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      Hyperthermia and chemotherapy using Fe(Salen) nanoparticles might impact glioblastoma treatment

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          Abstract

          We previously reported that μ-oxo N,N’-bis(salicylidene)ethylenediamine iron [Fe(Salen)], a magnetic organic compound, has direct anti-tumor activity, and generates heat in an alternating magnetic field (AMF). We showed that Fe(Salen) nanoparticles are useful for combined hyperthermia-chemotherapy of tongue cancer. Here, we have examined the effect of Fe(Salen) on human glioblastoma (GB). Fe(Salen) showed in vitro anti-tumor activity towards several human GB cell lines. It inhibited cell proliferation, and its apoptosis-inducing activity was greater than that of clinically used drugs. Fe(Salen) also showed in vivo anti-tumor activity in the mouse brain. We evaluated the drug distribution and systemic side effects of intracerebrally injected Fe(Salen) nanoparticles in rats. Further, to examine whether hyperthermia, which was induced by exposing Fe(Salen) nanoparticles to AMF, enhanced the intrinsic anti-tumor effect of Fe(Salen), we used a mouse model grafted with U251 cells on the left leg. Fe(Salen), BCNU, or normal saline was injected into the tumor in the presence or absence of AMF exposure. The combination of Fe(Salen) injection and AMF exposure showed a greater anti-tumor effect than did either Fe(Salen) or BCNU alone. Our results indicate that hyperthermia and chemotherapy with single-drug nanoparticles could be done for GB treatment.

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          CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009.

          Therese A Dolecek, Jennifer M Propp, Nancy E. Stroup … (2012)
          Article 0 comments Cited 544 times – based on 0 reviews     Review now
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            Glioma extent of resection and its impact on patient outcome.

            Nader Sanai, Mitchel S. Berger, Andrew Henry Kaye (2008)
            There is still no general consensus in the literature regarding the role of extent of glioma resection in improving patient outcome. Although the importance of resection in obtaining tissue diagnosis and alleviating symptoms is clear, a lack of Class I evidence prevents similar certainty in assessing the influence of extent of resection. We reviewed every major clinical publication since 1990 on the role of extent of resection in glioma outcome. Twenty-eight high-grade glioma articles and 10 low-grade glioma articles were examined in terms of quality of evidence, expected extent of resection, and survival benefit. Despite persistent limitations in the quality of data, mounting evidence suggests that more extensive surgical resection is associated with longer life expectancy for both low- and high-grade gliomas.
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              Heating the patient: a promising approach?

              J. van der Zee (2002)
              There is a clear rationale for using hyperthermia in cancer treatment. Treatment at temperatures between 40 and 44 degrees C is cytotoxic for cells in an environment with a low pO(2) and low pH, conditions that are found specifically within tumour tissue, due to insufficient blood perfusion. Under such conditions radiotherapy is less effective, and systemically applied cytotoxic agents will reach such areas in lower concentrations than in well perfused areas. Therefore, the addition of hyperthermia to radiotherapy or chemotherapy will result in at least an additive effect. Furthermore, the effects of both radiotherapy and many drugs are enhanced at an increased temperature. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources, regional hyperthermia by perfusion of organs or limbs, or by irrigation of body cavities, and whole body hyperthermia. The use of hyperthermia alone has resulted in complete overall response rates of 13%. The clinical value of hyperthermia in addition to other treatment modalities has been shown in randomised trials. Significant improvement in clinical outcome has been demonstrated for tumours of the head and neck, breast, brain, bladder, cervix, rectum, lung, oesophagus, vulva and vagina, and also for melanoma. Additional hyperthermia resulted in remarkably higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects and/or better overall survival rates. Generally, when combined with radiotherapy, no increase in radiation toxicity could be demonstrated. Whether toxicity from chemotherapy is enhanced depends on sequence of the two modalities, and on which tissues are heated. Toxicity from hyperthermia cannot always be avoided, but is usually of limited clinical relevance. Recent developments include improvements in heating techniques and thermometry, development of hyperthermia treatment planning models, studies on heat shock proteins and an effect on anti-cancer immune responses, drug targeting to tumours, bone marrow purging, combination with drugs targeting tumour vasculature, and the role of hyperthermia in gene therapy. The clinical results achieved to date have confirmed the expectations raised by results from experimental studies. These findings justify using hyperthermia as part of standard treatment in tumour sites for which its efficacy has been proven and, furthermore, to initiate new studies with other tumours. Hyperthermia is certainly a promising approach and deserves more attention than it has received until now.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 20 February 2017
                Publication date Collection: 2017
                Volume: 7
                Electronic Location Identifier: 42783
                Affiliations
                [1 ]Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine , Yokohama, 236-0004, Japan
                [2 ]Department of Neurosurgery, Yokohama City University, Graduate School of Medicine , Yokohama, 236-0004, Japan
                [3 ]Department of Oral and Maxillofacial Surgery, Yokohama City University, Graduate School of Medicine , Yokohama, 236-0004, Japan
                [4 ]Department of Veterinary Medicine, Nihon University , Fujisawa, 252-8510, Japan
                [5 ]Department of Environment and Natural Sciences, Graduate School of Environment and Information Sciences, Yokohama National University , Yokohama, 240-8501, Japan
                [6 ]Advanced Applied Science Department, Research Laboratory, IHI Corporation , Yokohama, 235-0031, Japan
                [7 ]Heat and Fluid Dynamics Department, Research Laboratory, IHI Corporation , Yokohama, 235-0031, Japan
                [8 ]Collage of Science and Engineering, Kanazawa University , Kakuma, 920-1192, Japan
                [9 ]Neutron Science Laboratory, Institute for Solid State Physics, the University of Tokyo, Shirakata , Tokai, 319-1106, Japan
                [10 ]Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, QST , Chiba, 263-8555, Japan
                [11 ]Electrical and Computer Engineering, Yokohama National University , Yokohama, 240-8501, Japan
                Author notes
                Article
                Publisher Item ID: srep42783
                DOI: 10.1038/srep42783
                PMC ID: 5316938
                PubMed ID: 28218292
                SO-VID: 77482497-c14d-4496-bf30-c3d91e8cbc89
                Copyright © Copyright © 2017, The Author(s)
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 11 May 2016
                Date accepted : 16 January 2017
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