 24 h and then exposed to 6-MV X-ray radiation. After radiotherapy, the cells were subjected to an alternating magnetic field (AMF) hyperthermia. The therapeutic potential was assessed using clonogenic assay, ROS generation measurement, flow cytometry assay, and qRT-PCR analysis. Also, the diagnostic properties of the nanoparticles were assessed by MRI.
Key findings:
MRI scanning indicated that nanoparticles accumulated in C6 cells could be tracked by T2-weighted MR imaging. Colony formation assay proved that TMZ-MNP-FA NPs enhanced the anti-proliferation effects of AMF by 1.94-fold compared to AMF alone (P < 0.0001). Moreover, these NPs improved the radiation effects with a dose enhancement factor of 1.65. All results showed that the combination of carrier-based chemotherapy with hyperthermia and radiotherapy caused a higher anticancer efficacy than single- or two-modality treatments.
Significance:
The nanoparticles advanced in this study can be proposed as the promising theranostic and thermo-radio-sensitizer platform for the diagnosis and tri-modal synergistic cancer therapy.
The problem of the present work is to synthesize a nanomagnetic material with low TC below 45 °C and its particle size below 30 nm to be appropriate material for convert magnetic loss into heat energy. A series of Cu0.4Zn0.6+yZryFe2–2yO4 nanoparticles compositions where y = (0.05, 0.1) were synthesized via citrate sol–gel method. The prepared samples were characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM). The grains were observed from SEM confirming the crystalline structure of the ferrite which was detected by X-ray diffraction. Magnetic hysteresis loop measurements illustrate that materials exhibit soft magnetic properties at low Zr content, while at higher Zr content all materials behave as superparamagnetically without any saturation magnetization Ms. The initial magnetic permeability (μi) at frequency 10 kHz as a function of temperature was measured. A sudden change in μi appears around Curie temperature, making our samples good candidates for magnetic temperature transducer (MTT) devices. The DC resistivity for sample at y = 0.05, 0.1 was studied. The resistivity decreases linearly with increasing temperature within the given range of temperature up to 666 K for all samples. The dielectric constant of all samples is nearly independent on temperature through the range of 450 to 600 K which is a common character of ferrites. The dielectric loss was found to increase by increasing temperature, which may be related to the increase in AC conductivity. Hyperthermia measurements show the maximum specific power loss and temperature increase were 26 w/gr and 43 °C, respectively, for sample containing Zr = 0.05, after 2 min of measurements. One of the real applications of the material is that it is used as an effective method in tumor treatment by exposing the patient to external magnetic field.
Hyperthermia, the mild elevation of temperature to 40–45 °C, can induce cancer cell death and enhance the effects of radiotherapy and chemotherapy. Due to the nature of hyperthermia, especially their ability to combine nanotechnology, hyperthermia possesses the potential to open a novel paradigm for the therapeutic strategies. However, achievement of its full potential as a clinically relevant treatment modality has been restricted by its inability to effectively and preferentially heat malignant cells. The main challenge of current hyperthermia treatment is to adequately heat whole volumes of deep-seated tumors without overheating surrounding healthy tissues. So, hyperthermia is under clinical trials (research study with people) and is not widely available. In this Review, we summarize a basic knowledge of hyperthermia before focusing on their applications to the cancer therapy and synthesis. We try to give a comprehensive view of the role of nanomaterials in the designing of hyperthermia-based therapeutic protocols and compare the studies in this field with the purpose of providing a source of helpful information for planning forthcoming hyperthermia researches. However, establishing comparisons between hyperthermia studies is a challenge due to the widely different conditions used by different authors, which, in some cases, is aggravated by the lack of crucial information concerning a certain aspect of the procedure.
A green chemistry-based approach to nanoparticle synthesis is an eco-friendly, simple, and cost-effective way to fabricate nanoparticles. This study aims at the biomedical applications of green synthesized near-infrared (NIR) active superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs obtained by the green synthesis route are non-toxic and their surface is free from any chemical impurity. The MTT [3-(4, 5-Dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium Bromide] assay was accomplished on human cervical cancer (HeLa) cells and shows that the SPIONs are biocompatible and thus safe for cells even at higher concentrations up to 500 μg/ml. The synthesized SPIONs display an absorbance in the tissue transparent NIR wavelength region. The SPIONs exhibit a superparamagnetic behavior with high saturation magnetization of 66 emu/g. Owing to their excellent optical and magnetic properties, the potential of these green synthesized SPIONs as an exogenous contrast agent in deep-tissue magnetomotive optical coherence tomography (MM-OCT) imaging was evaluated ex-vivo using chicken breast tissue. A significant enhancement in the contrast and the penetration depth was observed with time. The heating response of green synthesized SPIONs was evaluated under the application of an external magnetic field. The results suggest that these SPIONs could be used as theranostic agents for deep tissue biomedical imaging and therapeutic applications.
Metastatic oral squamous cell carcinoma (SCC) displays a poor disease prognosis with a 5-year survival rate of 39%. Chemotherapy has emerged as the mainstream treatment against small clusters of cancer cells but poses more risks than benefits for metastatic cells due to the non-specificity and cytotoxicity. To overcome these obstacles, we conjugated antibodies specific for matrix metalloproteinase-1 (MMP-1), a prognostic biomarker of SCC, to iron–gold bimetallic nanoparticles (FeAu NPs) and explored the capability of this complex to target and limit SSC cell growth via magnetic field-induced hyperthermia. Our results showed that 4.32 ± 0.79 nm sized FeAu NPs were superparamagnetic in nature with a saturation magnetization (Ms) of 5.8 emu/g and elevated the media temperature to 45 °C, confirming the prospect to deliver hyperthermia. Furthermore, conjugation with MMP-1 antibodies resulted in a 3.07-fold higher uptake in HSC-3 (human tongue squamous cell carcinoma) cells as compared to L929 (fibroblast) cells, which translated to a 5-fold decrease in cell viability, confirming SCC targeting. Finally, upon magnetic stimulation, MMP-1-FeAu NPs conjugate triggered 89% HSC-3 cellular death, confirming the efficacy of antibody-conjugated nanoparticles in limiting SCC growth. The synergistic effect of biomarker-specific antibodies and magnetic nanoparticle-induced hyperthermia may open new doors towards SCC targeting for improved disease prognosis.
Superparamagnetic iron oxide nanoparticles (SPIONs) are interesting for biomedical applications in cancer treatment via magneto-hyperthermia. Its potential application contrasts with the challenges in producing systems with chemical and morphological uniformity and colloidal stability using simple, low-cost, and sustainable routes. Aqueous syntheses usually fail to control morphology and composition because SPIONs formation mechanisms are not fully understood. Here, we propose an aqueous route to synthesize SPIONs based on the controlled and stoichiometric reduction in situ of Fe³⁺ to Fe²⁺ ions in the presence of sulfite ions, followed by aging at 90 ∘C in an alkaline medium for 18h. SPIONs with high water-stable and controlled characteristics in a sustainable, inexpensive, and scalable procedure were obtained. The nucleation, growth, and hydrolysis rates were adjusted by the excess of OH⁻ ions, initial temperature, and iron precursor nature. The results are discussed concerning concepts of the classical and nonclassical nucleation theories, indicating an optimum pH of 9.5-10.5 for SPIONs formation. The SPIONs present an average size of 11 nn, narrow size distribution, and magnetite phase with about 34 mol% of maghemite due to structural defects. Nanoparticles are superparamagnetic, have a hydrodynamic diameter of 130 nm with a surface potential of ~ -40 mV (pH ≥ 7), and suitable magneto-hyperthermic properties fro cancer treatment. Specific Absorption Rate values were evaluated concerning the SPIONs physical-chemical properties, indicating a strong dependence on the average crystallite size and the magnetization at 250 Oe. Cell viability tests showed that SPIONs did not provide any significant change in cellular growth at used concentrations.
The use of different types of biomaterials as surfactant moities has a defined role in magnetic hyperthermia-mediated cancer therapy (MHCT). In this work, we present carboxymethyl-stevioside (CMS)-modified magnetic dots (MDs) as efficient magnetic hyperthermia agents for glioma therapy. The synthesized MDs with CMS biosurfactant coating exhibited significant water stability that resulted in a remarkable specific absorption rate of 209.25 W/g on application of alternating magnetic field of strength 359 kHz and 188 Oe. The MDs further demonstrated significant anti-migratory and anti-invasive effect on glioma C6 cells by inhibiting the gene expression of matrix metalloproteinases-2 and -9. The effect of immediate and long term hyperthermia treatment was then evaluated after repetitive exposure to hyperthermia, in terms of glioma cell viability, the effect of treatment on cell morphology, the cell cycle distribution and oxidative stress generation. The results obtained suggest the promising potential of CMS-modified nano-heaters for excellent magnetic hyperthermia-mediated glioma therapy.
Magnetic hyperthermia-based cancer therapy mediated by magnetic nanomaterials is a promising antitumoral nanotherapy, owning to its power to generate heat under the application of an alternating magnetic field. However, although the ultimate targets of these treatments, the heating potential and its relation with the magnetic behavior of the employed magnetic nanomaterials are rarely studied. Here we provide a bridge between the heating potential and magnetic properties such as anisotropy energy constant and saturation magnetization of the nano-magnets by simultaneous investigation of both hyperthermia and magnetism under a controlled set of variables given by response surface methodology. In the study, we have simultaneously investigated the effect of various synthesis parameters like cation ratio, reaction temperature and time on the magnetic response and heat generation of manganese-doped ferrite nanomaterials synthesized by a simple hydrothermal route. The optimum generation of heat and magnetization is obtained at a cationic ratio of approximately 42 at a temperature of 100 °C for a time period of 4 h. The optimized nanomaterial was then evaluated forin vitromagnetic hyperthermia application for cancer therapy against glioblastoma in terms of cell viability, effect on cellular cytoskeleton and morphological alterations. Furthermore, the correlation between the magnetic properties of the synthesized nanomaterial with its hyperthermia output was also established usingK.V.Msvariable whereK,VandMsare the anisotropy energy constant, volume, and saturation magnetization of the nanomaterial respectively. It was found that the intensity of heat generation decreases with an increase inK.V.Msvalue, beyond 950 J emu g
Controlling the magnetic properties of a nanoparticle efficiently via its particle size to achieve optimized heat under alternating magnetic field is the central point for magnetic hyperthermia-mediated cancer therapy (MHCT). Here, we have shown the successful use of stevioside (a natural plant-based glycoside) as a promising biosurfactant to control the magnetic properties of Fe3O4 nanoparticles by controlling the particle size. The biocompatibility and cellular uptake efficiency by rat C6 glioma cells and calorimetric magnetic hyperthermia profile of the nanoparticles were further examined. Our finding suggests superior properties of stevioside-coated magnetite nanoparticles in comparison to polysorbate-80 and oleic acid coated nanomagnets as far as particle size reduction, biocompatibility, hyperthermic effect, and cellular uptake by the glioblastoma cancer cells are concerned. The stevioside-coated nanomagnets exhibiting the maximum temperature rise were further investigated as heating agents in in vitro magnetic hyperthermia experiments (405 kHz, 168 Oe), showing their efficacy to induce cell death of rat C6 glioma cells after 30 min at a target temperature T = 43 °C.
Introduction:
Hyperthermia (HT) based on magnetic nanoparticles (MNPs) represents a promising approach to induce the apoptosis/necrosis of tumor cells through the heat generated by MNPs submitted to alternating magnetic fields. However, the effects of temperature distribution on the cancer cells' viability as well as heat resistance of various tumor cell types warrant further investigation.
Methods:
In this work, the effects induced by magnetic hyperthermia (MHT) and conventional water-based hyperthermia (WHT) on the viability of human osteosarcoma cells at different temperatures (37°C-47°C) was comparatively investigated. Fe-Cr-Nb-B magnetic nanoparticles were submitted either to alternating magnetic fields or to infrared radiation generated by a water-heated incubator.
Results:
In terms of cell viability, significant differences could be observed after applying the two HT treatment methods. At about equal equilibrium temperatures, MHT was on average 16% more efficient in inducing cytotoxicity effects compared to WHT, as assessed by MTT cytotoxicity assay.
Conclusion:
We propose the phenomena can be explained by the significantly higher cytotoxic effects initiated during MHT treatment in the vicinity of the heat-generating MNPs compared to the effects triggered by the homogeneously distributed temperature during WHT. These in vitro results confirm other previous findings regarding the superior efficiency of MHT over WHT and explain the cytotoxicity differences observed between the two antitumor HT methods.
Abstact
We report on a new, environment-friendly synthesis route to produce Fe3O4 magnetic nanoparticles (MNPs) from extracts of the plants Vanilla planifolia and Cinnamomun verum. These aqueous plant extracts have the double function of reducing agents due to their phenolic groups, and also capping materials through the –OH bonding over the MNPs surface. The resulting MNPs have average sizes ≈10–14 nm with a core–shell Fe3O4–γFe2O3 structure due to surface oxidation driven by the phenolic groups through OH⁻ covalent bonding. Saturation magnetization values of MS = 70.84 emu g⁻¹ (C. verum) and MS = 59.45 emu g⁻¹ (V. planifolia) are among the largest reported so far from biosynthetic samples. Electron microscopy and infrared spectroscopy data showed a thin organic layer coating the Fe3O4 @γFe2O3 MNPs, composed by the phenolic groups from the starting extracts of both C. verum and V. planifolia. A proof of concept for these MNPs as heating agents in magnetic hyperthermia experiments (570 kHz, 23.9 kA m⁻¹) was performed in-vitro, showing their efficacy to induce cell death on BV2 microglial cells after 30 min at a target temperature T = 46 °C.
In this study, biologically synthesized iron oxide nanoparticles, called magnetosomes, are made fully biocompatible by removing potentially toxic organic bacterial residues such as endotoxins at magnetosome mineral core surfaces and by coating such surface with poly-L-lysine, leading to magnetosomes-poly-L-lysine (M-PLL). M-PLL antitumor efficacy is compared with that of chemically synthesized iron oxide nanoparticles (IONPs) currently used for magnetic hyperthermia. M-PLL and IONPs are tested for the treatment of glioblastoma, a dreadful cancer, in which intratumor nanoparticle administration is clinically relevant, using a mouse allograft model of murine glioma (GL-261 cell line). A magnetic hyperthermia treatment protocol is proposed, in which 25 μg in iron of nanoparticles per mm3 of tumor are administered and exposed to 11 to 15 magnetic sessions during which an alternating magnetic field of 198 kHz and 11 to 31 mT is applied for 30 minutes to attempt reaching temperatures of 43-46 °C. M-PLL are characterized by a larger specific absorption rate (SAR of 40 W/gFe compared to 26 W/gFe for IONPs as measured during the first magnetic session), a lower strength of the applied magnetic field required for reaching a target temperature of 43-46 °C (11 to 27 mT compared with 22 to 31 mT for IONPs), a lower number of mice re-administered (4 compared to 6 for IONPs), a longer residence time within tumours (5 days compared to 1 day for IONPs), and a less scattered distribution in the tumour. M-PLL lead to higher antitumor efficacy with full tumor disappearances achieved in 50% of mice compared to 20% for IONPs. This is ascribed to better ability of M-PLL, at equal iron concentrations, to maintain tumor temperatures at 43-46°C over a longer period of times.
Background
Biologics magnetics nanoparticles, magnetosomes, attract attention because of their magnetic characteristics and potential applications. The aim of the present study was to develop and characterize novel magnetosomes, which were extracted from magnetotactic bacteria, purified to produce apyrogen magnetosome minerals, and then coated with Chitosan, Neridronate, or Polyethyleneimine. It yielded stable magnetosomes designated as M-Chi, M-Neri, and M-PEI, respectively. Nanoparticle biocompatibility was evaluated on mouse fibroblast cells (3T3), mouse glioblastoma cells (GL-261) and rat glioblastoma cells (RG-2). We also tested these nanoparticles for magnetic hyperthermia treatment of tumor in vitro on two tumor cell lines GL-261 and RG-2 under the application of an alternating magnetic field. Heating, efficacy and internalization properties were then evaluated.
Results
Nanoparticles coated with chitosan, polyethyleneimine and neridronate are apyrogen, biocompatible and stable in aqueous suspension. The presence of a thin coating in M-Chi and M-PEI favors an arrangement in chains of the magnetosomes, similar to that observed in magnetosomes directly extracted from magnetotactic bacteria, while the thick matrix embedding M-Neri leads to structures with an average thickness of 3.5 µm² per magnetosome mineral. In the presence of GL-261 cells and upon the application of an alternating magnetic field, M-PEI and M-Chi lead to the highest specific absorption rates of 120–125 W/gFe. Furthermore, while M-Chi lead to rather low rates of cellular internalization, M-PEI strongly associate to cells, a property modulated by the application of an alternating magnetic field.
Conclusions
Coating of purified magnetosome minerals can therefore be chosen to control the interactions of nanoparticles with cells, organization of the minerals, as well as heating and cytotoxicity properties, which are important parameters to be considered in the design of a magnetic hyperthermia treatment of tumor.
Electronic supplementary material
The online version of this article (doi:10.1186/s12951-017-0293-2) contains supplementary material, which is available to authorized users.
We present evidence on the effects of exogenous heating by water bath (WB) and magnetic hyperthermia (MHT) on a glial micro-tumor phantom. To this, magnetic nanoparticles (MNPs) of 30-40 nm were designed to obtain particle sizes for maximum heating efficiency. The specific power absorption (SPA) values (f = 560 kHz, H = 23.9 kA/m) for as prepared colloids (533-605 W/g) dropped to 98-279 W/g in culture medium. The analysis of the intracellular MNPs distribution showed vesicle-trapped MNPs agglomerates spread along the cytoplasm, as well as large (~0.5-0.9 μm) clusters attached to the cell membrane. Immediately after WB and MHT (T = 46 °C for 30 min) the cell viability was ≈70% and, after 4.5 h, decreased to 20-25%, demonstrating that metabolic processes are involved in cell killing. The analysis of the cell structures after MHT revealed a significant damage of the cell membrane that is correlated to the location of MNPs clusters, while local cell damage were less noticeable after WB without MNPs. In spite of the similar thermal effects of WB and MHT on the cell viability, our results suggest that there is an additional mechanism of cell damage related to the presence of MNPs at the intracellular space.
Previous studies showed that magnetic hyperthermia could efficiently destroy tumors both preclinically and clinically, especially glioma. However, antitumor efficacy remained suboptimal and therefore required further improvements. Here, we introduce a new type of nanoparticles synthesized by magnetotactic bacteria, called magnetosomes, with improved properties compared with commonly used chemically synthesized nanoparticles. Indeed, mice bearing intracranial U87-Luc glioma tumors injected with 13 μg of nanoparticles per mm³ of tumor followed by 12 to 15 of 30 min alternating magnetic field applications displayed either full tumor disappearance in 40% of mice or no tumor regression using magnetosomes or chemically synthesized nanoparticles, respectively. Magnetosome superior antitumor activity could be explained both by a larger production of heat and by endotoxins release under alternating magnetic field application. Most interestingly, this behavior was observed when magnetosomes occupied only 10% of the whole tumor volume, which suggests that an indirect mechanism, such as an immune reaction, takes part in tumor regression. This is desired for the treatment of infiltrating tumors, such as glioma, for which whole tumor coverage by nanoparticles can hardly be achieved.
Iron-salen, i.e., μ-oxo-N,N'- bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25mg/kg)- induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.
Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs.
We previously reported that μ-oxo N,N’-bis(salicylidene)ethylenediamine iron [Fe(Salen)], a magnetic organic compound, has direct anti-tumor activity, and generates heat in an alternating magnetic field (AMF). We showed that Fe(Salen) nanoparticles are useful for combined hyperthermia-chemotherapy of tongue cancer. Here, we have examined the effect of Fe(Salen) on human glioblastoma (GB). Fe(Salen) showed in vitro anti-tumor activity towards several human GB cell lines. It inhibited cell proliferation, and its apoptosis-inducing activity was greater than that of clinically used drugs. Fe(Salen) also showed in vivo anti-tumor activity in the mouse brain. We evaluated the drug distribution and systemic side effects of intracerebrally injected Fe(Salen) nanoparticles in rats. Further, to examine whether hyperthermia, which was induced by exposing Fe(Salen) nanoparticles to AMF, enhanced the intrinsic anti-tumor effect of Fe(Salen), we used a mouse model grafted with U251 cells on the left leg. Fe(Salen), BCNU, or normal saline was injected into the tumor in the presence or absence of AMF exposure. The combination of Fe(Salen) injection and AMF exposure showed a greater anti-tumor effect than did either Fe(Salen) or BCNU alone. Our results indicate that hyperthermia and chemotherapy with single-drug nanoparticles could be done for GB treatment.
Glioblastoma multiforme (Gb) is considered the most frequent brain tumor. The Gb represents 12–15% of all intracranial tumors and 50–60% of all astrocytic tumors. The poor survival of patients (3–5% in 5 years) along with the marginal improvement produced by drugs, and the recurrence after surgery treatment, indicates that Gb is the most aggressive of the gliomas. Hyperthermia has been successfully applied since late 50’s in many animal models to induce the catabolism of many tumor. The challenge of this work is to show that hyperthermia helps reducing intracranial brain malignant astrocytoma in a reliable mouse model with immunity preserved, as well as to test the safety of the intervention. First, we showed in vitro that ferro-magnetic microparticles (MP) exposed to 200 kA m⁻¹ magnetic strength for 1 h increased temperature. To see if our “in vitro” results could be replicated ”in vivo” we grafted 20,000 CT-2A tumoral cells in the striatum of C57 mice. We divided the grafted mice (36) in four groups, as follows: 1st, grafted group only (Gb), 2nd grafted group exposed to MFss (Gb + ELFMFS), 3rd grafted group injected with MP (Gb + MP) and 4th grafted group injected with MP and exposed to MFs (Gb + MP + ELFMFS). MP were injected intrastriatally four days after the graft, with 4 μl of ferromagnetic MP at the same coordinates used to graft tumoral cells. The selected groups were exposed to the MF 200 kA m⁻¹ for two hours daily during 7 days while the control groups were exposed to the equipment in off. Mice were sacrificed 1 h. after the magnetic stimulation to study their brains. Further, striatal sections were evaluated for proliferation and astrocyte activation by using Ki67, Iba1 and GFAP markers. We found that TMS reduces microglia 3.5% in the Gb + TMS group and 7.5% in the Gb + MP + TMS group when compared with the Gb group. Microglia increased (7.3%) after intrastriatal administration of MP. We then studied the growth of tumor with Ki67 and observed a 55% reduction of tumor area in mice exposed to TMS versus the control group. In agreement with these results, 30% of mice injected with MP and exposed to MF survived to Gb graft at 21 days. In summary, our study shows the effectiveness of TMS against intracranial neoplasms possibly due to the rise in the temperature of MP after TMS and opens the possibility for further studies in tumor cells.
This study reports the production of magnetic nanoemulsions (MNEs) loaded with citrate-coated maghemite nanoparticles (0.15 × 10¹⁶ or 1.50 × 10¹⁶ particle per mL) and chloroaluminum-phthalocyanine (0.05 mg mL⁻¹). Using different cell line models (BM-MSC, U87MG, and T98G) an in vitro test was performed to assess the cell viability while incubating the cells with the two prepared formulations, before and after performing hyperthermia (HPT: 1 MHz frequency, 40 Oe magnetic field amplitude) and photodynamic therapy (PDT at 670 nm wavelength, 700 mJ cm⁻² energy density). We found from all cell lines that under the HPT treatment the cell viability reduction has averaged 15%, regardless the magnetic nanoparticle content within the MNE. Using both MNE formulation (0.15 × 10¹⁶ or 1.54 × 10¹⁶ magnetic particle per mL) and applying only PDT light treatment we reach an average decrease of 52%. However, a total reduction of about 70% was found while combining the HPT and PDT treatments. Confocal studies clearly indicated the cytoplasm localization and active site of the drug delivery device. Therefore, the combined treatment of HPT and PDT represents a promising paradigm for brain cancer intervention, such as glioblastoma.
The temperature variation rule of nano-magnetic fluid in the specific magnetic field and the effect on the treatment of malignant glioma were examined. The temperature variation of nano-magnetic fluid in the specific magnetic field was investigated by heating in vitro, and cell morphology was observed through optical microscopy and electron microscopy. MTT detection also was used to detect the effect of Fe3O4 nanometer magnetic fluid hyperthermia (MFH) on the proliferation of human U251 glioma cell line. The Fe3O4 nano MFH experiment was used to detect the inhibition rate of the tumor volume in nude mice with tumors. The results of the experiment showed that the heating ability of magnetic fluid was positively correlated with its concentration at the same intensity of the magnetic field. The results also indicated the prominent inhibitory effect of nanometer MFH on the proliferation of glioma cells, which was a dose-dependent relationship with nanometer magnetic fluid concentration. The hyperthermia experiment of nude mice with tumors displayed a significant inhibiting effect of Fe3O4 nanometer magnetic fluid in glioma volume. These results explain that iron (II, III) oxide (Fe3O4) nanometer MFH can inhibit the proliferation of U251 glioma cells, and has an obvious inhibitory effect on glioma volume, which plays a certain role in the treatment of brain glioma.
Background
A new transcranial focused ultrasound device has been developed that can induce hyperthermia in a large tissue volume. The purpose of this work is to investigate theoretically how glioblastoma multiforme (GBM) can be effectively treated by combining the fast hyperthermia generated by this focused ultrasound device with external beam radiotherapy.
Methods/Design
To investigate the effect of tumor growth, we have developed a mathematical description of GBM proliferation and diffusion in the context of reaction–diffusion theory. In addition, we have formulated equations describing the impact of radiotherapy and heat on GBM in the reaction–diffusion equation, including tumor regrowth by stem cells. This formulation has been used to predict the effectiveness of the combination treatment for a realistic focused ultrasound heating scenario.
Our results show that patient survival could be significantly improved by this combined treatment modality.
Discussion
High priority should be given to experiments to validate the therapeutic benefit predicted by our model.
Electronic supplementary material
The online version of this article (doi:10.1186/s40349-016-0078-3) contains supplementary material, which is available to authorized users.
Delivery of diagnostic or therapeutic agents across the blood-brain barrier (BBB) remains a major challenge of brain disease treatment. Magnetic nanoparticles are actively being developed as drug carriers due to magnetic targeting and subsequently reduced off-target effects. In this paper, we developed a magnetic SiO2@Fe3O4 nanoparticle-based carrier bound to cell-penetrating peptide Tat (SiO2@Fe3O4
-Tat) and studied its fates in accessing BBB. SiO2@Fe3O4-Tat nanoparticles (NPs) exhibited suitable magnetism and good biocompatibility. NPs adding to the apical chamber of in vitro BBB model were found in the U251 glioma cells co-cultured at the bottom of the Transwell, indicating that particles passed through the barrier and taken up by glioma cells. Moreover, the synergistic effects of Tat and magnetic field could promote the efficient cellular internalization and the permeability across the barrier. Besides, functionalization with Tat peptide allowed particles to locate into the nucleus of U251 cells than the non-conjugated NPs. These results suggest that SiO2@Fe3O4-Tat NPs could penetrate the BBB through the transcytosis of brain endothelial cells and magnetically mediated dragging. Therefore, SiO2@Fe3O4-Tat NPs could be exploited as a potential drug delivery system for chemotherapy and gene therapy of brain disease.
Among the primary brain tumors, gliomas are the most commonly found. In the United States, these tumors account for approximately 78% of the new cases of primary malignant brain and central nervous system (CNS) tumors diagnosed annually. Glioblastoma multiforme (GBM) is the most common and aggressive type of glioma, with the poorest survival duration. Although surgical techniques, radiotherapy and chemotherapy have improved, the prognoses of patients with glioblastomas are still poor (∼1 year), which is largely because of the spread of tumor cells to other regions of the brain. Intravenous administration of chemotherapy drugs is the standard procedure for treat these spreaded cells, but the treatment effect is limited because of the adverse side effect and the delivery blockage from the blood-brain barrier (BBB). Thus, developing an effective treatment system to conquer this blockage will be beneficial for those who suffer from malignant brain tumor.
Background:
Glioblastoma multiforme, one of the most aggressive brain tumors, has a very poor clinical outcome. Despite the introduction of the alkylating reagent temozolomide (TMZ) to surgery and radiotherapy, the survival of patients could only be modestly increased up to less than 15 months. Therefore, innovative treatment strategies are urgently needed to improve survival of glioma patients.
Objective:
Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted a lot of attention due to their widespread diagnostic and therapeutic applications in neuro-oncology. In this review article we discuss the possible application of the SPIONs for the diagnostic and theraputic approaches in brain cancer. Additionally we report on recent pre-clinical and clinical developments on the generation of heat in the tumors through the application of SPIONs subjected to an alternating magnetic field (AMF).
Methods:
A comprehensive review of the literature on the current status of using targeted SPIONs in brain tumor detection and therapy and also the potential hurdles to overcome was performed.
Results:
Functionalized nanoparticles carrying tumor-specific agents, such as antibodies or proteins might further improve their tumor targeting capacity. Furthermore, multifunctional, theranostic SPIONs can be used for simultaneous in vivo tumor imaging and targeted drug deliery. Application of the ultrasound and external magnetic field technologies significantly improves accumulation of nanoparticles in brain tumors. Hyperthermic treatment using AMF has a therapeutic potential in management of brain tumors.
Conclusion:
Superparamagnetic nanoparticle-based imaging, drug delivery and hyperthermic treatment can potentially be a powerful tool for precise diagnosis and treatment of brain tumors.
Targeting nanoparticles to malignant tissues for improved diagnosis and therapy is a popular concept. However, after surveying the literature from the past 10 years, only 0.7% (median) of the administered nanoparticle dose is found to be delivered to a solid tumour. This has negative consequences on the translation of nanotechnology for human use with respect to manufacturing, cost, toxicity, and imaging and therapeutic efficacy. In this article, we conduct a multivariate analysis on the compiled data to reveal the contributions of nanoparticle physicochemical parameters, tumour models and cancer types on the low delivery efficiency. We explore the potential causes of the poor delivery efficiency from the perspectives of tumour biology (intercellular versus transcellular transport, enhanced permeability and retention effect, and physicochemical-dependent nanoparticle transport through the tumour stroma) as well as competing organs (mononuclear phagocytic and renal systems) and present a 30-year research strategy to overcome this fundamental limitation. Solving the nanoparticle delivery problem will accelerate the clinical translation of nanomedicine.
We previously investigated the utility of μ-oxo N,N′- bis(salicylidene)ethylenediamine iron (Fe(Salen))
nanoparticles as a new anti-cancer agent for magnet-guided delivery with anti-cancer activity. Fe(Salen)
nanoparticles should rapidly heat up in an alternating magnetic field (AMF), and we hypothesized
that these single-drug nanoparticles would be effective for combined hyperthermia-chemotherapy.
Conventional hyperthermic particles are usually made of iron oxide, and thus cannot exhibit anticancer
activity in the absence of an AMF. We found that Fe(Salen) nanoparticles induced apoptosis in
cultured cancer cells, and that AMF exposure enhanced the apoptotic effect. Therefore, we evaluated
the combined three-fold strategy, i.e., chemotherapy with Fe(Salen) nanoparticles, magnetically
guided delivery of the nanoparticles to the tumor, and AMF-induced heating of the nanoparticles to
induce local hyperthermia, in a rabbit model of tongue cancer. Intravenous administration of Fe(Salen)
nanoparticles per se inhibited tumor growth before the other two modalities were applied. This
inhibition was enhanced when a magnet was used to accumulate Fe(Salen) nanoparticles at the tongue.
When an AMF was further applied (magnet-guided chemotherapy plus hyperthermia), the tumor
masses were dramatically reduced. These results indicate that our strategy of combined hyperthermiachemotherapy
using Fe(Salen) nanoparticles specifically delivered with magnetic guidance represents a
powerful new approach for cancer treatment.
Magnetic hyperthermia is a promising technique for the minimally invasive elimination of solid tumors. In this study, uniform magnetite nanoparticles (MNPs) with different particle sizes were used as a model system to investigate the size and surface effects of human-like collagen protein-coated MNPs (HLC-MNPs) on specific absorption rate and biocompatibility. It was found that these HLC-MNPs possess rapid heating capacity upon alternating magnetic field exposure compared to that of MNPs without HLC coating, irrespective of the size of MNPs. The significant enhancement of specific absorption rate is favorable for larger sized nanoparticles. Such behavior is attributed to the reduced aggregation and increased stability of the HLC-MNPs. By coating HLC on the surface of certain sized MNPs, a significant increase in cell viability (up to 2.5-fold) can be achieved. After subcutaneous injection of HLC-MNPs into the back of Kunming mice, it was observed that the inflammatory reaction hardly occurred in the injection site. However, there was a significant presence of phagocytes and endocytosis after the injection of nonconjugated counterparts. The overall strategy to fabricate HLC-MNPs can serve as a general guideline to address the current challenges in clinical magnetic hyperthermia, improved biocompatibility, and enhanced heating characteristics through protein coating.
Maintaining a high concentration of therapeutic agents in the brain is difficult due to the restrictions of the blood-brain barrier (BBB) and rapid removal from blood circulation. To enable controlled drug release and enhance the blood-brain barrier (BBB)-crossing efficiency for brain tumor therapy, a new dual-targeting magnetic polydiacetylene nanocarriers (PDNCs) delivery system modified with lactoferrin (Lf) is developed. The PDNCs are synthesized using the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) monomers through spontaneous assembling onto the surface of superparamagnetic iron oxide (SPIO) nanoparticles to form micelles-polymerized structures. The results demonstrate that PDNCs will reduce the drug leakage and further control the drug release, and display self-responsive fluorescence upon intracellular uptake for cell trafficking and imaging-guided tumor treatment. The magnetic Lf-modified PDNCs with magnetic resonance imaging (MRI) and dual-targeting ability can enhance the transportation of the PDNCs across the BBB for tracking and targeting gliomas. An enhanced therapeutic efficiency can be obtained using Lf-Cur (Curcumin)-PDNCs by improving the retention time of the encapsulated Cur and producing fourfold higher Cur amounts in the brain compared to free Cur. Animal studies also confirm that Lf targeting and controlled release act synergistically to significantly suppress tumors in orthotopic brain-bearing rats.
Hyperthermia therapy is a medical treatment based on the exposition of body tissue to slightly higher temperatures than physiological (i.e., between 41 and 46 °C) to damage and kill cancer cells or to make them more susceptible to the effects of radiation and anti-cancer drugs. Among several methods suitable for heating tumor areas, magnetic hyperthermia involves the introduction of magnetic micro/nanoparticles into the tumor tissue, followed by the application of an external magnetic field at fixed frequency and amplitude. A very interesting approach for magnetic hyperthermia is the use of biocompatible thermo-responsive magnetic gels made by the incorporation of the magnetic particles into cross-linked polymer gels. Mainly because of the hysteresis loss from the magnetic particles subjected to a magnetic field, the temperature of the system goes up and, once the temperature crosses the lower critical solution temperature, thermo-responsive gels undergo large volume changes and may deliver anti-cancer drug molecules that have been previously entrapped in their networks. This tutorial review describes the main properties and formulations of magnetic gel composites conceived for magnetic hyperthermia therapy.
Magnetic Particle Imaging (MPI) is a new real-time imaging modality, which promises high tracer mass sensitivity and spatial resolution directly generated from iron oxide nanoparticles. In this study, monodisperse iron oxide nanoparticles with median core diameters ranging from 14 to 26 nm were synthesized and their surface was conjugated with lactoferrin to convert them into brain glioma targeting agents. The conjugation was confirmed with the increase of the hydrodynamic diameters, change of zeta potential, and Bradford assay. Magnetic particle spectrometry (MPS), performed to evaluate the MPI performance of these nanoparticles, showed no change in signal after lactoferrin conjugation to nanoparticles for all core diameters, suggesting that the MPI signal is dominated by Néel relaxation and thus independent of hydrodynamic size difference or presence of coating molecules before and after conjugations. For this range of core sizes (14-26 nm), both MPS signal intensity and spatial resolution improved with increasing core diameter of nanoparticles. The lactoferrin conjugated iron oxide nanoparticles (Lf-IONPs) showed specific cellular internalization into C6 cells with a 5-fold increase in MPS signal compared to IONPs without lactoferrin, both after 24 h incubation. These results suggest that Lf-IONPs can be used as tracers for targeted brain glioma imaging using MPI.
The blood-brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood-brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE). These technologies can lead to transient BBB and blood-brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal.
Malignant gliomas remain aggressive and lethal primary brain tumors in adults. The epidermal growth factor receptor (EGFR) is frequently overexpressed in the most common malignant glioma, glioblastoma (GBM), and represents an important therapeutic target. GBM stem-like cells (GSCs) present in tumors are felt to be highly tumorigenic and responsible for tumor recurrence. Multifunctional magnetic iron-oxide nanoparticles (IONPs) can be directly imaged by magnetic resonance imaging (MRI) and designed to therapeutically target cancer cells. The targeting effects of IONPs conjugated to the EGFR inhibitor, cetuximab (cetuximab-IONPs), were determined with EGFR- and EGFRvIII-expressing human GBM neurospheres and GSCs. Transmission electron microscopy revealed cetuximab-IONP GBM cell binding and internalization. Fluorescence microscopy and Prussian blue staining showed increased uptake of cetuximab-IONPs by EGFR- as well as EGFRvIII-expressing GSCs and neurospheres in comparison to cetuximab or free IONPs. Treatment with cetuximab-IONPs resulted in a significant antitumor effect that was greater than with cetuximab alone due to more efficient, CD133-independent cellular targeting and uptake, EGFR signaling alterations, EGFR internalization, and apoptosis induction in EGFR-expressing GSCs and neurospheres. A significant increase in survival was found after cetuximab-IONP convection-enhanced delivery treatment of 3 intracranial rodent GBM models employing human EGFR-expressing GBM xenografts.
Glioma stem-like cells (GSCs) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells and it is re-emerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment.
Copyright © 2015, American Association for Cancer Research.
Cerebral edema commonly accompanies brain tumors and contributes to neurologic symptoms. The role of the interleukin-1 receptor antagonist conjugated to superparamagnetic iron oxide nanoparticles (SPION–IL-1Ra) was assessed to analyze its anti-edemal effect and its possible application as a negative contrast enhancing agent for magnetic resonance imaging (MRI). Rats with intracranial C6 glioma were intravenously administered at various concentrations of IL-1Ra or SPION–IL-1Ra. Brain peritumoral edema following treatment with receptor antagonist was assessed with high-field MRI. IL-1Ra administered at later stages of tumor progression significantly reduced peritumoral edema (as measured by MRI) and prolonged two-fold the life span of comorbid animals in a dose-dependent manner in comparison to control and corticosteroid-treated animals (P < .001). Synthesized SPION–IL-1Ra conjugates had the properties of negative contrast agent with high coefficients of relaxation efficiency. In vitro studies of SPION–IL-1Ra nanoparticles demonstrated high intracellular incorporation and absence of toxic influence on C6 cells and lymphocyte viability and proliferation. Retention of the nanoparticles in the tumor resulted in enhanced hypotensive T2-weighted images of glioma, proving the application of the conjugates as negative magnetic resonance contrast agents. Moreover, nanoparticles reduced the peritumoral edema confirming the therapeutic potency of synthesized conjugates. SPION–IL-1Ra nanoparticles have an anti-edemal effect when administered through a clinically relevant route in animals with glioma. The SPION–IL-1Ra could be a candidate for theranostic approach in neuro-oncology both for diagnosis of brain tumors and management of peritumoral edema.
The interface of bio−nano science and cancer medicine is an area experiencing much progress but also beset with controversy. Core concepts of the fielde.g., the enhanced permeability and retention (EPR) effect, tumor targeting and accumulation, and even the purpose of " nano " in cancer medicineare hotly debated. In parallel, considerable advances in neighboring fields are occurring rapidly, including the recent progress of " immuno-oncology " and the fundamental impact it is having on our understanding and the clinical treatment of the group of diseases collectively known as cancer. Herein, we (i) revisit how cancer is commonly treated in the clinic and how this relates to nanomedicine; (ii) examine the ongoing debate on the relevance of the EPR effect and tumor targeting; (iii) highlight ways to improve the next-generation of nanomedicines; and (iv) discuss the emerging concept of working with (and not against) biology. While discussing these controversies, challenges, emerging concepts, and opportunities, we explore new directions for the field of cancer nanomedicine.
We have successfully introduced sugar alcohol (mannitol) onto the surface of iron oxide magnetic nanoparticles and investigated its role on their colloidal stabilization. The mannitol functionalized magnetic nanoparticles (MMNPs) were prepared through co-precipitation of Fe⁺² and Fe³⁺ ions in basic medium under N2 atmosphere followed by in-situ coating of D-mannitol. The formation of iron oxide nanoparticles is evident from XRD and TEM analysis. The coating of nanoparticles with mannitol is analyzed by FTIR, TGA, DLS and zeta-potential measurements. It has been observed that the presence of mannitol on the surface nanoparticles strongly affect their surface potential and colloidal stability. They show room temperature superparamagnetism with optimal magnetization of 60.5 emu/g at 20 kOe and protein resistant behaviour in physiological medium. These MMNPs were employed as drug delivery carrier using anticancer drug, doxorubicin hydrochloride (DOX). The drug molecules were loaded onto the surface of nanoparticles through electrostatic interactions between positively charged DOX and negatively charged MMNPs. A loading efficiency of 60% has been observed at DOX to MMNPs ratio (w/w) of 1:10 and the loaded drug showed pH dependent sustained release characteristics. Further, MMNPs exhibited good self-heating ability under applied AC magnetic field, thus they can be used as efficient heating source for hyperthermia therapy.
Magnetic hyperthermia was reported to increase the survival of patients with recurrent glioblastoma by 7 months. This promising result may potentially be further improved by using iron oxide nanoparticles, called magnetosomes, which are synthesized by magnetotactic bacteria, extracted from these bacteria, purified to remove most endotoxins and organic material, and then coated with poly-l-lysine to yield a stable and non-pyrogenic nanoparticle suspension. Due to their ferrimagnetic behavior, high crystallinity and chain arrangement, these magnetosomes coated with poly-l-lysine (M-PLL) are characterized by a higher heating power than their chemically synthesized counterparts currently used in clinical trials. M-PLL-enhanced antitumor efficacy was demonstrated by administering 500–700 μg in iron of M-PLL to intracranial U87-Luc tumors of 1.5 mm³ and by exposing mice to 27 magnetic sessions each lasting 30 min, during which an alternating magnetic field of 202 kHz and 27 mT was applied. Treatment conditions were adjusted to reach a typical hyperthermia temperature of 42 °C during the first magnetic session. In 100% of treated mice, bioluminescence due to living glioblastoma cells fully disappeared 68 days following tumor cell implantation (D68). These mice were all still alive at D350. Histological analysis of their brain tissues revealed an absence of tumor cells, suggesting that they were fully cured. In comparison, antitumor efficacy was less pronounced in mice treated by the administration of IONP followed by 23 magnetic sessions, leading to full tumor bioluminescence disappearance in only 20% of the treated mice.
We have simulated the rise in temperature (ΔT) of uniaxial single domain nanomagnets (particle size r) placed under alternating (AC) magnetic field (frequency ω) in 'r-ω' plane. Based on this, a phase space of 'ΔTmax-r-ω' has been constructed. This phase space suggests two bio-compatible ferrites namely Fe3O4 and MnFe2O4 which may generate necessary temperature for hyperthermia effect. Our simulated results further show that introduction of particle size distribution drastically reduces the efficiency of heat generation. On the other hand, introduction of inter-particle magnetic dipolar interactions may enhance the temperature rise.
Characterizing the orientation of covalently conjugated proteins on nanoparticles, produced for in vitro and in vivo targeting, though an important feature of such a system, has proved challenging. Although extensive physicochemical characterization of targeting nanoparticles can be addressed in detail, relevant biological characterization of the nano-interface is crucial in order to select suitable nanomaterials for further in vitro or in vivo experiments. In this work we adopt a methodology using antibody fragments (Fab) conjugated to gold nanoparticles (immunogold) to map the available epitopes on a transferrin grafted silica particle (SiO2 - PEG8 - Tf) as a proxy methodology to predict nanoparti-cle biological function; and therefore cellular receptor engagement. Data from the adopted method suggest that, on average, only ~3.5 % of proteins grafted on the SiO2 - PEG8 - Tf nanoparticle surface have a favorable orientation for recognition by the cellular receptor.
Magnetic hyperthermia is a new type of cancer treatment designed for overcoming
resistance to chemotherapy during the treatment of solid, inaccessible human tumors. The main
challenge of this technology is increasing the local tumoral temperature with minimal side
effects on the surrounding healthy tissue. This work consists of an in vitro study that compared
the effect of hyperthermia in response to the application of exogenous heating (EHT) sources
with the corresponding effect produced by magnetic hyperthermia (MHT) at the same target
temperatures. Human neuroblastoma SH-SY5Y cells were loaded with magnetic nanoparticles
(MNPs) and packed into dense pellets to generate an environment that is crudely similar to that
expected in solid micro-tumors, and the above-mentioned protocols were applied to these cells.
These experiments showed that for the same target temperatures, MHT induces a decrease in cell
viability that is larger than the corresponding EHT, up to a maximum difference of
approximately 45% at T = 46°C. An analysis of the data in terms of temperature efficiency
demonstrated that MHT requires an average temperature that is 6°C lower than that required with
EHT to produce a similar cytotoxic effect. An analysis of electron microscopy images of the
cells after the EHT and MHT treatments indicated that the enhanced effectiveness observed with
MHT is associated with local cell destruction triggered by the magnetic nano-heaters. The
present study is an essential step toward the development of innovative adjuvant anti-cancer
therapies based on local hyperthermia treatments using magnetic particles as nano-heaters.
Chitosan nanoparticles (CSNPs) ionically crosslinked with tripolyphosphate salts (TPP) were employed as nanocarriers in combined drug delivery and magnetic hyperthermia (MH) therapy. To that aim, three different ferrofluid concentrations and a constant 5-fluorouracil (5-FU) concentration were efficiently encapsulated to yield magnetic CSNPs with core-shell morphology. In vitro experiments using normal cells, fibroblasts (FHB) and cancer cells, human glioblastoma A-172, showed that CSNPs presented a dose-dependent cytotoxicity and that they were successfully uptaken into both cell lines. The application of a MH treatment in A-172 cells resulted in a cell viability of 67-75% whereas no significant reduction of cell viability was observed for FHB. However, the A-172 cells showed re-growth populations 4 hours after the application of the MH treatment when CSNPs were loaded only with ferrofluid. Finally, a combined effect of MH and 5-FU release was observed with the application of a second MH treatment for CSNPs exhibiting a lower amount of released 5-FU. This result demonstrates the potential of CSNPs for the improvement of MH therapies.
Superparamagnetic iron oxide nanoparticles (SPIO NPs), utilized as carriers are attractive materials widely applied in biomedical fields, but target-specific SPIO NPs with lower toxicity and excellent biocompatibility are still lacking for intracellular visualization in human brain tumor diagnosis and therapy. Herein, bovine serum albumin (BSA) coated superparamagnetic iron oxide, i.e. γ-Fe2O3 nanoparticles (BSA-SPIO NPs), are synthesized. Tumor-specific ligand folic acid (FA) is then conjugated onto BSA-SPIO NPs to fabricate tumor-targeted NPs, FA-BSA-SPIO NPs as a contrast agent for MRI imaging. The FA-BSA-SPIO NPs are also labeled with fluorescein isothiocyanate (FITC) for intracellular visualization after cellular uptake and internalization by glioma U251 cells. The biological effects of the FA-BSA-SPIO NPs are investigated in human brain tumor U251 cells in detail. These results show that the prepared FA-BSA-SPIO NPs display undetectable cytotoxicity, excellent biocompatibility, and potent cellular uptake. Moreover, the study shows that the made FA-BSA-SPIO NPs are effectively internalized for MRI imaging and intracellular visualization after FITC labeling in the targeted U251 cells. Therefore, the present study demonstrates that the fabricated FITC-FA-BSA-SPIO NPs hold promising perspectives by providing a dual-modal imaging as non-toxic and target-specific vehicles in human brain tumor treatment in future.
Purpose:
The blood-retina barrier (BRB) is a biological barrier consisting of tightly interconnected endothelial cells inside the retinal vascular network that protects the neural tissue from harmful pathogens and neurotoxic molecules circulating in the bloodstream. Unfortunately, with regard to retinoblastoma, this barrier also prevents systemically administered therapeutics reaching the retinal tissue. In this study we introduce a novel technique to locally and transiently increase BRB permeability for drug delivery using hyperthermia of magnetic nanoparticles (MNPs).
Materials and methods:
An alternating current (AC) magnetic field was used to induce hyperthermia of locally injected MNPs in the left ophthalmic artery of a rat model. To improve adherence on the surface of the endothelium, commercially available MNPs coated with human transferrin glycoproteins were used. After hyperthermia we assessed the extravasation of systemically injected sodium fluorescein (NaF) as well as Evans blue dye (EBD) into the retinal tissue.
Results:
Spectrofluorometry and fluorescent microscopy image analysis show a significant increase of dye penetration in the retina where hyperthermia of MNPs was applied.
Conclusions:
Our proposed new technique can allow both small and large dye molecules to cross the BRB. While the results are preliminary and thorough evaluation of the retinal tissue following hyperthermia is necessary, this technique has the potential to be an effective mean for the treatment of various diseases such as retinoblastoma.
In this paper we investigate the ability of zinc rich ferrite nanoparticles to induce hyperthermia on cancer cells using an alternating magnetic field (AMF). First, we synthesized ferrites and then we analyzed their physico-chemical properties by transmission electron microscopy, X-ray diffraction and magnetic and magnetocalorimetric measurements. We found that the polyol-made magnetically diluted particles are of 11 nm in size. They are superparamagnetic at body temperature (310 K) with a low but non-negligible magnetization. Interestingly, as nano-ferrimagnets they exhibit a Curie temperature of 366 K, close to the therapeutic temperature range. Their effect on human healthy endothelial (HUVEC) and malignant glioma (U87-MG) cells was also evaluated using MTT viability assays. Incubated with the two cell lines, at doses ≤100 µg.mL−1 and contact times ≤4 h, they exhibit a mild in vitro toxicity. In these same operating biological conditions and coupled to AMF (700 kHz and 34.4 Oe) for 1 h, they rapidly induce a net temperature increase. In the case of tumor cells it reaches 4 K, making the produced particles particularly promising for self-regulated magnetically-induced heating in local glioma therapy.
In this study we evaluate the thermosensitivity of healthy endothelial cells (HUVEC) and malign gioblastom (U87-MG) to magnetic hyperthermia (ac-magnetic field of 700 kHz, 23.10 kA.m-1) for 1 hour with and without the presence of superparamagnetic 10 nm sized polyol-made γ-Fe2O3 nanoparticles (NPs). Interestingly, despite their reduced size, NPs exhibit a high magnetization, close to that of the bulk material, in relation with their high crystalline quality. In practice, they ensured an efficient heating capacity, leading to about 20 % and more than 50 % cell death of HUVEC and U87-MG lines, respectively, when hyperthermia assays were achieved in presence of these NPs. Magnetophoresis and X-Ray fluorescence spectrometry measurements evidenced a more important internalization of NPs in U87-MG than in HUVECs. Surprisingly both cell lines reached the same maximal temperature, namely 42°C, after hyperthermia treatment suggesting a higher thermosensitivity of the former compared to the latter, establishing the fact that polol-madeγ-Fe2O3 NPs assisted hyperthermia is a harmful agent to glioma treatment.
The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. Herein, we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific targeting before and after ionizing irradiation. In vitro experiments demonstrated the selectivity of SPION-cmHsp70.1 conjugates to free and mHsp70 in different tumor cell types (C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI (11 T) on T2-weighted images showed the retention of the conjugates in the C6 glioma model. Accumulation of SPION-cmHsp70.1 nanoparticles in the glioma resulted in a nearly 2-fold drop of values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M2 measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of SPION-cmHsp70.1 conjugates in glioma-bearing rats in comparison to SPIONs. This accumulation within Hsp70-positive glioma was further enhanced after a single dose (10 Gy) of ionizing radiation. Elevated accumulation of the magnetic conjugates in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors.
In this review, Neuropilin-1 (NRP-1) has been focused as a novel molecular target for potential treatment of gliomas. The properties of NRP-1 were described briefly. The role of NRP-1 in gliomas was explored in details, including relationships of NRP-1 expression and glioma prognosis, Sema3A-NRP-1 signaling in gliomas, NRP-1 signaling and VEGF/VEGFR、PlGF、TGF-β、PDGF、LD22-4 of FGF2、autocrine of HGF/SF、p130Cas tyrosine phosphorylation and integrin-associated tumor microenvironment in gliomas, NRP-1 intracellular trafficking, NRP-1 and glioma stem-like cells, as well as magnetic nanoparticles related to targeting gliomas. NRP-1, a multifunctional-receptors protein, would mediate diverse cellular signaling pathways in gliomas, and might potentially act as a novel therapeutic target. In future, magnetic nanoparticles coated with NRP-1 may play a vital role on diagnosis and therapy of gliomas.
Glioblastoma multiforme (GBM) is the most common and malignant brain tumor. Current standard treatment for GBM following maximum safe resection includes temozolomide (TMZ) with concurrent radiotherapy. Despite the improvement of survival by TMZ and radiation, the overall prognosis remains poor for GBM patients. This is partially attributed to drug resistance. Expression of DNA repair protein O6-methylguanine methyltransferase (MGMT) in gliomas confers TMZ resistance and a worse prognosis. Therefore, development of novel therapy to suppress MGMT expression and overcome TMZ resistance is highly desired. Hyperthermia has been shown to increase TMZ sensitivity in melanoma and this provides a good rationale to evaluate whether hyperthermia overcomes TMZ resistance in glioblastoma cells.
In this study, we investigated the effect of hyperthermia treatment (43
°C) on TMZ sensitivity of four human glioblastoma cell lines using clonogenic assays. Our results showed that hyperthermia treatment increased TMZ-induced cell death in TMZ-resistant glioma cells, but had no additional beneficial effect in the TMZ-sensitive cells. Hyperthermia in combination with radiation further overcame TMZ resistance. To study the molecular targets, we found that hyperthermia downregulated MGMT expression through increasing proteasome-mediated MGMT degradation, which can be reversed by the proteasome inhibitor bortezomib. Hyperthermia had no effects on p53 expression and MGMT promoter methylation which was responsible for MGMT gene silencing. In addition, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed an increase of TMZ and its downstream product 5-aminoimidazole-4-carboxamide (AIC) in hyperthermia-treated cells, indicating an increase of TMZ drug uptake and breakdown.
In conclusion, these results suggest that hyperthermia overcomes MGMT-mediated resistance of glioblastoma cell lines to TMZ and increases TMZ drug uptake. This study suggests a potential benefit of using hyperthermia in the treatment of GBM, particularly those with more adverse prognosis.
This work was supported by Debrule Research Fund.
Citation Format: Chen-Ting Lee, Aaron Blackley, Chelsea Landon, Ivan Spasojevic, John P. Kirkpatrick, Mark W. Dewhirst. Hyperthermia treatment overcomes temozolomide resistance in glioma cells by downregulating MGMT expression and increasing temozolomide uptake. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3774. doi:10.1158/1538-7445.AM2014-3774
Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the ClinicalTrials.gov registry.
The records of 175,538 clinical trials registered at ClinicalTrials.gov were downloaded on 29 September 2014 and a database was established. We searched this database for hyperthermia or equivalent words.
A total of 109 trials were identified in which hyperthermia was part of the treatment regimen. Of these, 49 trials (45%) had hyperthermic intraperitoneal chemotherapy after cytoreductive surgery (HIPEC) as the primary intervention, and 14 other trials (13%) were also testing some form of intraperitoneal hyperthermic chemoperfusion. Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural n = 4, limb n = 2, hepatic n = 1). Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%) interstitial hyperthermia. One remaining trial tested laser hyperthermia.
In contrast to the general opinion, this analysis shows continuous interest and ongoing clinical research in the field of hyperthermia. Interestingly, the majority of trials focused on some form of intraperitoneal hyperthermic chemoperfusion. Despite the high number of active clinical studies, HIPEC is a topic with limited attention at the annual meetings of the European Society for Hyperthermic Oncology and the Society of Thermal Medicine. The registration of on-going clinical trials is of paramount importance for the achievement of a comprehensive overview of available clinical research activities involving hyperthermia.
Magnetization relaxation mechanisms strongly influence how magnetic nanoparticles respond to high-frequency fields in applications such as magnetic hyperthermia. The dominant mechanism depends on the mobility of the particles, which will be affected in turn by their microenvironment. In this study AC susceptometry was used to follow the in situ magnetic response of model systems of blocked and superparamagnetic nanoparticles, following their cellular internalization and subsequent release by freeze-thaw lysis. The AC susceptibility signal from internalized particles in live cells showed only Néel relaxation, consistent with measurements of immobilized nanoparticle suspensions. However, Brownian relaxation was restored after cell lysis, indicating that the immobilization effect was reversible and that nanoparticle integrity was maintained in the cells. The results presented demonstrate that cellular internalization can disable Brownian relaxation, which has significant implications for designing suitable nanoparticles for intracellular hyperthermia applications. Further to this, the results highlight the possibility that particles could be released in reusable form from degrading cells following hyperthermia treatment, and subsequently reabsorbed by viable cells.
