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      Therapeutic evaluation of magnetic hyperthermia using Fe 3O 4-aminosilane-coated iron oxide nanoparticles in glioblastoma animal model Translated title: Avaliação terapêutica da técnica de magneto-hipertermia utilizando nanopartículas de Fe 3O 4 recobertas com aminosilana em modelo animal de glioblastoma

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          ABSTRACT

          Objective:

          To evaluate the potential of magnetic hyperthermia using aminosilane-coated superparamagnetic iron oxide nanoparticles in glioblastoma tumor model.

          Methods:

          The aminosilane-coated superparamagnetic iron oxide nanoparticles were analyzed as to their stability in aqueous medium and their heating potential through specific absorption rate, when submitted to magnetic hyperthermia with different frequencies and intensities of alternating magnetic field. In magnetic hyperthermia in vitro assays, the C6 cells cultured and transduced with luciferase were analyzed by bioluminescence in the absence/presence of alternating magnetic field, and also with and without aminosilane-coated superparamagnetic iron oxide nanoparticles. In the in vivo study, the measurement of bioluminescence was performed 21 days after glioblastoma induction with C6 cells in rats. After 24 hours, the aminosilane-coated superparamagnetic iron oxide nanoparticles were implanted in animals, and magnetic hyperthermia was performed for 40 minutes, using the best conditions of frequency and intensity of alternating magnetic field tested in the in vitro study (the highest specific absorption rate value) and verified the difference of bioluminescence before and after magnetic hyperthermia.

          Results:

          The aminosilane-coated superparamagnetic iron oxide nanoparticles were stable, and their heating capacity increased along with higher frequency and intensity of alternating magnetic field. The magnetic hyperthermia application with 874kHz and 200 Gauss of alternating magnetic field determined the best value of specific absorption rate (194.917W/g). When these magnetic hyperthermia parameters were used in in vitro and in vivo analysis, resulted in cell death of 52.0% and 32.8%, respectively, detected by bioluminescence.

          Conclusion:

          The magnetic hyperthermia was promissing for the therapeutical process of glioblastoma tumors in animal model, using aminosilane-coated superparamagnetic iron oxide nanoparticles, which presented high specific absorption rate.

          RESUMO

          Objetivo:

          Avaliar o potencial da técnica de magneto-hipertermia utilizando nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana em modelo de tumores de glioblastoma.

          Métodos:

          As nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana foram avaliadas quanto à sua estabilidade em meio aquoso e a seu potencial de aquecimento pela taxa de absorção específica, quando submetidas à magneto-hipertermia, com diferentes frequências e intensidades de campo magnético alternado. Nos ensaios de magneto-hipertermia in vitro, as células C6 cultivadas e transduzidas com luciferase foram avaliadas por bioluminescência na presença/ausência do campo magnético alternado, como também com e sem nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana. No estudo in vivo, a medida de bioluminescência foi adquirida no 21º dia após indução do glioblastoma com células C6 nos ratos. Após 24 horas, as nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana foram implantadas no animal, tendo sido realizada a magneto-hipertermia por 40 minutos, nas melhores condições de frequência e intensidade de campo magnético alternado testado no estudo in vitro (maior valor da taxa de absorção específica); foi verificada a diferença do bioluminescência antes e após a magneto-hipertermia.

          Resultados:

          As nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana se mostraram estáveis, e sua capacidade de aquecimento aumentou com o incremento da frequência e da intensidade de campo magnético alternado. A aplicação da magneto-hipertermia, com 874kHz e 200 Gauss do campo magnético alternado, determinou o melhor valor da taxa de absorção específica (194,917W/g). Quando utilizados, estes parâmetros de magneto-hipertermia in vitro resultaram em morte celular de 52,0% e in vivo de 32,8% por bioluminescência.

          Conclusão:

          A técnica de magneto-hipertermia foi promissora para o processo terapêutico de tumores de glioblastoma no modelo animal utilizando as nanopartículas superparamagnéticas de óxido de ferro recobertas com aminosilana recobertas com aminosilana, que apresentaram alta taxa de absorção específica.

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          Most cited references31

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          Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme.

          We aimed to evaluate the feasibility and tolerability of the newly developed thermotherapy using magnetic nanoparticles on recurrent glioblastoma multiforme. Fourteen patients received 3-dimensional image guided intratumoral injection of aminosilane coated iron oxide nanoparticles. The patients were then exposed to an alternating magnetic field to induce particle heating. The amount of fluid and the spatial distribution of the depots were planned in advance by means of a specially developed treatment planning software following magnetic resonance imaging (MRI). The actually achieved magnetic fluid distribution was measured by computed tomography (CT), which after matching to pre-operative MRI data enables the calculation of the expected heat distribution within the tumor in dependence of the magnetic field strength. Patients received 4-10 (median: 6) thermotherapy treatments following instillation of 0.1-0.7 ml (median: 0.2) of magnetic fluid per ml tumor volume and single fractions (2 Gy) of a radiotherapy series of 16-70 Gy (median: 30). Thermotherapy using magnetic nanoparticles was tolerated well by all patients with minor or no side effects. Median maximum intratumoral temperatures of 44.6 degrees C (42.4-49.5 degrees C) were measured and signs of local tumor control were observed. In conclusion, deep cranial thermotherapy using magnetic nanoparticles can be safely applied on glioblastoma multiforme patients.
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            Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas.

            In this review we will describe eight commonly used rat brain tumor models and their application for the development of novel therapeutic and diagnostic modalities. The C6, 9L and T9 gliomas were induced by repeated injections of methylnitrosourea (MNU) to adult rats. The C6 glioma has been used extensively for a variety of studies, but since it arose in an outbred Wistar rat, it is not syngeneic to any inbred strain, and its potential to evoke an alloimmune response is a serious limitation. The 9L gliosarcoma has been used widely and has provided important information relating to brain tumor biology and therapy. The T9 glioma, although not generally recognized, was and probably still is the same as the 9L. Both of these tumors arose in Fischer rats and can be immunogenic in syngeneic hosts, a fact that must be taken into consideration when used in therapy studies, especially if survival is the endpoint. The RG2 and F98 gliomas were both chemically induced by administering ethylnitrosourea (ENU) to pregnant rats, the progeny of which developed brain tumors that subsequently were propagated in vitro and cloned. They are either weakly or non-immunogenic and have an invasive pattern of growth and uniform lethality, which make them particularly attractive models to test new therapeutic modalities. The CNS-1 glioma was induced by administering MNU to a Lewis rat. It has an infiltrative pattern of growth and is weakly immunogenic, which should make it useful in experimental neuro-oncology. Finally, the BT4C glioma was induced by administering ENU to a BD IX rat, following which brain cells were propagated in vitro until a tumorigenic clone was isolated. This tumor has been used for a variety of studies to evaluate new therapeutic modalities. The Avian Sarcoma Virus (ASV) induced tumors, and a continuous cell line derived from one of them designated RT-2, have been useful for studies in which de novo tumor induction is an important requirement. These tumors also are immunogenic and this limits their usefulness for therapy studies. It is essential to recognize the limitations of each of the models that have been described, and depending upon the nature of the study to be conducted, it is important that the appropriate model be selected.
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              Magnetic hyperthermia therapy for the treatment of glioblastoma: a review of the therapy’s history, efficacy and application in humans

              Hyperthermia therapy (HT) is the exposure of a region of the body to elevated temperatures to achieve a therapeutic effect. HT anticancer properties and its potential as a cancer treatment have been studied for decades. Techniques used to achieve a localised hyperthermic effect include radiofrequency, ultrasound, microwave, laser and magnetic nanoparticles (MNPs). The use of MNPs for therapeutic hyperthermia generation is known as magnetic hyperthermia therapy (MHT) and was first attempted as a cancer therapy in 1957. However, despite more recent advancements, MHT has still not become part of the standard of care for cancer treatment. Certain challenges, such as accurate thermometry within the tumour mass and precise tumour heating, preclude its widespread application as a treatment modality for cancer. MHT is especially attractive for the treatment of glioblastoma (GBM), the most common and aggressive primary brain cancer in adults, which has no cure. In this review, the application of MHT as a therapeutic modality for GBM will be discussed. Its therapeutic efficacy, technical details, and major experimental and clinical findings will be reviewed and analysed. Finally, current limitations, areas of improvement, and future directions will be discussed in depth.
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                Author and article information

                Journal
                Einstein (Sao Paulo)
                Einstein (Sao Paulo)
                EINS
                Einstein
                Instituto Israelita de Ensino e Pesquisa Albert Einstein
                1679-4508
                2317-6385
                25 July 2019
                2019
                : 17
                : 4
                : eAO4786
                Affiliations
                [1 ]Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
                [2 ]Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
                Author notes
                Corresponding author: Lionel Fernel Gamarra, Avenida Albert Einstein, 627/701 – Morumbi Zip code: 05652-900 – São Paulo, SP, Brazil Phone: (55 11) 3747-0243 E-mail: lionelgamarra7@ 123456gmail.com

                Conflict of interest:

                none.

                Author information
                http://orcid.org/0000-0003-2011-0373
                http://orcid.org/0000-0001-5038-0070
                http://orcid.org/0000-0001-9931-5296
                http://orcid.org/0000-0002-1502-9215
                http://orcid.org/0000-0002-1173-745X
                http://orcid.org/0000-0002-3910-0047
                Article
                einstein_journal/2019AO4786 00201
                10.31744/einstein_journal/2019AO4786
                6668731
                31390427
                c4a150f4-6fe5-43c9-a8d7-b77f7ef41893

                This content is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 04 October 2018
                : 28 March 2019
                Page count
                Figures: 10, Tables: 2, Equations: 2, References: 35
                Categories
                Original Article

                glioblastoma/therapy,magnetic, hyperthermia,nanoparticles,magnetite nanoparticles,cell tracking/methods,aminosilane,tumoral model,rats,glioblastoma/terapia,magneto, hipertermia,nanopartículas,nanopartículas de magnetita,aminosilana,modelo tumoral,ratos

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