Evolution of Magnetic Hyperthermia for Glioblastoma Multiforme

Subscriber access provided by TULANE UNIVERSITY

Review

Evolution of Magnetic Hyperthermia for Glioblastoma Multiforme Therapy Ruby Gupta, and Deepika Sharma ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00652 • Publication Date (Web): 04 Feb 2019 Downloaded from http://pubs.acs.org on February 5, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Chemical Neuroscience

Evolution of Magnetic Hyperthermia for Glioblastoma Multiforme Therapy Ruby Guptaa and Deepika Sharmaa,* aInstitute

of Nano Science and Technology, Habitat Centre, Phase-10, Sector-64,

Mohali, Punjab-160062, India *Corresponding

author

Ruby Gupta M. Res (Cancer Biology) Ph.D. Scholar, INST, Mohali Dr. Deepika Sharma* Ph.D. Scientist, INST, Mohali Tel: +91-9888582534 Email ID: [email protected]

ACS Paragon Plus Environment

1

ACS Chemical Neuroscience 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 56

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. Keywords: Magnetic Hyperthermia, Glioblastoma, Blood-Brain Barrier, Combinatorial Therapy, Magnetic nanoparticles.


2

Page 3 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1. Introduction Understanding the biological phenomena underlying the generation of cancerous growth in the central nervous system (CNS), as well as the design and development of therapies against these tumors has been a major challenge in the fight against these tumors. Brain tumors represent 1.8% of all cancers, although relatively rare they cause significant morbidity and mortality[1]. The tumors originating from the glial cells of the brain are termed as gliomas which account for total of nearly 24.7% of all primary brain tumors and 74.6% of all malignant tumors. Glioblastoma (GBM) is the most frequent and malignant glioma, accounting for 55.4% cases[2]. Despite advances in its diagnostics and therapeutics, their prognosis remains dismal. The development of new effective therapies is therefore urgently needed. Hyperthermia, a therapeutic therapy based on generation of heat at the tumor site in order to cause alterations in the cellular machinery has emerged as a potential therapeutic tool over the years for effective cancer therapy. Its mode of action is based on the fact that a temperature rise from 37C to 42C-45C can induce tumor cell death by triggering activation of certain intracellular and extracellular degradation mechanisms[3,4]. Various methods can be employed to achieve this hyperthermic effect in tumor tissues, namely ultrasound, electromagnetic radiation (using radiofrequency or microwave), laser or magnetic nanoparticles (summarized in Table 1). Table 1: Modes of hyperthermia therapy tested for GBM. Type of

Heat

Hyperthermia

Source

Thermal

Heated

conduction

water

Advantages

Disadvantages

Reference

-

Heat penetration

[5]

upto only 3–5 mm

Radiation

Radiowaves Moderate penetration

Non-specific

[6]

temperature rise of surrounding healthy tissues

Ultrasound

Pressure

Optimization

Limited

waves

of penetration

application in


[7,8]

3


capability by

anatomic body

altering

locations

Page 4 of 56

frequency of the waves Microwave

-

Moderate

Low diffusion

penetration

of heat to target

[9,10]

tissues Magnetic

Alternating

hyperthermia

magnetic field

Deep

Toroidal heating

penetration

pattern and low

[11-13]

magnetic energy absorption

The application of magnetic nanoparticles (MNPs) for magnetic hyperthermia for desired therapeutic effect in cancer therapy is known as magnetic hyperthermiamediated cancer therapy (MHCT) and was first attempted as a cancer therapy in

Figure 1: Emergence of magnetic hyperthermia-mediated cancer therapy over the years. Data collected from Google Scholar (10 March 2018).

1957[14]. The technique involves localisation of magnetic materials within the tumor site followed by subsequent application of an alternating magnetic field (AMF), which generates heat at the tumor site[15]. At present, MHCT is presented as a non-invasive promising therapy system, efficient in implementing hyperthermia in deep-seated and inaccessible tumors with high specificity[16]. The emergence of MHCT since its advent


4

Page 5 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


in 1950’s is shown in Figure 1. It clearly shows the increasing interest in the potential of MHCT among the researchers worldwide in the fight against cancer. However, despite more recent advancements, MHCT has still not become part of the standard of care for cancer treatment. Precise temperature measurement within the tumor tissues and controlled heating of the tumors presents a challenge for widespread application of MHCT as a treatment modality for cancer. In continuation of our work on MHCT[17] this article gives an overview of MHCT as a therapeutic modality for GBM both alone or in combination with other adjuvant therapies. Its therapeutic efficacy, current limitations, possible areas of improvement, and future directions have been further discussed in depth. The limitations of various therapy systems for GBM have been discussed with reference to MHCT. 1.1 Limitations of magnetic hyperthermia in cancer therapy Although MHCT is come out to be a very promising approach for cancer treatment, as discussed in this paper, certain limitations of MHCT have come to the forefront that limits the use of MHCT to ex vivo and animal levels to a greater extent for GBM therapy. These general limitations include: (i) Safety, effectiveness and suitable dose of the MHCT which remain unknown. This includes the amount of the magnetic nanomaterials administered, magnetic parameters selection and magnetic field strength applied which can be the major factors responsible for low magnetic performance. (ii) Delivering effective quantities of drugs into the targeted glioma cells through clinically feasible methods represents a major challenge. Majority of the small-drug molecules are incapable of penetrating through the blood-brain barrier (BBB), which significantly hampers the delivery of drugs to the tumor site. (iii) Several physical limitations further affect the performance of hyperthermia therapy which are heat distribution, the degree of toxicity, efficiency of using magnetic nanotranducers and the reduced hyperthermia performance of MNPs in cellular environment i.e. once they are internalized by cells (aggregation in endolysosomes phenomena) which significantly affects the dose and efficiency of the therapy[18-19]. (iv) The lack of precise methodologies to accurately measure the local temperature rise achieved in the area of application in vivo system pose another hinderance for estimating the hyperemia out of these MNPs[20-21]. (v) Highly specific targeting of MNPs to tumor cells is also one of the major challenges faced for GBM therapy. According to a recent metaanalysis report, only less than 1%


5


Page 6 of 56

of the injected particles are typically found to be accumulated at the tumor site[22]. In this regard, the use of targeting strategies to attach specific moieties onto the surface of nanomaterials has also emerged as an important area of research. However, only for some techniques, 4% of the attached targeting moieties are favorably oriented for recognition by their targeted receptors, which can lead to heterogenous and poor outcomes[23]. (vi) In addition to this, the poor translation of targeting strategies from bench to bed-side is another factor responsible for the slow translation of nanotechnology-based therapies to the clinics, MHCT in particular. A study reports, the accumulation of antibodies in xenograft models in mice to vary typically between 0.550% of the injected dose (ID) per gram of tumor tissue[24]. However, in contrast, it is observed that the accumulation of antibodies in human tumors is less than 0.01% ID per gram of tumor tissue[25]. Hence the route of administration of MNPs into brain tumor tissues becomes one of the most challenging parameter to optimize the actual magnetic content localized in the tumor microenvironment for achieving desired therapeutic effect mediated by MHCT. 2. Application of MHCT for GBM Therapy Due to the various drawbacks, the ability to use single therapy module for GBM patients is limited. Still, in our next section, we have highlighted the potential of MHCT as a therapy system either alone or in conjugation with other therapies with particular reference to GBM. 2.1 Hyperthermia alone The application of magnetic materials to promote MHCT for inductive heating of lymph nodes selectively was first attempted as a cancer therapy by Gilchrist et al., in 1957[14]. The study reported that lymph nodes could be heated with a 1.2 MHz magnetic field of strength 200-240 Oe, to kill lymphatic metastases after the administration of 20-100 nm sized Fe2O3 nanoparticles with a temperature rise of 14°C achieved. As the study reported no control experiments, much of the temperature rise observed could be attributed directly to the induced electric field produced as a result of high frequency application rather than through magnetic hyperthermia.


6

Page 7 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Since then, many studies have reported the use of hyperthermia for potential application in pre-clinical and clinical stages as discussed below. In this section, we have discussed the application of MHCT alone for GBM treatment. 2.1.1

In-vitro applications One of the main advantages of MHCT over other anti-cancer therapies is the selective thermosensitivity of tumor cells than their healthy counterparts on application of AMF in the former case[26]. Temperatures greater than 42°C results in irreversible damage to the cancer cell respiration causing their apoptosis, whereas by contrast, the healthy cells normally require much higher temperature (55°C) for this same heat sensitivity. This thermo-specificity has led to extensive investigation and use of hyperthermia as a potential tumor therapy. One such study reports selective thermosensitivity of malignant glioma (U87-MG) cells, in comparison to healthy endothelial cells (HUVEC), towards MHCT (AMF of 700 kHz, 289.67 Oe) for 1 hour on treatment with superparamagnetic polyol-made -Fe2O3 nanoparticles (NPs).

Figure 2: Schematic representation of exogenous hyperthermia (EHT) versus magnetic hyperthermiamediated cancer therapy (MHCT).


7


Page 8 of 56

Application of MHCT in presence of the nanoparticles, caused about 50% cell death of U87-MG cell lines in comparison to 20% cell death of HUVEC cells[27]. Many studies also report that to achieve higher specific absorption rate (SAR) values for magnetite-based nanomaterials it is essential to enhance the magnetic properties of nanoparticles, including saturation magnetization and anisotropy energy constant, by doping at the optimum level[17,28,29]. In one such study, the ability of zincdoped ferrite nanoparticles to induce hyperthermia in U87-MG glioma cells was checked using an AMF (700 kHz and 34.4 Oe) for 1 h[30]. On incubation with glioma cells for 4 h at 50 g/ml concentration, 41.5°C temperature was achieved which is often enough to induce cell death in malignant cells. The hyperthermic effect observed in response to the application of AMF for MHCT with the corresponding effect produced by hyperthermia-mediated by exogenous heating (EHT) sources at the same target temperatures have also been compared (Figure 2). A study conducted on human neuroblastoma SH-SY5Y cells revealed the superior capability of MHCT on the application of magnetic nano-heaters to produce a similar cytotoxic effect at 6°C lower temperature than the one required for treatment employing water bath as the EHT source[31]. A similar comparative study has also been conducted to determine the extent of microglial BV2 cell damage as a consequence of heat treatment given by EHT and MHCT (T = 46°C for 30 min). The cell morphology analysis post MHCT revealed significant alterations of the cell membrane which was correlated to the nanomagnetic clusters, while local cell damage was less apparent after EHT treatment without the MNPs addition[32]. Not only for GBM therapy, this superior cytotoxic effect of MHCT in comparison to traditional heating system (EHT) has also been reported for other biological systems like planktonic and biofilm cells[33-34], and other human cancer cells including epithelial colorectal adenocarcinoma (Caco-2) and breast cancer (MCF-7)[35]; osteocarcoma cells[36]. For MHCT applications, the nanoparticle size plays an important influential factor role to tune the magnetic as well as hyperthermic efficiency of the nanosystems. For use in biomedical applications, MNPs with small diameter (10–100 nm size range) and narrow size distribution are preferred to prevent their rapid clearance from the systemic


8

Page 9 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


circulation by the reticuloendothelial system[37]. Due to the high surface area to volume ratio, van der Waals attractive forces and the strong dipole–dipole interactions, the MNPs tend to agglomerate resulting in increased particle size and reduced magnetic properties. As a consequence, the high polydispersity of the nanoparticles size reduces the magnetic heating capability of the MNP systems. Surface coating of the nanoparticles has shown to prevent aggregation and may contribute to colloidal stability by steric and/or electrostatic repulsion[38]. To this end, numerous coating materials have been reported till date, such as inorganic materials (e.g., alumina, silica), polymers (e.g., dextran, chitosan, polyethylene glycol, stevioside), fatty acids (e.g., oleic acid) and liposomes[38,39]. Table 2 below lists the MNP systems designed for use in MHCT for GBM.


9

ACS Chemical Neuroscience 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

Page 10 of 56

Table 2: Designs of MNP systems for use in in-vitro MHCT for GBM. AMF

Time of AMF

MNP/Coating

Amount

Cell

f

H

exposure

Temperature

Reference

[Size]

of MNP

line

(kHz)

(Oe)

(minutes)

achieved (C)

T-9

118

383.72

60

42.6

[40]

T-9

118

383.72

30

42.0

[41]

M059K

297

225.72

5

63

[42]

700

289.67

60

42.0

[27]

700

289.67

60

41.5

[30]

added 1

Fe3O4/TMAG,

7.2

DLPC, DOPE

mg/mL

(1:2:2) [35 nm] 2

Fe3O4/TMAG,

100

DLPC, DOPE

g/mL

(1:2:2) [35 nm] 3

Fe3O4/PEGM

7.93

MA-

mg/mL

PEGDMA [20-30 nm] 4

-

50

U87-

Fe2O3/Polyol

g/mL

MG

Zn0.9Fe2.1O4

50

U87-

[11 nm]

g/mL

MG

[10 nm] 5


10

Page 11 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46


6 7 8

570

299.71

30

46.0

[31]

BV-2

570

299.71

30

46.0

[43]

1 mg/mL

GL-261

198

339.83

30

T = 11.8

[44]

Fe3O4/Steviosi

100

C6

405

168

30

43

[45]

de

g/mL

MNPs/PEI

100

SH-

g/mL

SY5Y

Fe3O4@Fe2O

100

3/Polyphenol

g/mL

Magnetosome/ Chitosan

9

[4.62 nm] (TMAG - N-(a-trimethylammonio-acetyl)-didodecyl-D-glutamate chloride; DLPC - dilauroyl phosphatidylcholine; DOPE - dioleoyl phosphatidyl- ethanolamine; PEGMA poly(ethylene glycol) methacrylate; PEGDMA - poly(ethylene glycol) dimethacrylate; T – rise in temperature on AMF application)

F


F i g u r e 2 : C o r r e l a t i

11


Page 12 of 56

A study reports use of human-like collagen protein-coated MNPs (HLC-MNPs) as model systems to evaluate the size and surface effects on the hyperthermic efficiency[46]. The results indicated rapid heating capacity of HLC-MNPs on exposure to AMF as compared to the uncoated MNP systems, irrespective of the size of MNPs. Such behavior is attributed to the reduced agglomeration and enhanced stability with surface coating of the MNPs. Most studies have reported the use of magnetite-coated cationic liposomes (MCL) for MHCT owning to their enhanced cellular affinity than their neutral counterparts due to their electrostatic interaction with the negatively charged phospholipids in the cell membrane[12,27,28]. The hyperthermia efficiency on application of AMF was investigated for use in T-9 glioma cells[40]. The observed temperature rise in 20 minutes was 42.6°C. Cell viability was found to decrease on AMF application, achieving 100% cell death after 40 min of AMF exposure. Temperature measurements were done using an optical fiber thermometer (FX-9020; Anritsu Meter Co., Ltd., Tokyo). In our lab, we are working on different coating materials to prevent agglomeration of MNPs. The result of one of the coating material is mentioned in Box 1. With citric acid coating onto magnetic nanoparticles, we have observed approximate 27C rise in temperature on AMF application of 405 kHz at 168 Oe for 20 min. We have also determined the change in thermal profile of the MNPs as a function of magnetic field and frequency applied (Box 1). Application of magnetic gel composites consisting of MNPs embedded into polymer hydrogel matrices represents another interesting approach for MHCT[47]. The ability of a polyethylene glycol-based hydrogel with MNPs to promote hyperthermia using M059K glioblastoma cells has been evaluated[42]. On application of the nanoparticles-loaded hydrogels, cell death due to thermal ablation (63°C) was observed particularly in the plate region, but no death was observed in the surrounding region. Such systems have also been evaluated for dual hyperthermia and drug delivery[48,49].


12

Page 13 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Box 1: Thermal profile of citric acid-coated MNPs (observed in our lab).

Effect of frequency (A) at a fixed field of strength 168 Oe and variation in magnetic field at a fixed frequency of 405 kHz on total degree rise by citric acid-coated MNPs on AMF application of 405 kHz and 168 Oe for 20 min. The region-shaded blue represents the hyperthermia therapeutic window required for cancer therapy (58C).

Heat shock (elevated temperature) has been known to induce the expression of a set of heat shock proteins (HSPs) that act as molecular chaperons to protect proteins from thermal denaturation and to assist in protein refolding, inducing thermotolerance in the cells[50,51]. These HSPs have been found to play a vital role in providing thermoresistance to cancer cells against MHCT with HSP 27, 70, 73, and 90 been identified as key constitutively overexpressed HSPs in gliomas[52,53]. The details of some of these HSPs active in GBM is mentioned in Box 2. In a study, hyperthermia in addition to cell lysis was reported to activate HSP70 which results in an antitumor immune response[41]. Another study reported the use of NVP-HSP990- HSP90 inhibitor, to sensitize the U251 GBM cells to both hyperthermia and ionizing radiation by arresting the cells at the G2/M checkpoint, mitotic catastrophe and associated apoptosis[58]. Moreover, novel immunotherapeutic agents have also been used to specifically target glioma cells by inducing immune response against these tumor-specific overexpression of HSPs. A study reports exploiting the readily internalization property of membrane-bound HSP70 (mHSP70) by conjugating the superparamagnetic iron oxide nanoparticles (SPIONS) with Hsp70-specific antibody (cmHsp70.1) which is


13


Page 14 of 56

capable of recognizing the mHsp70[59]. The selectivity of SPION-cmHsp70.1 conjugates to free and mHsp70 in C6 glioma cell line was demonstrated in a dosedependent manner. The SPION-cmHsp70.1 conjugates exhibited approximate 7-fold increase in the tumor-to-normal brain uptake ratio as compared to SPIONs alone in the glioma-bearing rats. 2.1.2

In-vivo applications After approximate four decades of introduction of MHCT for in vitro anticancer studies, the effectiveness of MHCT in models of gliomas was first reported by Yanase and group in 1997[60]. The study involved subcutaneous injection of T-9 glioma cells pre-incubated with magnetite-coated cationic liposomes (MCL) in Fisher F344 rat models. After 20 minutes of AMF application, the temperature rise of 43°C-45°C was observed with rectal temperature maintained between 35°C-36.5°C. The temperature was monitored using an optical fiber thermometer inserted under the skin of the tumor model. Three sessions of AMF application for 60 minutes each with intervals of 12 hours, exhibited complete tumor growth inhibition in animal models for a period of 90 days. In another study, similar results were obtained; however, this time the MCLs were injected in the tumor (already previously developed in Fisher rats) using a 25 gauge needle through an infusion pump (SP100i; World Precision Instruments Inc., Sarasota, FL, USA)[61]. After 15 minutes of AMF exposure, the maximum temperature observed in the tumor tissue reached 44°C, with rectal temperature maintained at 35°C-37°C. The treatment group exposed to three cycles of AMF application for 30 minutes each with intervals of 24 hours showed tumor reduction of 87.5%. Histological analysis revealed homogenous distribution of MCLs (coincided with necrotic regions) in groups receiving AMF treatment as compared to the control groups in which the MCLs were found to be restricted to the area of administration only. In the same year, Yanase and group investigated the hyperthermia-induced antitumor immune response in the same tumor model as mentioned above (T-9)[62]. However, this time, tumor was induced on both sides of the model while MCL was injected via a needle (size: 25 gauge) by means of the infusion pump (SP100i; World Precision Instruments Inc., Sarasota, FL, USA) only in the tumor on the left side. The temperature in the tumor tissues reached 43°C on AMF exposure for 10 mins. The


14

Page 15 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


treatment group receiving three applications of magnetic irradiation for 30 min each in 24 hours, showed complete tumor regression on the left side. The complete tumor regression was also observed on the right side even though it didn’t receive any MCL application. The presence of immunocytes (CD3, CD4, CD8 and natural killer cells) in the cancerous tissues on both sides of the treatment group was confirmed by the histological analysis. After AMF exposure, the treated rats were injected again with T-9 cells and also with malignant fibrous histiocytoma (MFH) cells. However, the models showed development of MFH cell tumors only, suggesting generation of a specific immune response of the tissues against T-9 cells. The same hyperthermia-triggered antitumor immune response was confirmed in F344 rats by Shinkai and group[63]. Soon after T-9 cells tumor growth in Fisher rats, MCL were injected via a needle (size: 25 gauge) by means of an infusion pump (SP100i; World Precision Instruments Inc., Sarasota, FL, USA). After 24 h of MCL injection, AMF was applied for 15 mins and the maximum temperature achieved in tumor was observed to be 44°C. The rectum and tumor temperatures were measured using an optical fiber probe (FX-9020; Anritsu Meter Co., Ltd., Tokyo). Further the study reported that the treatment group receiving AMF for 30 mins exhibited complete tumor regression on repeated MHCT cycles. After regression, no recurrence was observed for a time period of 3 months. Majority of the injected MCL (80% to 90%) were found to be accumulated in the tumor tissues. It was suggested that tumor regression and non-recurrence were due to immune response activation by hyperthermia. The magnetic thermotherapy has been made more specific by conjugating the magnetic nano-heaters with tumor-specific moieties like tumor-specific antigens, antibodies, etc (Table 3). In addition to conferring specificity, such surface modifications of the particles also enhance the biocompatibility of these nanomaterials. Le et al. demonstrated one such approach, in 2001 by coupling Fab fragment of a specific antibody for tumors with MCL to enhance their effectiveness in the destruction of tumor growth in mice with human glioma cells (U251-SP)[77]. Table 3: Examples of antigens and antibodies used to functionalize MNPs to enhance their glioma cell-specific uptake. Targeting agent

MNPs


Reference

15


Page 16 of 56

Antigens Used 1

Lactoferin

Poly(maleic anhydride-alt-1-

[64]

octadecene)-Iron oxide nanoparticle (PMAO-IONP) Polydiacetylene nanocarriers-SPIONs

2

Arginylglycylaspartic

RGD-labeled ultrasmall

acid (RGD) peptide

superparamagnetic iron oxide

[65]

[66]

(USPIO)

3

Neuropilin-1 (NRP-1)

4

Epidermal growth factor

IONPs

[67]

Dextran-Fe3O4

[68]

Dextran-Fe3O4

[69]

(EGF) 5

Interleukin-1 receptor antagonist (IL-1Ra)

6

Chlorotoxin

Chitosan-IONP

[70]

7

TAT peptide

Magnetosomes

[71]

SiO2@Fe3O4 8

Folic acid (FA)

Bovine serum albumin (BSA)-γ-

[72] [73]

Fe2O3 Antibodies Used 9

Anti-vascular endothelial

BSA-Fe3O4

[74]

IONP

[75]

Amphiphilic triblock copolymer-

[76]

growth factor (VEGF) antibodies 10

Anti-epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII)


16

Page 17 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


IONPs

11

Anti-Heat-shock protein

Dextran-Fe3O4

[59]

70 (cmHsp70-SPIONS)

Many researchers across the world have also compared the effect of different coatings on SPIONS. Jordan et al, compared the dextran- or aminosilane-coated ironoxide nanoparticles for their anti-tumor hyperthermia efficacy in RG-2-injected cells into the brains of Fisher rats[78]. The intratumoral MNP administration into the tumor region was done stereotactically under anesthesia through the burr hole created in the skull via a needle (23 gauge) using an infusion pump (Precidor, Infors AG, Basel, Switzerland). The proliferative rate of the cells was found to decrease with aminosilanecoated MNPs upon application of AMF of strength 100 kHz and 0-225.72 Oe. GarciasMontes reports the prospects of using functionalized magnetic microparticles with CD133 antigen in reducing the GBM growth in CT-2A tumoral cells grafted in the striatum of C57 mice model systems on MHCT application[79]. After intrastriatally injection of MNPs, the mice under study were subjected to AMF of 2508 Oe for 2 h daily for a period of 7 days, which resulted in 55% reduction in tumor area. Ohno et al. tested the efficacy of a new SPION, stick type carboxymethylcellulose (CMC)magnetite, for its heat generating capability in T-9 cell tumors developed in Fisher rat brains[80]. The implanted tumor mass was stereotactically pierced with 0.5 cm of CMCmagnetite stick. The temperature of the tumor tissue rose to 44.4°C as measured using an optical fiber thermometer probe (FX-9020; Anritsu Meter Co. Ltd., Tokyo, Japan), after AMF exposure of amplitude 88.9 kHz and 380 Oe, for 30 min a day, besides being widely distributed after three applications. Total tumor remission was observed only in one animal model in the group which received three sessions of MHCT. Recently, magnetosomes, synthesized by magnetotactic bacteria, have gained importance for their superior efficacy than the chemically synthesized counterparts for use in MHCT. The magnetosomes can give rise to homogenous temperature distribution within the cancerous tissues as they are not prone to aggregation. Alphandery and group have exploited the use of poly-L-lysine-coated magnetosomes


17


Page 18 of 56

(M-PLL) for hyperthermia treatment in glioma model[81–83]. The antitumor efficacy of these M-PLL particles has been studied and compared with chemically synthesized IONPs routinely employed for MHCT using a mouse allograft model of murine glioma (GL-261 cell line)[81]. The MHCT protocol involved 11-15 magnetic sessions of AMF application at 198 kHz and 110-310 Oe field strength for a duration of 30 mins. These M-PLL particles were further investigated for enhanced antitumor efficacy in intracranial U87-Luc tumors in mice where 27 magnetic sessions each lasting 30 min, and AMF of strength 202 kHz and 270 Oe was used to get a typical hyperthermia temperature of 42°C[84]. The M-PLL were directly injected into the brain of the mice. An optical fibre probe (Fluoroptic Temperature Probe, LumaSense Technologies, France) was used to monitor the tumor temperature at the site of M-PLL administration. While, an Infrared camera (EasIR-2, Optophase, France) positioned 20 cm above the coil was used to record the thermal distribution at the tumor surface. The absence of tumor cells in the histological analysis of the brain tissues suggested 100% cure rate for these mice. A detailed comparison of different MHCT protocols followed in GBM tumor models is summarized in Table 4. Overall the comparison of in vitro and in vivo MHCT studies (Table 3 and 4 respectively) in terms of strength and frequency of the oscillating magnetic field used, highlights the variability of the experimental conditions employed to measure the effect of MHCT for GBM therapy. This difference further complicates the comparison of hyperthermia output obtained from calorimetric measurement of MNP systems and that achieved in in vivo environment, thus misleading the hyperthermia therapy efficiency outcome.


18

Page 19 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2.2. Hyperthermia in conjugation with chemotherapy

Figure 3: Schematic representation of blood-brain barrier disruption by AMF application. The localized heat produced by MNPs on AMF application opens up the tight junction causing enhanced delivery of the payload.

The BBB acts as a biological barrier that hinders passage of the majority of chemotherapeutic agents to reach glioma cells via the brain blood vessels. This hindrance limits the therapeutic index of variety of traditional chemotherapeutics. Therefore, to date, chemotherapy for GBM has been used most effectively as an adjuvant to radiotherapy and surgery[88]. Lately, studies have reported that application of hyperthermia in combination with chemotherapy aids the drug-loaded nano-heaters to cross the BBB by temporarily impairing the permeability of the barrier and hence enhancing the amount of drug delivered at the desired tumor site, also maximizing the therapeutic efficiency of hyperthermia approach (Figure 3)[89-91]. One study reports the breakdown of BBB in a dog brain on exposure to 8 MHz radiofrequency interstitial hyperthermia for 60 min; achieving 43°C temperature[92]. Disruptions of the BBB via intra-arterial (IA) administration of osmotic agents like mannitol, has also been in practice since 1970s[93]. Administration of mannitol causes shrinkage of the endothelial cells and the subsequent opening of the tight junctions resulting in approximate 10-100 times increase in the drug delivery efficiency[94-96]. In a recent study, mannitol-functionalized MNPs were also synthesized as drug carriers for the anti-cancer drug, doxorubicin hydrochloride and as


19


Page 20 of 56

hyperthermia agents on application of AMF measured at 507 Oe and 300 kHz for 20 min[97].


20

Page 21 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46


Table 4: Comparative study of different MHCT treatment protocols used in glioma animal models. Cell line

MNP/ Size

Animal

(nm) [Amount

Injection site

No. of

Tumor

(Gender/Ag

cells

size

e)

inoculated

(mm)

Fe3O4/35

Fisher rats

Subcutaneously

[3 g/150 L]

(F-344)

at left femoral

(Female/7-8

region

Duration

No. of

Time

Combined

of AMF

AMF

between

therapy

(min)

cycles

AMF

Reference

f

H

(kHz)

(Oe)

3

118

384

30

3

24 h

-

[60]

1 x 107

13-18

118

384

30

1/2/3

24 h

-

[61]

1 x 107

13-18

118

384

30

3

24 h

-

[62]

1 x 107

13-18

118

384

30

3

24 h

-

[63]

2 x 105

10

118

384

30

3

24 h

-

[77]

administered] T-9

AMF

1x

104

treatments

weeks) T-9

Fe3O4/-

Fisher rats

Subcutaneously

[3 mg/400 L]

(F-344)

at left femoral

(Female/6-7

region

weeks) T-9

Fe3O4/10

Fisher rats

Subcutaneously

[3 mg/400 L]

(F-344)

at left femoral

(Female/6-7

region

weeks) T-9

Fe3O4/10

Fisher rats

Subcutaneously

[3 mg/400 L]

(F-344)

at both femoral

(Female/6-7

regions

weeks) U251-SP

G22 mAb-

KSN –nu/nu

Subcutaneously


21


Fe3O4/35

nude mice

at femoral

[500 g/100 L]

(Female/ 4

region

Page 22 of 56

weeks) U251-SP

Fe3O4/10

Athymic

Right flank

3 x 107

8

118

384

30

1

-

[3 mg/200 L]

nude mice

gene

(Female/ 4

therapy

TNF-

[85]

weeks) T-9

T-9

Carboxymethylc

Fisher rats

Stereotactically

ellulose (CMC)-

(F-344)

implanted in

Fe3O4/10

(Female/4

right cerebral

[N/I]

weeks)

hemisphere

Fe3O4/35

Fisher rats

Subcutaneous

[3 mg/400 L]

(F-344)

space

5 x 106

-

88.9

380

30

3

24 h

-

[80]

1 x 107

10

118

384

30

1/2/3

24 h

HSP70

[41]

gene

(Female/6

therapy

weeks) RG2

Dextran-IONP/3

Fisher rats

Subcutaneously

[1.8 mol/L] or

(F-344)

at area anterior

Aminosilane-

(Male)

of bregma

IONP/15

1 x 105

3-4

100

0-

40

1

-

-

[78]

20

1

-

-

[86]

226.2

region

[2.0 mol/L] C6

Dextran--

Wistar rats

Subcutaneously

Fe2O3/10-12

(Male)

at area anterior

[3 mg/150 L]

8 x 106

5-10

150

138.2

of bregma


22

Page 23 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46


region U

Fe3O4/35

2

[2.4 mg/300 L]

-

Subcutaneous

1 x 107

-

200

-

60

2

24 h

-

[87]

space

5 1


23


Page 24 of 56

Box 2: HSPs involved in GBM progression. HSP70

HSP90

HSP27

HSP73 or HSPA8

Cytosol and endoplasmic reticulum Expression levels increases by heat-stress Maintains expression of HSF1; stabilizes growth factor receptors and cell signaling proteins like PI3K and AKT; promotes angiogenesis

Cytosol, endoplasmic reticulum and nucleus Expression levels are upregulated by heat-stress Provides thermotolerance in vivo, cytoprotection, and supports cell survival under stress conditions by inhibiting procaspase-9 activation

Cytoplasm and lysosome

[56] 4MJH

[57] 3FZF

Structure*

Location

Cytosol, endoplasmic reticulum and mitochondria Expression Heat inducible Function

Protein refolding; protection against stress and Down-regulates HSF1 expression

Reference [54] [55] PDB ID 1S3X 2CG9 *The structures of the HSPs were obtained from Protein Data Bank (PDB).


Constitutive Regulates the nuclear accumulation of cyclin D1; binds to nascent polypeptides to facilitate correct protein folding

24

Page 25 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46



25


Page 26 of 56

The effect of heat on activity of various chemotherapeutic drugs has also been reported, such as supra-additive (alkylating agents, platinum compounds), threshold behaviour (doxorubicin), and synergistic (fluorouracil, taxanes)[15]. In addition, the combinatorial effect of chemotherapy-hyperthermia on the cytotoxicity of normally oxygenated and chronically hypoxic glioma cells have been studied in in vitro glioma models[98]. The results suggested that drugs like mitomycin C (MMC) and adriamycin (ADM) exhibited synergistic killing of tumour cells with heat under both oxygenated and hypoxic conditions not only at 37°C but also at elevated temperatures (42°C-43°C). On the other hand, agents like cis-diamminedichloroplatinum (II) (CDDP), bleomycin (BLM) and vincristine (VCR) were preferentially cytotoxic to oxygenated cells at both 37°C and higher temperatures (42°C-43°C). The effect of MHCT on the activity of various chemotherapeutic drugs as summarized in Table 5. 2.2.1

In-vitro applications MNP-based core-shell delivery systems are able to deliver drugs in a controlled manner by altering the frequency and strength of the AMF applied[108]. One recent example of such magnetic systems was reported by Hernandez and group in 2017[109]. Tripolyphosphate salts (TPP)-crosslinked chitosan nanoparticles (CSNPs) have been applied for combined MHCT and 5-fluorouracil (5-FU) delivery in human glioblastoma A-172 cells. These dual functional magnetic CSNPs with coreshell morphology presented improved dose-dependent cytotoxicity with reduction in cell viability of glioma cells to 67-75% on AMF application. On the other hand, no significant reduction of cell viability was observed for normal fibroblasts (FHB) cells. Magnetic core-shell nanoparticle (MCNP)-mediated delivery of a mitochondriatargeting pro-apoptotic amphipathic tail-anchoring peptide (ATAP) in combination with MHCT for malignant brain cancer cells has also been reported[110]. Induction of MCNP-mediated MHCT significantly enhanced the chemotherapeutic efficacy of ATAP, leading to increased rate of apoptosis as a result of their addictive effect on mitochondrial dysfunction. Many studies have also reported use of hyperthermia therapy to overcome chemoresistance during the treatment of inaccessible solid human tumors. The main


26

Page 27 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


challenge of MHCT is to increase the temperature within localized tumor microenvironment with minimal damage to the surrounding healthy tissues. In a study, hyperthermia treatment at 42°C has been shown not only to completely reverse cisplatin resistance but it could be employed as a sensitizer for cisplatin resistant cancer cells[111]. The cisplatin resistant line was found to be more sensitive to 42°C heating than its cisplatin sensitive counterpart. Further, MHCT was applied to overcome chemoresistance in 4 human malignant glioma cells lines, LN-229, T98G, LN-18 and U87MG[112]. Compared to normal culturing conditions, pulsed 24 h drug exposure was shown to increase the glioma cell sensitivity towards multiple anti-cancer drugs including cisplatin, teniposide, topotecan and treosulfan, moderately with CCNU, doxorubicin and vincristine, but not with gemcitabine. In yet another study, MHCT has also been shown to overcome temozolomide resistance in numerous human glioblastoma tumor cell lines by downregulating the expression of MGMT and augmenting the drug uptake in the tumor areas[113]. Hyperthermia may thus be a useful approach not only to overcome the chemoresistance of human malignant glioma cells but also in enhancing their thermopotentiation in combination therapy. 2.2.2

In-vivo applications The hyperthermia-chemotherapy combinatorial treatment has been extensively tested in in-vivo glioma models using exogenous heating source[114,115]. The studies suggested the superior cytotoxicity of simultaneous treatment with hyperthermia and anti-neoplastic drugs as compared to that of other treatment modalities. Hyperthermia in combination with chemotherapy has also been tested in in vivo glioma models for their capability to disrupt the BBB and enhance the penetrating power of a variety of molecules into the tumor microenvironment. To this end, Adriamycin-encapsulated thermosensitive liposomes have been used to target C6 glioma bearing mice models in conjugation with hyperthermia (EHT) in order to enhance the efficacy of Adriamycin in crossing the BBB[116]. After intravenous systemic administration of MNPs in the tail vein of the mice, the heads of mice were


27


Page 28 of 56

heated at 42°C for 30 min using an exogenous water source. On application of MHCT, the concentration of Adriamycin was observed to be 3.7-fold higher in the brain when delivered via thermosensitive-liposomal nano-carriers as compared with the nonthermosensitive-liposomal mediated Adriamycin delivery. Recently, Iron-salen (Fe(Salen)), i.e., μ-oxo N,N’-bis(salicylidene)ethylenediamine iron, has been identified as a new potential anti-neoplastic agent with intrinsic magnetic properties[117] for applications in MHCT[118]. Carmustine (BCNU)-loaded Fe(Salen) NPs have been tested for their therapeutic efficacy on AMF exposure in glioma models implanted with U251 cells[119]. After injection of NPs directly into the burr hole created in the skull, an AMF was applied for 20 minutes and temperatures above 43°C were observed in the animal group administered with Fe(Salen) nanoparticles. A fiber optic thermometer (FL-2400; Anritsu Meter Co., Tokyo, Japan) was used to monitor the temperature. The mice receiving the treatment demonstrated the least tumor growth among all the treatment groups exposed to an AMF.


28

Page 29 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46


Table 5: Activity of various anti-neoplastic agents in presence of hyperthermia. Hyperthermia conditions Drug

Iron oxide based

[Concentration]

nanosystems

Melphalan [4 g]

Effect on

Experimental

Drug

system

30%

In vivo

Ehlich carcinoma

Fe2O3 and Fe3O4)

regression of

experiments in

and Lewis

[25.2 mg/300 l]

non-metastatic

P388 tumors

carcinoma

P388 tumors

generated in

in BDF1 mice

BDF1 mice

Dextran-ferrite (-

Mode of heat

MHCT

f

H

(kHz)

(Oe)

880

91.54

T/SAR 46 C

Cancer

Ref.

[99]

was achieved; significant increase of 290% in life span of the mice were observed Cisplatin

Starch polymer-

Electromagnetic

coated magnetic

hyperthermia

-

-

180 W/g

Synergistic

In vitro study

effect of the

in BP6 cell

nanoparticles

combination

line

[5 mg/ml]

treatment was

Sarcoma

[100]

observed


29


Starch polymer-

MHCT

400

308.48

coated magnetic

75.5 

Synergistic

1.6 W/g

effect of the

nanoparticles

combination

[5 mg/200 l]

treatment was

Page 30 of 56

-

-

[101]

Prostate

[102]

[103]

observed; controlled drug release achieved  150

Synergistic

In vitro study

W/g

effect of the

in DU-145 cell

magnetic

combination

line

nanoparticles

treatment was

Carbon

MHCT

128

752.4

encapsulated

observed Carboxymethyl

MHCT

237

188.1

41 C

Enhanced

In vitro study

Human colon

dextran-coated iron

toxic effect at

in Caco-2 cell

adenocarcinoma

oxide nanoparticles

lower drug

line

concentration Paclitaxel

Citric acid coatedFe3O4 nanoparticles

MHCT

423

125.4

42.5  

Combined

In vitro study

1.0 C

treatment was

in Hela cells

encapsulated in

effective than

thermosensitive

the individual

liposomes [6 mg]

treatments


Human cervical

[104]

30

Page 31 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46


5-bromotetrandrine

Fe3O4 nanoparticles

MHCT

219

and daunorubicin

131.67-

-

3893.7



Significant

In vivo

tumor

experiments

reductions

with human

were noticed

chronic

Leukemia

[105]



[106]

myeloid leukemia cell lines Bortezomib

Carboxymethyl

MHCT

233

435.51

45 C

Combination

In vitro

dextran coated-iron

treatment was

experiments in

epithelial

oxide nanoparticles

found to be

various BZ

breast

[3.8 mg/mL]

more effective

sensitive

carcinoma

in both

(MDA-MB-

resistant and

468, Caco-2)

adenocarcino

non-resistant

and resistant

ma

cell lines a

cells (A2780)

compared with





Human

Colorectal

Ovarian cancer

hot water treatment


31


Cyclophosphamide

Dextran-coated Fe3O4

MHCT

880

90.29

46C

Page 32 of 56

Combined

In vivo



therapy lead to

experiments

y adenocarcinoma

40% tumor

with

regression and

mammary

300%

adenocarcino

increases in

ma Ca 755 in

survival time.

female

Mammar

[107]

C57Bl/6j mice.


32

Page 33 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2.3. Hyperthermia in conjugation with radiotherapy Radiotherapy is based on application of ionizing radiation to control or kill tumor cells[120]. Moreover, the mammalian cells have mechanisms to repair radiation damage and these modifications can cause a major effect on the fate of the cell [121,122]. Many studies have reported the potential use of MHCT to enhance radiosensitivity of mammalian cells cultured in vitro. Hyperthermia can inhibit the repair capacity of mammalian cells through inhibition of the pathway responsible for repair mechanisms[123,124]. Many studies have reported similar synergistic effect of exogenous hyperthermia and radiation therapy for glioma cells also[125-128]. 2.3.1

In-vitro applications In the 1990s, Kida et al. first demonstrated the application of thermoseed magnetic induction hyperthermia for treatment of metastatic brain tumours in combination with radiotherapy[129]. The metastatic tumors were treated with ferromagnetic implants made up of 15-20 nm sized Fe-Pt alloy and heated to 44-46°C at 240 kHz. Repeated CT scans revealed complete response in 2 cases, minor response in one case and progression in 3 out of the 6 cases studied. Therefore, these preliminary results suggested the application of interstitial hyperthermia as a promising therapy for intracranial brain metastases. The synergistic effect of the combination treatment of silver nanoparticles (AgNPs)-mediated radiotherapy with MHCT using maghemite nanoparticles has been investigated on human Glioma U251 cells[130]. All treatment groups received 0 to 6 Gy of ionizing radiation (IR) and were then exposed to an AMF for 15-minutes. The combination therapy resulted in both radio and thermo sensitivity on U251 cells with the lowest tumor cell survival as a result of the combinatorial therapy using 6 Gy radiation and subsequent AMF exposure. The mechanisms of thermo-radiosensitization in glioma stem-like cells (GSCs) by investigating the activity of the survival kinase - Protein Kinase B (AKT), have also been studied[131]. The combinatorial treatment of hyperthermia followed by


33


Page 34 of 56

radiotherapy resulted in significant reduction in AKT activation than treatment with radiation alone. Thus suggesting the need for further in-depth evaluation of combined hyperthermia and radiation therapy for GBM treatment. To this end, theoretical models investigating the combined effect of external beam radiotherapy with fast hyperthermia generated by a focused ultrasound device for effective GBM therapy have also been studied[132]. The results showed significant improvement in patient survival using such combined treatment modality. To our knowledge, no in vivo studies for glioma involving the combinatorial effect of radiotherapy and MHCT have been done so far. 2.4 Hyperthermia in combination with photothermal therapy Nano-heaters can be activated to generate heat either by magnetism (MHCT) or light (photothermal therapy) by application of near-infrared light (NIR), the spectrum in which absorption of tissues in minimum. Photothermal therapy by various metallic (silver, gold, copper) or semiconducting (carbon nanotubes or graphene) nanoparticles has emerged as a cancer treatment over the time. Recently, iron based oxide have also been evaluated for their potential as photothermal agents for preclinical studies[133-135]. 2.4.1

In-vitro applications

Paula et al., in 2017 reported the application of chloroaluminum-phthalocyanine (0.05 mg/mL) encapsulated-magnetic nanoemulsions (MNEs) as a drug nanocarrier to treat GBM using combinatorial treatment of MHCT and photodynamic therapy[136]. Using different glioma cell line models (BM-MSC, U87MG, and T98G), in-vitro analysis was performed to assess the cell viability treated with MNES, before and after performing MHCT using AMF of 1 MHz and 40 Oe; and photodynamic therapy (670 nm wavelength, 700 mJ cm-2 energy density). The cell viability was found to decrease by 70% as a result of the combinatorial treatment in comparison to just 15% reduction in cell viability by hyperthermia alone. Not much research has been done in examining the synergistic effect of MHCT along with photothermal therapy for treatment of GBM. However, the dual heating


34

Page 35 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


modality comprising of MHCT and photothermal therapy has been reported to significantly enhance the therapeutic effect in prostate cancer (PC3), human squamous carcinoma (A431) and ovarian carcinoma (SKOV3) cell lines[137]. The study reports simultaneous stimulation of iron oxide nanocubes with an AMF of strength 62.7-300.96 Oe and 320 kHz - 1.1 MHz; and NIR laser irradiation (0.3 W/cm2) provides unparalleled heating efficiency at compatible clinical doses, thus overcoming the main disadvantage of independent usage of iron oxide nanoparticle for MHCT or photothermal therapy. However, multiple studies have reported application of hyperthermia therapy based on gold nanomaterials[138] or application of MNPs as photothermal agents alone for glioblastoma therapy[139]. As far as our knowledge is concerned, no work has been done on the animal Glioma models to check the combinatorial effect of photothermal therapy and MHCT. The basic differences and similarities between MHCT with radiotherapy and photothermal therapy are summarized in Box 3. The base of all the three treatments is to use heat as a therapy system to kill the cancerous cells. Our group is also working on hyperthermia as a treatment module for cancer, so here we have shown the effect of heat generated on cytoskeleton of C6 glioma cells on AMF application (Box 3).


35


Page 36 of 56

Box 3: Comparison of MHCT with radiotherapy and photothermal therapy for GBM. Parameter

MHCT

Radiotherapy

Phototherapy

Mechanism of action

Heat

Heat

Heat

Source

Alternating magnetic field

Radiofrequency waves

Laser

Capability to affect at cellular level

Yes

No

Yes

The effect of heating through AMF exposure on cytoskeleton of cancer cell is depicted in the image below.

The effect of heat on glioma cells when subjected to an AMF of strength 168 Oe and 405 kHz for 20 mins. As seen in the image, the cells treated with AMF in presence of MNPs (C) show clear evidence of cytoskeletal damage while cells treated with AMF alone (B) show minimal distortion when compared with untreated control cells (A). In the image, actin is stained red using Phailloidin-TRITC and nucleus is stained blue using Hoescht3342 (Scale bar = 5 m; 63X magnification). 2.5 Clinical studies Numerous preclinical studies indicate the potential of MHCT to enhance the effectiveness of GBM treatment in combination with chemotherapy and radiotherapy. Till date, approximate 100 clinical trials have been identified in which hyperthermia has been included in the treatment regimen indicating continuous interest in the field of MHCT[140]. Some clinical trials have also been performed in India using hyperthermia


36

Page 37 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


as the treatment module but are done for Head and Neck cancer[141,142]. Despite such active trials using hyperthermia, so far only three trials corresponding to MHCT for GBM have been conducted and all of them have been done at MagForce Nanotechnologies AG, Berlin, Germany (summarized in Table 6). The first clinical study on MHCT on 14 GBM patients was performed by MaierHauff in 2003[143]. All patients received the neuro-navigationally guided injection of the 15 nm sized aminosilane-coated IONP suspension (MFL AS; MagForce Nanotechnologies AG, Berlin, Germany) into the tumor followed by 4-10 thermotherapy sessions. Thermotherapy was tolerated at magnetic field strengths of 47.65-169.29 Oe with only minor side effects observed. In 90% of the tumor volumes, therapeutic temperatures of 39.3°C–45.5°C were achieved[146]. Following this, in 2009, van Landeghem et al., demonstrated the first postmortem study of three GBM patients undergoing MHCT[144]. After the recurrence of the tumor, MHCT was given as a second line of treatment in combination with other adjuvant therapies. Instillation of aminosilane-coated IONPs (MFL AS; MagForce Nanotechnologies AG, Berlin, Germany) was done under neuro-navigational control (Stealth Station, Medtronic, Minneapolis, MN, USA) under general anesthesia. On AMF application, using fiberoptic thermometer probe the temperature was observed to rise to 49.5°C-65.6°C, with survival rate ranging from 2.1-7.9 months. A histological analysis revealed that nanoparticles were confined near the site of administration, indicating the need for administration at multiple sites for more uniform heat generation for an effective GBM therapy. Later, Maier-Hauff et al., showed another clinical study of 66 patients using MHCT in combination with radiotherapy. In this study, they studied the role of MHCT in increasing survival rates in case of recurrent GBM[145]. The results demonstrated increase in survival rates of patients, which could be attributed to thermo-radiotherapy combination used in the study. For temperature measurements, a closed-end thermometry catheter (with outside diameter of 1.0 mm) was placed in the target area. In contrast to the minor side effects observed for magnetic thermotherapy, a study based on radiofrequency-mediated thermotherapy on 15 patients with malignant glioma resulted in some serious side-effects like increased intracranial pressure and


37


Page 38 of 56

necrosis[147]. Besides this, other effects like headache, fatigue, local pain, thrombocytopenia, vomiting, confusion and leukopenia have also been reported. Overall in the clinical studies, MHCT depicted only few side effects and no serious complications thus proving its potential in comparison to other conventional therapies for GBM. 3. Conclusion The aim to identify the most suitable therapy for GBM is still a challenge. As judged from the previously reported studies, MHCT has extensively demonstrated its capability to act either alone or synergistically with other conventional therapies available for treatment of glioblastoma in the pre-clinical models. It has shown to enhance the potential of commonly used chemotherapeutic drugs by altering the BBB and thus increasing the drug concentration in the tumor area. This increased drug delivery in the brain would reduce the need for subsequent chemotherapeutic sessions required to achieve the therapeutic goal, thus improving the patient’s quality of life. In addition to enhanced chemotherapeutic effect, MHCT has also been reported to radiosensitize the GBM cells when administered as a combined therapy. Most of the in vivo studies that we have reviewed in this article are based on the application of MHCT alone as a treatment module for glioblastomas. However, there are still hindrances in the way of establishing MHCT as the sole line of treatment for GBM but by an intelligent combination regime, it can be achieved to increase the survival and quality of GBM patients by reducing the non-specific toxicities associated with conventional treatments. This suggests the promising near future of MHCT to at least aid in enhancing the therapeutic effect of other therapies for cancer treatment, if not replacing them. Considering the history of usage pattern, it is expected that MHCT has the potential to become the indispensable treatment module for GBM and other cancers. So to conclude this review, we critically need better therapeutic approaches and new options to treat glioblastoma and MHCT is one of such therapies.


38

Page 39 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46


Table 6: Summary of clinical trials for MHCT. No. of

Combinatorial

Magnetic fluid

AMF

patients

treatment

concentration

f

under

administered (iron

(kHz)

study

concentration = 112

No. of

Intratumoral

Survival

H

thermothera

temperature

(months)

(Oe)

py

achieved (C)

Reference

sessions

mg/mL) 14

Radiotherapy

1.5-3.0 mL

100

31.35-225.72

4-10

39.3-45.5

2.7-11.5

[143]

3

Radiotherapy and

4.2-4.6 mL

100

31.35-225.72

6

49.5-65.6

2.1-7.9

[144]

4.5 mL

100

25.08-188.1

6

51.2

13.4-23.2

[145]

chemotherapy 66

Radiotherapy


39


Page 40 of 56

Acknowledgement: The authors acknowledge the support by Department of Science and Technology and Institute of Nano Science and Technology, Mohali. Funding source: This work was financially supported by Department of Science and Technology - Science and Engineering Research Board (ECR/2017/000049). Conflict of Interest: There are no conflicts to declare. Author Contributions Ruby Gupta - Drafting of the manuscript, literature search and compilation of the data. Deepika Sharma - Conceived the paper and contributed towards drafting and final editing of the manuscript. References

1.

Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M.,

Parkin, D.M., Forman, D., Bray, F. (2015) Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386. 2.

Ostrom, Q.T., Gittleman, H., Xu, J., Kromer, C., Wolinsky, Y., Kruchko, C.,

Barnholtz-Sloan, J.S. (2016) CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2009-2013. Neuro. Oncol. 18, v1–v75. 3.

Zhang, Y., Calderwood, S.K. (2011) Autophagy, Protein Aggregation and

Hyperthermia: A Minireview. Int. J. Hyperth. 27, 409–414.


40

Page 41 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4.

Krawczyk, P.M., Eppink, B., Essers, J., Stap, J., Rodermond, H., Odijk, H.,

Zelensky, A., van Bree, C., Stalpers, L.J., Buist, M.R., Soullie, T., Rens, J., Verhagen, H.J., O’Connor, M.J., Franken, N.A., Ten Hagen, T.L., Kanaar, R., Aten, J.A. (2011) Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proc. Natl. Acad. Sci. 108, 9851–9856. 5.

Pei-yu, P., Ya-zhuo, Z., De-hua, J. (2000) Apoptosis Induced By

Hyperthermia in Human Glioblastoma Cell Line and Murine. Chinese J. Cancer Res. 12, 257–262. 6.

Sneed, P.K., Stauffer, P.R., McDermott, M.W., Diederich, C.J., Lamborn,

K.R., Prados, M.D., Chang, S., Weaver, K.A., Spry, L., Malec, M.K., Lamb, S.A., Voss, B., Davis, R.L., Wara, W.M., Larson, D.A., Phillips, T.L., Gutin, P.H. (1998) Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost ± hyperthermia for glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 40, 287–295. 7.

Liu, H.L., Hua, M.Y., Chen, P.Y., Chu, P.C., Pan, C.H., Yang, H.W., Huang,

C.Y., Wang, J.J., Yen, T.C., Wei, K.C. (2010) Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology 255, 415–425. 8.

Lin, Y.J., Chen, K.T., Huang, C.Y., Wei, K.C. (2016) Non-invasive focused

ultrasound-based synergistic treatment of brain tumors. J. Cancer Res. Pract. 3, 63– 68. 9.

Winter, A., Laing, J., Paglione, R., Sterzer, F. (1985) Microwave hyperthermia

for brain tumors. Neurosurgery 17, 387-399. 10.

Lyons, B.E., Britt, R.H., Strohbehn, J.W. (1984) Localized Hyperthermia in

the Treatment of Malignant Brain Tumors Using an Antenna Array. IEEE Trans. Biomed. Eng. BME 31, 53–62. 11.

Silva, A.C., Oliveira, T.R., Mamani, J.B., Malheiros, S.M.F., Malavolta, L.,

Pavon, L.F., Sibov, T.T., Amaro, E., Tannús, A., Vidoto, E.L.G., Martins, M.J., Santos, R.S., Gamarra, L.F. (2011) Application of hyperthermia induced by superparamagnetic iron oxide nanoparticles in glioma treatment. Int. J. Nanomedicine 6, 591–603. 12.

Shevtsov, M.A., Multhoff, G. (2016) Recent developments of magnetic

nanoparticles for theranostics of brain tumor. Curr. Drug Metab. 737–744.


41


13.

Page 42 of 56

Glaser, T., Han, I., Wu, L., Zeng, X. (2017) Targeted nanotechnology in

glioblastoma multiforme. Front. Pharmacol. 8, 166. 14.

Gilchrist, R.K., Medal, R., Shorey, W.D., Hanselman, R.C., Parrott, J.C.,

Taylor, C.B. (1957) Selective inductive heating of lymph nodes. Ann Surg. 146, 596606. 15.

Verma, J., Lal, S., Van Noorden, C.J. (2014) Nanoparticles for hyperthermic

therapy: Synthesis strategies and applications in glioblastoma. Int. J. Nanomedicine 9, 2863–2877. 16.

Pourgholi, F., Hajivalili, M., Farhad, J.N., Kafil, H.S., Yousefi, M. (2016)

Nanoparticles: Novel vehicles in treatment of Glioblastoma. Biomed. Pharmacother. 77, 98–107. 17.

Wadhera, N., Gupta, R., Prakash, B., Sharma, D., Chakraverty, S. (2017)

Biocompatible ferrite nanoparticles for hyperthermia: effect of polydispersity, anisotropy energy and inter-particle interaction. Mater. Res. Express 4, 5–7. 18.

Di Corato, R., Espinosa, A., Lartigue, L., Tharaud, M., Chat, S., Pellegrino,

T., Menager, C., Gazeau, F., Wilhelm, C. (2014) Magnetic hyperthermia efficiency in the cellular environment for different nanoparticle designs. Biomater. 35, 6400-6411. 19.

Soukup, D., Moise, S., Cespedes, E., Dobson, J., Telling, N.D. (2015) In-situ

measurement of magnetization relaxation of internalised nanoparticles in live cells. ACS Nano 9, 231-240. 20.

Dewhirst, M.W., Prosnitz, L., Thrall, D., Prescott, D., Cleff, S., Charles, C.,

Macfall, J., Rosner, G., Samulski, T., Gillette, E., LaRue, S. (1997) Hyperthermic treatment of malignant diseases: Current status and a view toward the future. Semin. Oncol. 24, 616–625. 21.

Arthur, R.M., Straube, W.L., Trobaugh, J.W., Moros, E.G. (2005) Non-

invasive estimation of hyperthermia temperatures with ultrasound. Int. J. Hyper. 21, 589-600. 22.

Wilhelm, S., Tavares, A.J., Dai, Q., Ohta, S., Audet, J., Dvorak, H.F., Chan,

W.C.W. (2016) Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014. 23.

Herda, L.M., Hristov, D.R., Lo Giudice, M.C., Polo, E., Dawson, K.A. (2017)

Mapping of molecular structure of the nanoscale surface in bionanoparticles. J. Am. Chem. Soc. 139, 111−114. 24.

Sedlacek, H.H., Schulz, G., Steinstraesser, A., Kuhlman, L., Schwarz, A.,


42

Page 43 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Seidel, L., Seemann, G., Kraemer, H.P., Bosslet, K. (1988) Contributions to oncology: monoclonal antibodies in tumor therapy. Eds.; Karger: Basel, Switzerland, ISBN: 9783805547635. 25.

Björnmalm, M., Thurecht, K.J., Michael, M., Scott, A.M., Caruso, F. (2017)

Bridging bio-nano science and cancer nanomedicine. ACS Nano 11, 9594-9613. 26.

Babbs, C.F. (1982) Biology of local heat therapy for cancer. Weldon School

of Biomedical Engineering Faculty Publications. Paper 124. 27.

Hanini, A., Lartigue, L., Gavard, J., Schmitt, A., Kacem, K., Wilhelm, C.,

Gazeau, F., Chau, F., Ammar, S. (2016b) Thermosensitivity profile of malignant glioma U87-MG cells and human endothelial cells following γ-Fe2O3 NPs internalization and magnetic field application. RSC Adv. 6, 15415–15423. 28.

Jang, J., Nah, H., Lee, J.H., Moon, S.H., Kim, M.G., Cheon, J. (2009) Critical

Enhancements of MRI Contrast and Hyperthermic Effects by Dopant-Controlled Magnetic nanoparticles. Angew Chem. Int. Ed. Engl. 4, 1234–1238. 29.

Zélis, P.M., Pasquevich, G.A., Stewart, S.J., Fernandez van Raap, M.B.,

Aphesteguy, J., Bruvera, I.J., Laborde, C., Pianciola, B., Jacobo, S., Sánchez, F.H. (2013) Structural and magnetic study of zinc-doped magnetite nanoparticles and ferrofluids for hyperthermia applications. J. Phys. D. Appl. Phys. 46, 12. 30.

Hanini, A., Lartigue, L., Gavard, J., Kacem, K., Wilhelm, C., Gazeau, F.,

Chau, F., Ammar, S. (2016a) Zinc substituted ferrite nanoparticles with Zn0.9Fe2.1O4 formula used as heating agents for in vitro hyperthermia assay on glioma cells. J. Magn. Magn. Mater. 416, 315–320. 31.

Sanz, B., Calatayud, M.P., Torres, T.E., Fanarraga, M.L., Ibarra, M.R., Goya,

G.F. (2017) Magnetic hyperthermia enhances cell toxicity with respect to exogenous heating. Biomaterials 114, 62–70. 32.

Calatayud, M.P., Soler, E., Torres, T.E., Campos-Gonzalez, E., Junquera, C.,

Ibarra, M.R., Goya, G.F. (2017) Cell damage produced by magnetic fluid hyperthermia on microglial BV2 cells. Sci. Rep. 7, 8627. 33.

Rodrigues, D., Bañobre-López, M., Espiña, B., Rivas, J., Azeredo, J. (2013)

Effect of magnetic hyperthermia on the structure of biofilm and cellular viability of a food spoilage bacterium. Biofouling. 29, 1225-1232. 34.

Banobre-Lopez, M., Rodrigues, D., Espina, B., Azeredo, J., Rivas, J. (2013)

Control of bacterial cells growth by magnetic hyperthermia. IEEE Trans. Magn. 49, 3508-3511.


43


35.

Page 44 of 56

Rodríguez-Luccioni, H.L., Latorre-Esteves, M., Méndez-Vega, J., Soto, O.,

Rodríguez, A.R., Rinaldi, C., Torres-Lugo, M. (2011) Enhanced reduction in cell viability by hyperthermia induced by magnetic nanoparticles. Int. J. Nanomedicine 6, 373–380. 36.

Herea, D.D., Danceanu, C., Radu, E., Labusca, L., Lupu, N., Chiriac, H.

(2018) Comparative effects of magnetic and water-based hyperthermia treatments on human osteosarcoma cells. Int. J. Nanomed. 13, 5743-5751. 37.

Khandhar, A.P., Ferguson, R.M., Krishnan, K.M. (2011) Monodispersed

magnetite nanoparticles optimized for magnetic fluid hyperthermia: Implications in biological systems. J. Appl. Phys. 109, 7B310–7B3103. 38.

Tomitaka, A., Koshi, T., Hatsugai, S., Yamada, T., Takemura, Y. (2011)

Magnetic characterization of surface-coated magnetic nanoparticles for biomedical application. J. Magn. Magn. Mater. 323, 1398–1403. 39.

Karimi, Z., Karimi, L., Shokrollahi, H. (2013) Nano-magnetic particles used

in biomedicine: Core and coating materials. Mater. Sci. Eng. C 33, 2465–2475. 40.

Shinkai M, Yanase M, Honda H, Wakabayashi T, Yoshida j, Kobayashi, T.

(1996) Intracellular Hyperthermia for Cancer Using Magnetite Cationic Liposomes: In vitro Study. Jpn. J. Cancer Sci. 87, 1179-1183. 41.

Ito, A., Shinkai, M., Honda, H., Yoshikawa, K., Saga, S., Wakabayashi, T.,

Yoshida, J., Kobayashi, T. (2003) Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol. Immunother. 52, 80–88. 42.

Meenach, S.A., Hilt, J.Z., Anderson, K.W. (2010) Poly(ethylene glycol)-based

magnetic hydrogel nanocomposites for hyperthermia cancer therapy. Acta Biomater. 6, 1039–1046. 43.

Ramirez-Nunez, A.L., Jimenez-Garcia, L.F., Goya, G.F., Sanz, B., Santoyo-

Salazar, J. (2018) In vitro magnetic hyperthermia using polyphenol-coated nanoparticles from Cinnamomun verum and Vanilla planifolia: the concert of green synthesis and therapeutic possibilities. Nanotechnology 29, 074001. 44.

Hamdous, Y., Chebbi, I., Mandawala, C., Le Fèvre, R., Guyot, F., Seksek, O.,

Alphandéry, E. (2017) Biocompatible coated magnetosome minerals with various organization and cellular interaction properties induce cytotoxicity towards RG-2 and GL-261 glioma cells in the presence of an alternating magnetic field. J. Nanobiotechnology 15, 74.


44

Page 45 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


45.

Gupta, R., Sharma, D. (2019) Biofunctionalization of magnetite nanoparticles

with stevioside: effect on the size and thermal behaviour for use in hyperthermia applications. Int. J. Hyper. (In Press). https://doi.org/10.1080/02656736.2019.1565787 46.

Chang, L., Liu, X.L., Fan, D. Di, Miao, Y.Q., Zhang, H., Ma, H.P., Liu, Q.Y.,

Ma, P., Xue, W.M., Luo, Y.E., Fan, H.M. (2016) The efficiency of magnetic hyperthermia and in vivo histocompatibility for human-like collagen protein-coated magnetic nanoparticles. Int. J. Nanomedicine 11, 1175–1185. 47.

Häring, M., Schiller, J., Mayr, J., Grijalvo, S., Eritja, R., Díaz Díaz, D. (2015)

Magnetic Gel Composites for Hyperthermia Cancer Therapy. Gels 1, 135–161. 48.

Meenach, S.A., Otu, C.G., Anderson, K.W., Hilt, J.Z. (2012) Controlled

synergistic delivery of paclitaxel and heat from poly(β-amino ester)/iron oxide-based hydrogel nanocomposites. Int. J. Pharm. 427, 177–184. 49.

Meenach, S.A., Shapiro, J.M., Hilt, J.Z., Anderson, K. (2013) Characterization

of PEG-iron oxide hydrogel nanocomposites for dual hyperthermia and paclitaxel delivery. J. Biomater. Sci. Polym. Ed. 24, 1112–1126. 50.

Beere, H.M., Wolf, B.B., Cain, K., Mosser, D.D., Mahboubi, A., Kuwana, T.,

Tailor, P., Morimoto, R.I., Cohen, G.M., Green, D.R. (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat. Cell Biol. 2, 469–475. 51.

Gong, T.W., Fairfield, D.A., Fullarton, L., Dolan, D.F., Altschuler, R.A.,

Kohrman, D.C., Lomax, M.I. (2012) Induction of heat shock proteins by hyperthermia and noise overstimulation in Hsf1-/- mice. J. Assoc. Res. Otolaryngol. 13, 29–37. 52.

Hermisson, M., Strik, H., Rieger, J., Dichgans, J., Meyermann, R., Weller, M.

(2000) Expression and functional activity of heat shock proteins in human glioblastoma multiforme. Neurology 54, 1357–1365. 53.

Titsworth, W.L., Murad, G.J., Hoh, B.L., Rahman, M. (2014) Fighting fire

with fire: The revival of thermotherapy for gliomas. Anticancer Res. 34, 565–574. 54.

Brondani Da Rocha, A., Regner, A., Grivicich, I., Pretto Schunemann, D.,

Diel, C., Kovaleski, G., Brunetto De Farias, C., Mondadori, E., Almeida, L., Braga Filho, A., Schwartsmann, G. (2004) Radioresistance is associated to increased Hsp70 content in human glioblastoma cell lines. Int. J. Oncol. 25, 777–785. 55.

Sauvageot, C.M., Weatherbee, J.L., Kesari, S., Winters, S.E., Barnes, J.,


45


Page 46 of 56

Dellagatta, J., Ramakrishna, N.R., Stiles, C.D., Kung, A.L., Kieran, M.W., Wen, P.Y. (2009) Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro. Oncol. 11, 109–121. 56.

Sang, D.P., Li, R.J., Lan, Q. (2014) Quercetin sensitizes human glioblastoma

cells to temozolomide in vitro via inhibition of Hsp27. Acta Pharmacol. Sin. 35, 832– 838. 57.

Matsuda, Y., Ishiwata, T., Yoshimura, H., Hagio, M., Arai, T. (2015)

Inhibition of nestin suppresses stem cell phenotype of glioblastomas through the alteration of post-translational modification of heat shock protein HSPA8/HSC71. Cancer Lett. 357, 602–611. 58.

Milanovic, D., Firat, E., Grosu, A.L., Niedermann, G. (2013) Increased

radiosensitivity and radiothermosensitivity of human pancreatic MIA PaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitor NVP-HSP990. Radiat. Oncol. 8, 42. 59.

Shevtsov, M.A., Nikolaev, B.P., Ryzhov, V.A., Yakovleva, L.Y., Marchenko,

Y.Y., Parr, M.A., Rolich, V.I., Mikhrina, A.L., Dobrodumov, A. V., Pitkin, E., Multhoff, G. (2015a) Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION–cmHsp70.1). Nanoscale 7, 20652–20664. 60.

Yanase, M., Shinkai, M., Honda, H., Wakabayahi, T., Yoshida, J., Kobayashi,

T. (1997) Intracellular Hyperthermia for Cancer Using Magnetite Cationic Liposomes: Ex vivo Study. Jpn. J. Cancer Res. 88, 630-632. 61.

Yanase, M., Shinkai, M., Honda, H., Wakabayahi, T., Yoshida, J., Kobayashi,

T. (1998a) Intracellular Hyperthermia for Cancer Using Magnetite Cationic Liposomes: An in vivo Study. Jpn. J. Cancer Res. 88, 463–470. 62.

Yanase, M., Shinkai, M., Honda, H., Wakabayashi, T., Yoshida, J.,

Kobayashi, T. (1998b) Antitumor immunity induction by intracellular hyperthermia using magnetite cationic liposomes. Jpn. J. Cancer Res. 89, 775–782. 63.

Shinkai, M., Yanase, M., Suzuki, M., Honda, H., Wakabayashi, T., Yoshida,

J., Kobayashi, T. (1999) Intracellular hyperthermia for cancer using magnetite cationic liposomes. J. Magn. Magn. Mater. 194, 176–184. 64.

Tomitaka, A., Arami, H., Gandhi, S., Krishnan, K.M. (2015) Lactoferrin

conjugated iron oxide nanoparticles for targeting brain glioma cells in magnetic particle imaging. Nanoscale 7, 16890-16898.


46

Page 47 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


65.

Fang, J.H., Chiu, T.L., Huang, W.C., Lai, Y.H., Hu, S.H., Chen, Y.Y., Chen,

S.Y. (2016) Dual-Targeting Lactoferrin-Conjugated Polymerized Magnetic Polydiacetylene-Assembled Nanocarriers with Self-Responsive Fluorescence/Magnetic Resonance Imaging for In Vivo Brain Tumor Therapy. Adv. Healthc. Mater. 5, 688–695. 66.

Kiessling, F., Huppert, J., Zhang, C., Jayapaul, J., Zwick, S., Woenne, E.C.,

Mueller, M.M., Zentgraf, H., Eisenhut, M., Addadi, Y., Neeman, M., Semmier, W. (2009) RGD-labeled USPIO Inhibits Adhesion and Endocytotic Activity of  alpha v beta 3-Integrin–expressing Glioma Cells and Only Accumulates in the Vascular Tumor Compartment. Radiology 253, 462–469. 67.

Chen, L., Zhang, G., Shi, Y., Qiu, R., Khan, A.A. (2015) Neuropilin-1 (NRP-

1) and magnetic nanoparticles, a potential combination for diagnosis and therapy of gliomas. Curr. Pharm. Des. 21, 5434–5449. 68.

Shevtsov, M.A., Nikolaev, B.P., Yakovleva, L.Y., Marchenko, Y.Y.,

Dobrodumov, A. V., Mikhrina, A.L., Martynova, M.G., Bystrova, O.A., Yakovenko, I. V., Ischenko, A.M. (2014) Superparamagnetic iron oxide nanoparticles conjugated with epidermal growth factor (SPION-EGF) for targeting brain tumors. Int. J. Nanomedicine 9, 273–287. 69.

Shevtsov, M.A., Nikolaev, B.P., Yakovleva, L.Y., Dobrodumov, A. V.,

Zhakhov, A. V., Mikhrina, A.L., Pitkin, E., Parr, M.A., Rolich, V.I., Simbircev, A.S., Ischenko, A.M. (2015b) Recombinant Interleukin-1 Receptor Antagonist Conjugated to Superparamagnetic Iron Oxide Nanoparticles for Theranostic Targeting of Experimental Glioblastoma. Neoplasia 17, 32–42. 70.

Kievit, F.M., Veiseh, O., Fang, C., Bhattarai, N., Lee, D., Ellenbogen. R.G.,

Zhang, M. (2010) Chlorotoxin Labeled Magnetic Nanovectors for Targeted Gene Delivery to Glioma. ACS Nano 4, 4587–4594. 71.

Han, L., Zhang, A., Wang, H., Pu, P., Kang, C., Chang, J. (2011) Construction

of Novel Brain-Targeting Gene Delivery System by Natural Magnetic Nanoparticles. J. Appl. Polym. Sci. 121, 3446–3454. 72.

Zhao, X., Shang, T., Zhang, X., Ye, T., Wang, D., Rei, L. (2016) Passage of

Magnetic Tat-Conjugated Fe3O4@SiO2 Nanoparticles Across In Vitro Blood-Brain Barrier. Nanoscale Res. Lett. 11, 451. 73.

Wang, X., Tu, M., Tian, B., Yi, Y., Wei, Z., Wei, F. (2016) Synthesis of

tumor-targeted folate conjugated fluorescent magnetic albumin nanoparticles for


47


Page 48 of 56

enhanced intracellular dual-modal imaging into human brain tumor cells. Anal. Biochem. 512, 8–17. 74.

Abakumov, M.A., Nukolova, N.V., Sokolsky-Papkov, M., Shein, S.A.,

Sandalova, T.O., Vishwasrao, H.M., Grinenko, N.F., Gubsky, I.L., Abakumov, A.M., Kabanov, A. V., Chekhonin, V.P. (2015) VEGF-targeted magnetic nanoparticles for MRI visualization of brain tumor. Nanomedicine Nanotechnology, Biol. Med. 11, 825–833. 75.

Hadjipanayis, C.G., Machaidze, R., Kaluzova, M., Wang, L., Schuette, A.J.,

Chen, H., Mao, H. (2011) EGFRvIII Antibody Conjugated Iron Oxide Nanoparticles for MRI Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma. Cancer Res. 70, 6303–6312. 76.

Kaluzova, M., Bouras, A., Machaidze, R., Hadjipanayis, C.G. (2015) Targeted

therapy of glioblastoma stem-like cells and tumor non-stem cells using cetuximabconjugated iron-oxide nanoparticles. Oncotarget 6, 8788–8806. 77.

Le, B., Shinkai, M., Kitade, T., Honda, H., Yoshida, J., Wakabayashi, T.,

Kobayashi, T. (2001) Preparation of tumor-specific magnetoliposomes and their application for hyperthermia. J. Chem. Eng. Japan 34, 66–72. 78.

Jordan, A., Scholz, R., Maier-Hauff, K., van Landeghem, F.K., Waldoefner,

N., Teichgraeber, U., Pinkernelle, J., Bruhn, H., Neumann, F., Thiesen, B., von Deimling, A., Felix, R. (2006) The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J. Neurooncol. 78, 7–14. 79.

Garcia-Montes, J.R., Porceddu, P.F., Drucker-Colín, R., Moratalla, R.,

Martinez-Murillo, R. (2017) P022 Evidence that functionalized ferromagnetic microparticles with CD133 antigen decreases glioblastoma multiforme growth in vivo and in vitro by magnetic field induced hyperthermia. Clin. Neurophysiol. 128, e21. 80.

Ohno, T., Wakabayashi, T., Takemura, A., Yoshida, J., Ito, A., Shinkai, M.,

Honda, H., Kobayashi, T. (2002) Effective solitary hyperthermia treatment of malignant glioma using stick type CMC-magnetite. In vivo study. J. Neurooncol. 56, 233–239. 81.

Le Fèvre, R., Durand-Dubief, M., Chebbi, I., Mandawala, C., Lagroix, F.,

Valet, J.P., Idbaih, A., Adam, C., Delattre, J.Y., Schmitt, C., Maake, C., Guyot, F., Alphandéry, E. (2017) Enhanced antitumor efficacy of biocompatible magnetosomes for the magnetic hyperthermia treatment of glioblastoma. Theranostics 7, 4618–4631. 82.

Alphandéry, E., Idbaih, A., Adam, C., Delattre, J.Y., Schmitt, C., Guyot, F.,


48

Page 49 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Chebbi, I. (2017a) Chains of magnetosomes with controlled endotoxin release and partial tumor occupation induce full destruction of intracranial U87-Luc glioma in mice under the application of an alternating magnetic field. J. Control. Release 262, 259–272. 83.

Hamdous, Y., Chebbi, I., Mandawala, C., Le Fèvre, R., Guyot, F., Seksek, O.,

Alphandéry, E. (2017) Biocompatible coated magnetosome minerals with various organization and cellular interaction properties induce cytotoxicity towards RG-2 and GL-261 glioma cells in the presence of an alternating magnetic field. J. Nanobiotechnology 15, 74. 84.

Alphandéry, E., Idbaih, A., Adam, C., Delattre, J.Y., Schmitt, C., Guyot, F.,

Chebbi, I. (2017) Development of non-pyrogenic magnetosome minerals coated with poly-l-lysine leading to full disappearance of intracranial U87-Luc glioblastoma in 100% of treated mice using magnetic hyperthermia. Biomaterials 141, 210–222. 85.

Ito, A., Shinkai, M., Honda, H., Kobayashi, T. (2001) Heat-inducible TNF-α

gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy. Cancer Gene Ther. 8, 649–654. 86.

Rabias, I., Tsitrouli, D., Karakosta, E., Kehagias, T., Diamantopoulos, G.,

Fardis, M., Stamopoulos, D., Maris, T.G., Falaras, P., Zouridakis, N., Diamantis, N., Panayotou, G., Verganelakis, D.A., Drossopoulou, G.I., Tsilibari, E.C., Papavassiliou, G. (2010) Rapid magnetic heating treatment by highly charged maghemite nanoparticles on Wistar rats exocranial glioma tumors at microliter volume. Biomicrofluidics 4, 024111. 87.

Xu, H., Zong, H., Ma, C., Ming, X., Shang, M., Li, K., He, X., Cao, L. (2017)

Evaluation of nano-magnetic fluid on malignant glioma cells. Oncol. Lett. 13, 677– 680. 88.

Kumar, C.S., Mohammad, F. (2011) Magnetic nanomaterials for

hyperthermia-based therapy and controlled drug delivery. Adv Drug Deliv Rev. 63, 789–808. 89.

Giustini, A.J., Petryk, A.A., Cassim, S.M., Tate, J.A., Baker, I., Hoopes, P.J.

(2013) Magnetic nanoparticle hyperthermis in cancer treatment. Nano Life 1, 10. 90.

Urakawa, M., Yamaguchi, K., Tsuchida, E., Kashiwagi, S., Ito, H., Matsuda,T.

(1995) Blood - brain barrier disturbance following localized hyperthermia in rats. Int. J. Hyperth. 11, 709–718. 91.

Tabatabaei, S.N., Tabatabaei, M.S., Girouard, H., Martel, S. (2016)


49


Page 50 of 56

Hyperthermia of magnetic nanoparticles allows passage of sodium fluorescein and Evans blue dye across the blood–retinal barrier. Int. J. Hyperth. 32, 657–665. 92.

Ikeda, N., Hayashida, O., Kameda, H., Ito, H., Matsuda, T. (1994)

Experimental study on thermal damage to dog normal brain. Int. J. Hyperth. 10, 553– 561. 93.

Rodriguez, A., Tatter, S.B., Debinski, W. (2015) Neurosurgical techniques for

disruption of the blood–brain barrier for glioblastoma treatment. Pharmaceutics 7, 175–187. 94.

Chi, O.Z., Wei, H.M., Lu, X., Weiss, H.R. (1996) Increased blood-brain

permeability with hyperosmolar mannitol increases cerebral O2 consumption and O2supply/consumption heterogeneity. J. Cereb. Blood Flow Metab. 16, 327–333. 95.

Miller, G. (2002) Drug targeting. Breaking down barriers. Science 297, 1116–

1118. 96.

Bidros, D.S., Vogelbaum, M. (2009) Novel drug delivery strategies in neuro-

oncology. Neurotherapeutics 6, 539–546. 97.

Gawali, S.L., Barick, B.K., Barick, K.C., Hassan, P.A. (2017) Effect of sugar

alcohol on colloidal stabilization of magnetic nanoparticles for hyperthermia and drug delivery applications. J. Alloys Compd. 725, 800–806. 98.

Watanabe, M., Tanaka, R., Hondo, H., Kuroki, M. (1992) Effects of

antineoplastic agents and hyperthermia on cytotoxicity toward chronically hypoxic glioma cells. Int. J. Hyperth. 8, 131–138. 99.

Brusentsov, N.A., Brusentsova, T.N., Filinova, E.Y., Jurchenko, N.Y.,

Kupriyanov, D.A., Pirogov, Y.A., Dubina, A.I., Shumskikh, M.N., Shumakov, L.I., Anashkina, E.N., Shevelev, A.A., Uchevatkin, A.A. (2007) Magnetohydrodynamic thermochemotherapy and MRI of mouse tumors. J. Magn. Magn. Mater. 311, 176– 180. 100.

BabincovÁ, M., AltanerovÁ, V., Altaner, C., Bergemann, C., Babinec, P.

(2008) In Vitro Analysis of Cisplatin Functionalized Magnetic Nanoparticles in Combined Cancer Chemotherapy and Electromagnetic Hyperthermia. IEEE Trans. Nanobioscience 7, 15–19. 101.

Kettering, M., Zorn, H., Bremer-Streck, S., Oehring, H., Zeisberger, M.,

Bergemann, C., Hergt, R., Halbhuber, K.J., Kaiser, W.A., Hilger, I. (2009) Characterization of iron oxide nanoparticles adsorbed with cisplatin for biomedical applications. Phys. Med. Biol. 54, 5109–5121.


50

Page 51 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


102.

Taylor, A., Krupskaya, Y., Krämer, K., Füssel, S., Klingeler, R., Büchner, B.,

Wirth, M.P. (2010) Cisplatin-loaded carbon-encapsulated iron nanoparticles and their in vitro effects in magnetic fluid hyperthermia. Carbon 48, 2327–2334. 103.

Lee, J.S., Rodriguez-Luccioni, H.L., Mendez, J., Sood, A.K., Lpez-Berestein,

G., Rinaldi, C., Torres-Lugo, M. (2011) Hyperthermia induced by magnetic nanoparticles improves the effectiveness of the anticancer drug cisdiamminedichloroplatinum. J. Nanosci. Nanotechnol. 11, 4153–4157. 104.

Kulshrestha, P., Gogoi, M., Bahadur, D., Banerjee, R. (2012) In vitro

application of paclitaxel loaded magnetoliposomes for combined chemotherapy and hyperthermia. Colloids Surf B Biointerfaces 96, 1–7. 105.

Ren, Y., Zhang, H., Chen, B., Cheng, J., Cai, X., Liu, R., Xia, G., Wu, W.,

Wang, S., Ding, J., Gao, C., Wang, J., Bao, W., Wang, L., Tian, L., Song, H., Wang, X. (2012) Multifunctional magnetic Fe3O4 nanoparticles combined with chemotherapy and hyperthermia to overcome multidrug resistance. Int. J. Nanomedicine 7, 2261–2269. 106.

Alvarez-Berríos, M.P., Castillo, A., Rinaldi, C., Torres-Lugo, M. (2013)

Magnetic fluid hyperthermia enhances cytotoxicity of bortezomib in sensitive and resistant cancer cell lines. Int. J. Nanomedicine 9, 145–153. 107.

Brusentsov, N.A., Polyanskii, V.A., Pirogov, Y.A., Dubina, A.I., Uchevatkin,

A.A., Kupriyanov, D.A., Tishchenko, D.A., Nikitin, P.I., Brusentsova, T.N., Ksenevich, T.I., Nikitin, M.P., Vol'ter, E.R., Ivanov, A. V. (2010) Antitumor Effects of the Combination of Magnetohydrodynamic Thermochemotherapy and Magnetic Resonance Tomography. Pharm. Chem. J. 44, 291–295. 108.

Kost, J., Noecker, R., Kunica, E., Langer, R. (1985) Magnetically Controlled

Release Systems - Effect of Polymer Composition. J. Biomed. Mater. Res. 19, 935– 940. 109.

Zamora-Mora, V., Fernández-Gutiérrez, M., González-Gómez, Á., Sanz, B.,

Román, J.S., Goya, G.F., Hernández, R., Mijangos, C. (2017) Chitosan nanoparticles for combined drug delivery and magnetic hyperthermia: From preparation to in vitro studies. Carbohydr. Polym. 157, 361–370. 110.

Shah, B.P., Pasquale, N., De, G., Tan, T., Ma, J., Lee, K.B. (2014) Core-shell

nanoparticle-based peptide therapeutics and combined hyperthermia for enhanced cancer cell apoptosis. ACS Nano 8, 9379–9387. 111.

Raaphorst, G.P., Chabot, P., Doja, S., Wilkins, D., Stewart, D., Ng, C.E.


51


Page 52 of 56

(1996) Effect of hyperthermia on cisplatin sensitivity in human glioma and ovarian carcinoma cell lines resistant and sensitive to cisplatin treatment. Int. J. Hyperth. 12, 211–222. 112.

Hermisson, M., Weller, M. (2000) Hyperthermia enhanced chemosensitivity

of human malignant glioma cells. Anticancer Res. 20, 1819–1823. 113.

Lee, C.T., Blackley, A., Landon, C., Spasojevic, I., Kirkpatrick, J.P.,

Dewhirst, M.W. (2014) Hyperthermia treatment overcomes temozolomide resistance in glioma cells by downregulating MGMT expression and increasing temozolomide uptake. [abstract]. Cancer Res. 74, 3774. 114.

Tanaka T, Kobayashi T, Kida Y, Kageyama, N. (1986) The effect of

hyperthermia and antitumor drugs on brain tumor cell lines. Gan To Kagaku Ryoho. 13, 2993–2997. 115.

Schem, B.C., Dahl, O. (1991) Thermal enhancement of ACNU and

potentiation of thermochemotherapy with ACNU by hypertonic glucose in the BT4An rat glioma. J. Neurooncol. 10, 247–252. 116.

Gong, W., Wang, Z., Liu, N., Lin, W., Wang, X., Xu, D., Liu, H., Zeng, C.,

Xie, X., Mei, X., Lü, W. (2011) Improving efficiency of adriamycin crossing blood brain barrier by combination of thermosensitive liposomes and hyperthermia. Biol. Pharm. Bull. 34, 1058–1064. 117.

Umemura, M., Kim, J., Aoyama, H., Hoshino, Y., Fukumura, H., Nakakaji,

R., Sato, I., Ohtake, M. (2017) The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity. J. Pharmacol. Sci. 134, 203–210. 118.

Sato, I., Umemura, M., Mitsudo, K., Fukumura, H., Kim, J.H., Hoshino, Y.,

Nakashima, H., Kioi, M., Nakakaji, R., Sato, M., Fujita, T., Yokoyama, U., Okumura, S., Oshiro, H., Eguchi, H., Tohnai, I., Ishikawa, Y. (2016) Simultaneous hyperthermia-chemotherapy with controlled drug delivery using single-drug nanoparticles. Sci. Rep. 6, 24629. 119.

Ohtake, M., Umemura, M., Sato, I., Akimoto, T., Oda, K., Nagasako, A., Kim,

J.H., Fujita, T., Yokoyama, U., Nakayama, T., Hoshino, Y., Ishiba, M., Tokura, S., Hara, M., Muramoto, T., Yamada, S., Masuda, T., Aoki, I., Takemura, Y., Murata, H., Eguchi, H., Kawahara, N., Ishikawa, Y. (2017) Hyperthermia and chemotherapy using Fe(Salen) nanoparticles might impact glioblastoma treatment. Sci. Rep. 7, 42783. 120.

Bañobre-López, M., Teijeiro, A., Rivas, J. (2013) Magnetic nanoparticle-


52

Page 53 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


based hyperthermia for cancer treatment. Reports Pract. Oncol. Radiother. 18, 397– 400. 121.

Elkind, M.M., Sutton, H. (1960) Radiation response of mammalian cells

grown in culture: I. Repair of X-ray damage in surviving chinese hamster cells. Radiat. Res. 13, 556–593. 122.

Phillips, R.A., Tolmach, L.J. (1966) Repair of potentially lethal damage in x-

irradiated HeLa cells. Radiat Res. 29, 413–432. 123.

Li, G.C., Evans, R.G., Hahn, G. (1976) Modification and inhibition of repair

of potentially lethal x-ray damage by hyperthermia. Radiat. Res. 67, 491–501. 124.

Raaphorst, G.P., Freeman, M.L., Dewey, W.C. (1979) Radiosensitivity and

recovery from radiation damage in cultured CHO cells exposed to hyperthermia at 42.5 or 45.5°C. Radiat. Res. 79, 390–402. 125.

Borasi, G., Nahum, A. (2017) A New Glioblastoma Treatment , Potentially

Highly Effective , Combining Focused Ultrasound Generated Hyperthermia and Radiations. JSM Brain Sci. 2, 1010 126.

Raaphorst, G.P., Feeley, M.M., Chu, G.L., Dewey, W.C. (1993) A comparison

of the Enhancement of Radiation and DNA Sensitivity Inactivation in Human Glioma Cells Polymerase by Hyperthermia. Radiat. Res. 134, 331–336. 127.

Raaphorst, G.P., Feeley, M.M., Danjoux, C.E., DaSilva, V., Gerig, L.H.

(1991) Hyperthermia enhancement of radiation response and inhibition of recovery from radiation damage in human glioma cells. Int J Hyperth. 7, 629–641. 128.

Raaphorst, G.P., Feeley, M.M., Da Silva, V.F., Danjoux, C.E., Gerig, L.H.

(1989) A comparison of heat and radiation sensitivity of three human glioma cell lines. Int. J. Radiat. Oncol. Biol. Phys. 17, 615–622. 129.

Kida, Y., Ishiguri, H., Ichimi, K., Kobayashi, T. (1990) Hyperthermia of

metastatic brain tumor with implant heating system: A preliminary clinical results. Neurol. Surg. 18, 521–526. 130.

Jiang, H., Wang, C., Guo, Z., Wang, Z., Liu, L. (2012) Silver Nanocrystals

Mediated Combination Therapy of Radiation with Magnetic Hyperthermia on Glioma Cells. J. Nanosci. Nanotechnol. 12, 8276–8281. 131.

Man, J., Shoemake, J.D., Ma, T., Rizzo, A.E., Godley, A.R., Wu, Q.,

Mohammadi, A.M., Bao, S., Rich, J.N., Yu, J.S. (2015) Hyperthermia sensitizes Glioma stem-like cells to radiation by inhibiting AKT signaling. Cancer Res. 75, 1760–1769.


53


132.

Page 54 of 56

Borasi, G., Nahum, A., Paulides, M.M., Powathil, G., Russo, G., Fariselli, L.,

Lamia, D., Cirincione, R., Forte, G.I., Borrazzo, C., Caccia, B., di Castro, E., Pozzi, S., Gilardi, M.C. (2016) Fast and high temperature hyperthermia coupled with radiotherapy as a possible new treatment for glioblastoma. J. Ther. Ultrasound 4, 32. 133.

Shen, S., Kong, F., Guo, X., Wu, L., Shen, H., Xie, M., Wang, X., Jin, Y., Ge,

Y. (2013) CMCTS stabilized Fe3O4 particles with extremely low toxicity as highly efficient near-infrared photothermal agents for in vivo tumor ablation. Nanoscale 5, 8056-8066. 134.

Zhou, Z., Sun, Y., Shen, J., Wei, J., Yu, C., Kong, B., Liu, W., Yang, H.,

Yang, S., Wang, W. (2014) Iron/iron oxide core/shell nanoparticles for magnetic targeting MRI and near-infrared photothermal therapy. Biomaterials 35, 7470–7478. 135.

Chu, M., Shao, Y., Peng, J., Dai, X., Li, H., Wu, Q., Shi, D. (2013) Near-

infrared laser light mediated cancer therapy by photothermal effect of Fe3O4 magnetic nanoparticles. Biomaterials 34, 4078–4088. 136.

de Paula, L.B., Primo, F.L., Pinto, M.R., Morais, P.C., Tedesco, A.C. (2017)

Evaluation of a chloroaluminium phthalocyanine-loaded magnetic nanoemulsion as a drug delivery device to treat glioblastoma using hyperthermia and photodynamic therapy. RSC Adv. 7, 9115–9122. 137.

Espinosa, A., Di Corato, R., Kolosnjaj-Tabi, J., Flaud, P., Pellegrino, T.,

Wilhelm, C. (2016) Duality of Iron Oxide Nanoparticles in Cancer Therapy: Amplification of Heating Efficiency by Magnetic Hyperthermia and Photothermal Bimodal Treatment. ACS Nano 10, 2436–2446. 138.

Cabada, T.F., de Pablo, C.S.L., Serrano, A.M., Guerrero, F. del P., Olmedo,

J.J.S., Gomez, M.R. (2012) Induction of cell death in a glioblastoma line by hyperthermic therapy based on gold nanorods. Int. J. Nanomedicine 7, 1511–1523. 139.

Yuan, G., Yuan, Y., Xu, K., Luo, Q. (2014) Biocompatible PEGylated Fe3O4

nanoparticles as photothermal agents for near-infrared light modulated cancer therapy. Int. J. Mol. Sci. 15, 18776–18788. 140.

Cihoric, N., Tsikkinis, A., van Rhoon, G., Crezee, H., Aebersold, D.M., Bodis,

S., Beck, M., Nadobny, J., Budach, V., Wust, P., Ghadjar, P. (2015) Hyperthermiarelated clinical trials on cancer treatment within the ClinicalTrials.gov registry. Int. J. Hyperth. 31, 609–614. 141.

Huilgol, N.G., Gupta, S., Dixit, R. (2010b) Chemoradiation with hyperthermia

in the treatment of head and neck cancer. Int. J. Hyperth. 26, 21–25.


54

Page 55 of 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


142.

Huilgol, N.G., Gupta, S., Sridhar, C. (2010a) Hyperthermia with radiation in

the treatment of locally advanced head and neck cancer: A report of randomized trial. J. Cancer Res. Ther. 6, 492-496. 143.

Maier-Hauff, K., Rothe, R., Scholz, R., Gneveckow, U., Wust, P., Thiesen, B.,

Feussner, A., von Deimling, A., Waldoefner, N., Felix, R., Jordan, A. (2007) Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: Results of a feasibility study on patients with glioblastoma multiforme. J. Neurooncol. 81, 53–60. 144.

van Landeghem, F.K., Maier-Hauff, K., Jordan, A., Hoffmann, K.T.,

Gneveckow, U., Scholz, R., Thiesen, B., Brück, W., von Deimling, A. (2009) Postmortem studies in glioblastoma patients treated with thermotherapy using magnetic nanoparticles. Biomaterials 30, 52–57. 145.

Maier-Hauff, K., Ulrich, F., Nestler, D., Niehoff, H., Wust, P., Thiesen, B.,

Orawa, H., Budach, V., Jordan, A. (2011) Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J. Neurooncol. 103, 317–324. 146.

Thiesen, B., Jordan, A. (2008) Clinical applications of magnetic nanoparticles

for hyperthermia. Int J Hyperth. 24, 467–74. 147.

Wismeth, C., Dudel, C., Pascher, C., Ramm, P., Pietsch, T., Hirschmann, B.,

Reinert, C., Proescholdt, M., Rummele, P., Schuierer, G., Bogdahn, U., Hau, P. (2010) Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas: phase I clinical results. J Neurooncol 98, 395-405.


55


Page 56 of 56

For Table of Contents use only

Evolution of Magnetic Hyperthermia for Glioblastoma Multiforme Therapy Ruby Guptaa and Deepika Sharmaa,* aInstitute

of Nano Science and Technology, Habitat Centre, Phase-10, Sector-64,

Mohali, Punjab-160062, India *Corresponding

author


56

Evolution of Magnetic Hyperthermia for Glioblastoma Multiforme

Recommend Documents