|Year : 2016 | Volume
| Issue : 3 | Page : 1132-1137
Nanothermia: A heterogenic heating approach
Szasz Oliver, Szasz Andras
Department of Biotechnics, Faculty of Engineering, St. Istvan University, Godollo, Hungary
|Date of Web Publication||4-Jan-2017|
2071-Paty, Ibolya u. 2
Source of Support: None, Conflict of Interest: None
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
| > Introduction|| |
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.,
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|| |
New paradigm for heating
Despite the same temperature by conventional and microwave heating, the reaction was significantly different, gaining intensive debates about thermal and nonthermal effects.,, The control of the cells by electrical manipulations is proven well, when the field is static or the current is constant.
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.
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].
The energy absorption of the biomaterial fundamentally changes by the frequency due to the diversely structured and connected heterogenic material prefers miscellaneous effects  [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|
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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), dielectric constant (cellular connections) in the immediate vicinity of the malignant and healthy cells (Szentgyorgyi effect), frequency dispersion specialties of cellular membranes (Schwan effect), and structural differences between the malignant and healthy tissues (fractal physiology).,
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].
Technical realization of the method is discussed elsewhere.,,,
| > Results|| |
mEHT realizes a new type of heating: nanothermia. In silico calculated how the energy absorption in nanorange works. 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. The measured Arrhenius plot showed definite lowering of the activation energy in case of nanothermia compared to WHT. 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. 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.
Nanothermia rebuilds E-cadherin-beta-catenin complexes as the first step of the bystander effect.
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  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, which could lead to the bystander and abscopal effect.,
Nanothermia has multiple clinical studies, mainly in the Phase II category. Some special results are published for gliomas (n = 140), (n = 36), (n = 19), (n = 179), (n = 12), (n = 15), for hepatocellular carcinoma (n = 21), for liver (metastatic of colorectal origin) (n = 80), (n = 22), (n = 21), (n = 60), for bone metastasis from non-small cell lung cancer (NSCLC) (case report), for pancreas (n = 26), (n = 26), for cervix (n = 72), for ovary, for prostate (n = 184), for soft-tissue sarcoma (n = 24), for advanced sarcomas (n = 13), for biliary carcinoma, for SCLC (n = 31), and for NSCLC (n = 311) and (n = 4) (case report). 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|| |
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
Conflicts of interest
There are no conflicts of interest.
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