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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 3  |  Page : 1132-1137

Nanothermia: A heterogenic heating approach


Department of Biotechnics, Faculty of Engineering, St. Istvan University, Godollo, Hungary

Date of Web Publication4-Jan-2017

Correspondence Address:
Szasz Oliver
2071-Paty, Ibolya u. 2
Hungary
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.197568

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 > Abstract 

Aim of Study: The aim of the study is to show the possible differences on the same temperature and treatment time as control parameter of the variety of local hyperthermia techniques, pointing the possible differences in the local and systemic actions.
Materials and Methods: Debate about the apparent locality of malignancy and the problems of the local treatment.
Results: Consider the physiological feedback mechanisms, the spread of temperature, and the time which has active role in the spreading.
Conclusion: Points that the clinical results depend not only on the temperature but also on the technical solution of the heat delivery.

Keywords: Membrane rafts, nanoheating, technical differences


How to cite this article:
Oliver S, Andras S. Nanothermia: A heterogenic heating approach. J Can Res Ther 2016;12:1132-7

How to cite this URL:
Oliver S, Andras S. Nanothermia: A heterogenic heating approach. J Can Res Ther [serial online] 2016 [cited 2017 Feb 23];12:1132-7. Available from: http://www.cancerjournal.net/text.asp?2016/12/3/1132/197568


 > Introduction Top


In the first half of the 19th century, the bioelectro-effects, delivering energy in depth, were the hope to solve not only hyperthermia but also complete medicine. In hyperthermia, two concepts were competed: heating process by temperature increase of the absorbed energy and electromagnetic effects of the absorbed energy.[1],[2]

The missing thing at that time was physical and biological knowledge which could clear at least the part of the underlying interactions and the complex feedback controls in the phenomenon that hindered the bioelectric concept behind the thermal solutions.


 > Materials and Methods Top


New paradigm for heating

Despite the same temperature by conventional and microwave heating, the reaction was significantly different,[3] gaining intensive debates about thermal and nonthermal effects.[4],[5],[6] The control of the cells by electrical manipulations is proven well,[7] when the field is static or the current is constant.[8]

The physiologic regulations well depend on the temperature; all the systemic networks (blood flow, lymph network, and nerve system) have reaction on the temperature. We have to take into consideration the effect of the physiology conditions, mainly the blood flow which is responsible for thermal adjustment and drug delivery (chemotherapy), as well as oxygen delivery (radiotherapy), essential for complementary applications. It has been shown that an increase in temperature can cause vasoconstriction in certain tumors leading to decreased blood perfusion and heat conduction while causing vasodilatation in the healthy tissues lead to increased relative blood perfusion and heat conduction in this region, providing an effective heat trap.[9]

The conventional heating is based on the heat – convention and conduction; primarily, it has a heat flow from outside to inside the target while in case of the selective heating, the heat flow is opposite [Figure 1].
Figure 1: Concept of conventional and nanoheating

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The energy absorption of the biomaterial fundamentally changes by the frequency due to the diversely structured and connected heterogenic material prefers miscellaneous effects [10] [Figure 2]. The most frequently used frequency (the medical standard) is 13.56 MHz; it especially selects the lipids (membranes) and connected structures, such as transmembrane proteins and rafts.
Figure 2: The general bioelectromagnetic interactions are sharply depending on the frequency applied. The dielectric dispersion of the simple water also has specialties[16]

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There are two capacitive couplings exist: plane-wave “radiation” matching and impedance matching [Figure 3]. In the impedance matching, the perfect transfer between the applicator and the target mimics the invasive “resistive” impedance solution while the other one is based on wave reflection.
Figure 3: The plane wave radiative (a) and the tight impedance matching (b)

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The main difference between the two matching is shown in [Figure 4].
Figure 4: The differences between the “radiative-matched” (a-c) and “impedance-matched” (d-f) capacitive solutions. The radiative solution calculated planar waves from the electrodes which are the initial beam (a) and it has reflected one in every layers of the target (b). The result is their addition (c). In case of an impedance-matched solution, we have to calculate the free charges in the electrolytes (real conduction current, d), but when it has no charge to conduct the current, only dipoles have identical but opposite charge fixed together; the conduction by free charges is impossible. However, then any way flows a current (called “displacement current,” e). The reality of biomatter that both existing, but the Joule heat is produced only by the conductive current (f). The displacement current also may produce heat by the movement, rotation, friction of the dipoles which are in the material

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In these cases, the optimizing strategy is different; the wave one is concentrating on the reflected power. The other one is optimized with the phase shift of the voltage to the current, blocking the current when the isolation cannot be compensated [Figure 5].
Figure 5: The plane wave (a) and radiofrequency-impedance matching (b) in capacitive arrangements

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The modulated electrohyperthermia (mEHT; trade name: Oncothermia) uses the precise energy delivery using certain differences between the malignant and healthy cells. The selection is made by the concentration of ionic metabolites (Warburg effect),[11] dielectric constant (cellular connections) in the immediate vicinity of the malignant and healthy cells (Szentgyorgyi effect),[12] frequency dispersion specialties of cellular membranes (Schwan effect),[13] and structural differences between the malignant and healthy tissues (fractal physiology).[14],[15]

The radiofrequency currents could create hot-spots in nanorange at the membrane rafts, which could be heated high quickly. These spots heat up the complete cell, which heats up the tumor itself on the mild temperature [Figure 6].
Figure 6: Mechanism of nanoheating

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Technical realization of the method is discussed elsewhere.[17],[18],[19],[20]


 > Results Top


mEHT realizes a new type of heating: nanothermia. In silico calculated how the energy absorption in nanorange works.[21] Various in vitro and iv vivo experiments had proven the thermal origin of the nanoeffects. The U937 human lymphoma cell line was compared in the water bath hyperthermia (WHT) and nanothermia. It was rigorously shown that the membrane rafts are heated at least 3°C higher in temperature than the medium which was the reference with WHT. Note, this results is in good agreement with the much earlier in vivo experimental facts.[22] The measured Arrhenius plot showed definite lowering of the activation energy in case of nanothermia compared to WHT.[23] It is theoretically shown that the membrane rafts could be the basic target of the nanoheating, and the transient receptor potential vanilloid receptors have definite role in the temperature sensing.[24] This gave the idea to measure the Ca 2+ influx into the cell in comparison to a reference, which can be connected to transient receptor potential (TRPV) sensing. Experimental proofs showed the start of the Ca 2+ influx happening at least 3°C earlier in case of nanothermia, and direct staining temperature measurement also showed the same.[25]

Nanothermia rebuilds E-cadherin-beta-catenin complexes as the first step of the bystander effect.[26]

The apoptotic process by nanothermia has a new line of local hyperthermia treatment. Recognizing the problem that the malignancy is not a local disease so it could not be treated locally only, the nanothermia trend is to concentrate on the systemic effects. Nanothermia kills the cells by apoptosis [27] and develops damage associated molecular pattern by the apoptotic bodies, calreticulin and HMBB1 release, membrane expression of HSP70 and HSP90, and expression of the DR5 death receptor. This pattern leads to immunogenic cell death,[28] which could lead to the bystander and abscopal effect.[29],[30]

Nanothermia has multiple clinical studies, mainly in the Phase II category.[31] Some special results are published for gliomas (n = 140),[32] (n = 36),[33] (n = 19),[34] (n = 179),[35] (n = 12),[36] (n = 15),[37] for hepatocellular carcinoma (n = 21),[38] for liver (metastatic of colorectal origin) (n = 80),[39] (n = 22),[40] (n = 21),[38] (n = 60),[41] for bone metastasis from non-small cell lung cancer (NSCLC) (case report),[42] for pancreas (n = 26),[43] (n = 26),[44] for cervix (n = 72),[45] for ovary,[46] for prostate (n = 184),[47] for soft-tissue sarcoma (n = 24),[48] for advanced sarcomas (n = 13),[49] for biliary carcinoma,[50] for SCLC (n = 31),[51] and for NSCLC (n = 311)[52] and (n = 4)[53] (case report).[54] The comparison with the large databases was made in multiple clinics relations showing extremely large (minimum 20%) enhancement of the 1st year survival percentages.


 > Conclusion Top


Nanothermia (generic name: modulated hyperthermia; trade name: Oncothermia) is a new, nanoheating hyperthermia method, a committed fighter in the “war” against cancer. It has good clinical achievements in the far-advanced clinical cases, studies, making stable basis of the clinical applications in various advanced primary and metastatic malignancies. The nanothermia solution answers positively on the doubt and introduces the fourth column of the gold-standard oncological methods, additionally to the surgery, radio- and chemo-therapies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Short History of Bioelectrics. Available from: http://www.pulsedpower.eu/bioelectrics/bio_02_main.html. [Last accessed on 2015 Sep 28].  Back to cited text no. 1
    
2.
Kratzer GL, Onsanit T. Fulguration of selected cancers of the rectum: Report of 27 cases. Dis Colon Rectum 1972;15:431-5.  Back to cited text no. 2
    
3.
de Pomerai D, Daniells C, David H, Allan J, Duce I, Mutwakil M, et al. Non-thermal heat-shock response to microwaves. Nature 2000;405:417-8.  Back to cited text no. 3
    
4.
de la Hoz A, Díaz-Ortiz A, Moreno A. Review on non-thermal effects of microwave irradiation in organic synthesis. J Microw Power Electromagn Energy 2007;41:44-64.  Back to cited text no. 4
    
5.
de Pomerai DI, Dawe A, Djerbib L, Djerbib L, Allan J, Brunt G, et al. Growth and maturation of the nematode Caenorhabditis elegans following exposure to weak microwave fields. Enzyme Microb Technol 2002;30:73-9.  Back to cited text no. 5
    
6.
de Pomerai DI, Smith B, Dawe A, North K, Smith T, Archer DB, et al. Microwave radiation can alter protein conformation without bulk heating. FEBS Lett 2003;543:93-7.  Back to cited text no. 6
    
7.
McCaig CD, Rajnicek AM, Song B, Zhao M. Controlling cell behavior electrically: Current views and future potential. Physiol Rev 2005;85:943-78.  Back to cited text no. 7
    
8.
Astumian D. Direct electric field effects and sequential process in biosystems. Bioelectrochem Bioenerg 1991;25:455-62.  Back to cited text no. 8
    
9.
Takana Y. Thermal responses of microcirculation and modification of tumor blood flow in treating the tumors. In: Kosaka M, Sugahara T, Schmindt KL, Simon E, editors. Theoretical and Experimental Basis of Hyperthermia. Thermotherapy for Neoplasia, Inflammation, and Pain. Tokyo: Springer Verlag; 2001. p. 408-19.  Back to cited text no. 9
    
10.
Martinsen OG, Grimnes S, Schwan HP. Interface phenomena and dielectric properties of biological tissue. Encyclopedia of Surface and Colloid Science. New York: Marcel Dekker, Inc.; 2002. p. 2643-52.  Back to cited text no. 10
    
11.
Warburg O, editor. Oxygen, the creator of differentiation, biochemical energetics. In: The Prime Cause and Prevention of Cancer, Revised Lecture at the Meeting of the Nobel-Laureates at Lindau, Lake Constance, Germany. New York: Academic Press; 1966.  Back to cited text no. 11
    
12.
Szentgyorgyi A. Bioelectronics: A Study on Cellular Regulations, Defense and Cancer. New York, London: Academic Press; 1968.  Back to cited text no. 12
    
13.
Schwan HP. Determination of biological impedances. In: Physical Techniques in Biological Research. Vol. 6. New York: Academic Press; 1963. p. 323-406.  Back to cited text no. 13
    
14.
Bassingthwaighte JB, Leibovitch LS, West BJ. Fractal Physiology. New York, Oxford: Oxford University Press; 1994.  Back to cited text no. 14
    
15.
Szasz O, Andocs G, Meggyeshazi N. Modulation effect in oncothermia. Conf Pap Med 2013;2013:398678.  Back to cited text no. 15
    
16.
Pething R. Dielectric and Electronic Properties of Biological Materials. Chichester and New York: John Wiley & Sons; 1979.  Back to cited text no. 16
    
17.
Szasz O. Burden of oncothermia: Why is it special? Conf Pap Med 2013;2013:938689.  Back to cited text no. 17
    
18.
Szasz A, Szasz O, Szasz N. Physical background and technical realization of hyperthermia. In: Baronzio GF, Hager ED, editors. Hyperthermia in Cancer Treatment: A Primer. US: Springer-Verlag; 2005.  Back to cited text no. 18
    
19.
Szasz A. Oncothermia: Complex Therapy by EM and Fractal Physiology, General Assembly and Scientific Symposium (URSI GASS), XXXI Conference, IEEE; 2014.  Back to cited text no. 19
    
20.
Szasz A. Bioelectromagnetic paradigm of cancer treatment – Oncothermia. In: Rosch PJ, editor. Bioelectromagnetic and Subtle Energy Medicine. New York: CRC Press, Taylor and Francis Group; 2015. p. 323-36.  Back to cited text no. 20
    
21.
Papp E, Vancsik T, Kiss E, Szasz A. Membrane Raft Absorption in the Modulated Electro-hyperthermia (mEHT), Presentation at the 33rd Annual Conference of the International Clinical Hyperthermia Society (ICHS), Nidda, Germany; 2015.  Back to cited text no. 21
    
22.
Andocs G, Renner H, Balogh L, Fonyad L, Jakab C, Szasz A. Strong synergy of heat and modulated electromagnetic field in tumor cell killing. Strahlenther Onkol 2009;185:120-6.  Back to cited text no. 22
    
23.
Andocs G, Rehman MU, Zhao QL, Papp E, Kondo T, Szasz A. Nanoheating without artificial nanoparticles part II. Experimental support of the nanoheating concept of the modulated electro-hyperthermia method, using U937 cell suspension model. Biol Med 2015;7:1-9.  Back to cited text no. 23
    
24.
Vincze GY, Szigeti GY, Andocs G, Szasz A. Nanoheating without artificial nanoparticles. Biol Med 2015;7:249.  Back to cited text no. 24
    
25.
Vancsik T, Andocs G, Kovago C, Papp E, Meggyeshazi N, Kiss E, et al. Electro-hyperthermia may Target Tumor-cell Membranes, Presentation at the 33rd Annual Conference of the International Clinical Hyperthermia Society (ICHS), Nidda, Germany; 2015.  Back to cited text no. 25
    
26.
Andocs G, Szasz O, Szasz A. Oncothermia treatment of cancer: From the laboratory to clinic. Electromagn Biol Med 2009;28:148-65.  Back to cited text no. 26
    
27.
Meggyeshazi N, Andocs G, Balogh L, Balla P, Kiszner G, Teleki I, et al. DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia. Strahlenther Onkol 2014;190:815-22.  Back to cited text no. 27
    
28.
Andocs G, Meggyeshazi N, Balogh L, Spisak S, Maros ME, Balla P, et al. Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia. Cell Stress Chaperones 2015;20:37-46.  Back to cited text no. 28
    
29.
Qin W, Akutsu Y, Andocs G, Suganami A, Hu X, Yusup G, et al. Modulated electro-hyperthermia enhances dendritic cell therapy through an abscopal effect in mice. Oncol Rep 2014;32:2373-9.  Back to cited text no. 29
    
30.
Andocs G, Meggyeshazi N, Okamoto Y, Balogh L, Szasz O. Bystander effect of oncothermia. Conf Pap Med 2013;2013:953482.  Back to cited text no. 30
    
31.
Szasz A, Szasz N, Szasz O. Local hyperthermia in oncology. In: Huilgol N, editor. Hyperthermia. Ch. 1. Croatia: InTech; 2013.  Back to cited text no. 31
    
32.
Sahinbas H, Groenemeyer D, Boecher E, Szasz A. Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas. Dtsch Z Onkol 2007;39:154-60.  Back to cited text no. 32
    
33.
Hager ED, Dziambor H, App EM, Popa C, Popa O, Hertlein M. The treatment of patients with high-grade malignant gliomas with RF-hyperthermia. Proc Am Soc Clin Oncol 2003;22:118, #47  Back to cited text no. 33
    
34.
Douwes F, Douwes O, Migeod F, Grote C, Bogovic J. Hyperthermia in combination with ACNU chemotherapy in the treatment of recurrent glioblastoma. Germany: St. Georg Klinik; 2006. Available from: http://www.klinik-st-georg.de/fileadmin/publikationen/en/hyperthermia_in_combination_with_ACNU_chemotherapy_in_the_treatment_of_recurrent_glioblastoma.pdf. [Last accessed on 2015 Sep 28].  Back to cited text no. 34
    
35.
Hager ED, Sahinbas H, Groenemeyer DH, Migeod F. Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia. J Clin Oncol 2008;26:2047.  Back to cited text no. 35
    
36.
Fiorentini G, Giovanis P, Rossi S, Dentico P, Paola R, Turrisi G, et al. A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia.In Vivo 2006;20:721-4.  Back to cited text no. 36
    
37.
Wismeth C, Dudel C, Pascher C, Ramm P, Pietsch T, Hirschmann B, et al. Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas: Phase I clinical results. J Neurooncol 2010;98:395-405.  Back to cited text no. 37
    
38.
Gadaleta-Caldarola G, Infusino S, Galise I, Ranieri G, Vinciarelli G, Fazio V, et al. Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma: A phase II study. Oncol Lett 2014;8:1783-7.  Back to cited text no. 38
    
39.
Hager ED, Dziambor H, Höhmann D, Gallenbeck D, Stephan M, Popa C. Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer. Anticancer Res 1999;19:3403-8.  Back to cited text no. 39
    
40.
Ferrari VD, De Ponti S, Valcamonico F, Amoroso V, Grisanti S, Rangoni G, et al. Deep electro-hyperthermia (EHY) with or without thermo-active agents in patients with advanced hepatic cell carcinoma: Phase II study. J Clin Oncol 2007;25:18S, 15168.  Back to cited text no. 40
    
41.
Fiorentini G, Milandri C, Dentico P, Giordani P, Catalano V, Bunkeila F. Deep Electro-hyperthermia with Radiofrequencies Combined with Thermoactive Drugs in Patients with Liver Metastases form Colorectal Cancer (CRC) a Phase II Clinical Study. 31st Conference of International Clinical Hyperthermia Society (ICHS), Budapest, Hungary; 2012.  Back to cited text no. 41
    
42.
Rubovszky G, Nagy T, Godény M, Szász A, Láng I. Successful treatment of solitary bone metastasis of non-small cell lung cancer with bevacizumab and hyperthermia. Pathol Oncol Res 2013;19:119-22.  Back to cited text no. 42
    
43.
Dani A, Varkonyi A, Magyar T, Szász A. Clinical study for advanced pancreas cancer treated by oncothermia. Forum Hyperthermie 2008;1:13-20.  Back to cited text no. 43
    
44.
Volovat C, Volovat SR, Scripcaru V, Miron L. Second-line chemotherapy with gemcitabine and oxaliplatin in combination with loco-regional hyperthermia (EHY-2000) in patients with refractory metastatic pancreatic cancer – Preliminary results of a prospective trial. Rom Rep Phys 2014;66:166-74.  Back to cited text no. 44
    
45.
Pesti L, Dankovics ZS, Lorencz P, Csejtei A. Treatment of advanced cervical cancer with complex chemoradio – Hyperthermia. Conf Pap Med 2013;2013:192435.  Back to cited text no. 45
    
46.
Fiorentini G, Montagnanai F, Vaira M, Desimone M. Intraperitoneal Cisplatine and Paclitaxel Combined with External Capacitive Hyperthermia in Patients with Relapsed Epithelial Ovarian Cancer: A Phase II Clinical Study, International Oncothermia Symposium, Cologne, Germany; 2010. Available from: http://www.io-symposium.com/oncothermia/2010/pres/Fiorentini2.PDF. [Last accessed on 2015 Sep 28].  Back to cited text no. 46
    
47.
Douwes FR, Lieberman S. Radiofrequency transurethral hyperthermia and complete androgen blockade. Altern Complement Ther 2001;7:6, 291-5.  Back to cited text no. 47
    
48.
Volovat SR, Volovat C, Scripcariu V, Lupascu C, Miron L. The results of combination of ifosfamid and locoregional hyperthermia (EHY 2000) in patients with advanced abdominal soft-tissue sarcoma after relapse of first line chemotherapy. Rom Rep Phys 2014;66:175-81.  Back to cited text no. 48
    
49.
Jeung TS, Ma SY, Choi JH, Yu J, Lee SY, Lim S. Results of oncothermia combined with operation, chemotherapy and radiation therapy for primary, recurrent and metastatic sarcoma. Case Rep Clin Med 2015;4:157-68.  Back to cited text no. 49
    
50.
Mambrini A, Del Freo A, Pacetti P, Orlandi M, Torri T, Fiorentini G, et al. Intra-arterial and systemic chemotherapy plus external hyperthermia in unresectable biliary cancer. Clin Oncol (R Coll Radiol) 2007;19:805-6.  Back to cited text no. 50
    
51.
Lee DY, Haam SJ, Kim TH, Lim JY, Kim EJ, Kim NY. Oncothermia with chemotherapy in the patients with small cell lung cancer. Conf Pap Med 2013;2013:910363  Back to cited text no. 51
    
52.
Szasz A. Current status of oncothermia therapy for lung cancer. Korean J Thorac Cardiovasc Surg 2014;47:77-93.  Back to cited text no. 52
    
53.
Lee DY, Park JS, Jung HC, Byun ES, Haam SJ, Lee SS. The outcome of the chemotherapy and oncothermia for far advanced adenocarcinoma of the lung: Case reports of four patients. Adv Lung Cancer 2015;4:1-7.  Back to cited text no. 53
    
54.
Yeo SG. Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report. J Adv Phys 2015;10:2538-59.  Back to cited text no. 54
    


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