The dielectric properties of skin and their influence on the delivery of tumor treating fields to the torso: a study combining in vivo measurements with numerical simulations

Hershkovich, Hadas Sara; Urman, Noa; Yesharim, Ofir; Naveh, Ariel; Bomzon, Zéev

doi:10.1088/1361-6560/ab33c6

Cited by 23 publications

(25 citation statements)

References 39 publications

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“…It is also worth mentioning that the N1S1 murine cells used for this study, like the HepG2 cells, are p53 wild type. The intensity of TTFields applied to the rat liver was in good agreement with values obtained in field intensity simulations in humans [ 27 ], and all rats reached the required usage limit of ≥18 h/day. During the treatment period, average tumor volumes of control animals ( n = 11) increased 5.9-fold ( Figure 4 b,c and Figure S3 for tumor images).…”

Section: Resultssupporting

confidence: 69%

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Davidi¹,

Jacobovitch²,

Shteingauz³

et al. 2022

Cancers

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Hepatocellular carcinoma (HCC), a highly aggressive liver cancer, is a leading cause of cancer-related death. Tumor Treating Fields (TTFields) are electric fields that exert antimitotic effects on cancerous cells. The aims of the current research were to test the efficacy of TTFields in HCC, explore the underlying mechanisms, and investigate the possible combination of TTFields with sorafenib, one of the few front-line treatments for patients with advanced HCC. HepG2 and Huh-7D12 human HCC cell lines were treated with TTFields at various frequencies to determine the optimal frequency eliciting maximal cell count reduction. Clonogenic, apoptotic effects, and autophagy induction were measured. The efficacy of TTFields alone and with concomitant sorafenib was tested in cell cultures and in an orthotopic N1S1 rat model. Tumor volume was examined at the beginning and following 5 days of treatment. At study cessation, tumors were weighed and examined by immunohistochemistry to assess autophagy and apoptosis. TTFields were found in vitro to exert maximal effect at 150 kHz, reducing cell count and colony formation, increasing apoptosis and autophagy, and augmenting the effects of sorafenib. In animals, TTFields concomitant with sorafenib reduced tumor weight and volume fold change, and increased cases of stable disease following treatment versus TTFields or sorafenib alone. While each treatment alone elevated levels of autophagy relative to control, TTFields concomitant with sorafenib induced a significant increase versus control in tumor ER stress and apoptosis levels, demonstrating increased stress under the multimodal treatment. Overall, TTFields treatment demonstrated efficacy and enhanced the effects of sorafenib for the treatment of HCC in vitro and in vivo, via a mechanism involving induction of autophagy.

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Section: Resultssupporting

confidence: 69%

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Davidi¹,

Jacobovitch²,

Shteingauz³

et al. 2022

Cancers

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“…Between each transducer and the scalp, a thin layer of gel was added in Mimics. The average thickness of this layer was around 0.7 mm, which is very close to 0.6 mm of gel that already comes embedded in the arrays (Hershkovich et al, 2019 ).…”

Section: Methodssupporting

confidence: 65%

“…We started by investigating the information available in the log files of one patient treated with TTFields. These files are data stored in Optune's memory bank and which contain information about the voltage, current, and impedance throughout therapy, as well as the duration of treatment (Hershkovich et al, 2019 ). The impedance registered by the device is measured between the arrays and it is a result of the contribution of the impedance of the head, of the transducers, and of the contact impedance at the gel-scalp boundary.…”

Section: Methodsmentioning

confidence: 99%

Temperature and Impedance Variations During Tumor Treating Fields (TTFields) Treatment

Gentilal

Abend²,

Naveh³

et al. 2022

Front. Hum. Neurosci.

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Tumor Treating Fields (TTFields) is an FDA-approved cancer treatment technique used for glioblastoma multiforme (GBM). It consists in the application of alternating (100–500 kHz) and low-intensity (1–3 V/cm) electric fields (EFs) to interfere with the mitotic process of tumoral cells. In patients, these fields are applied via transducer arrays strategically positioned on the scalp using the NovoTAL™ system. It is recommended that the patient stays under the application of these fields for as long as possible. Inevitably, the temperature of the scalp increases because of the Joule effect, and it will remain above basal values for most part of the day. Furthermore, it is also known that the impedance of the head changes throughout treatment and that it might also play a role in the temperature variations. The goals of this work were to investigate how to realistically account for these increases and to quantify their impact in the choice of optimal arrays positions using a realistic head model with arrays positions obtained through NovoTAL™. We also studied the impedance variations based on the log files of patients who participated in the EF-14 clinical trial. Our computational results indicated that the layouts in which the arrays were very close to each other led to the appearance of a temperature hotspot that limited how much current could be injected which could consequently reduce treatment efficacy. Based on these data, we suggest that the arrays should be placed at least 1 cm apart from each other. The analysis of the impedance showed that the variations seen during treatment could be explained by three main factors: slow and long-term variations, array placement, and circadian rhythm. Our work indicates that both the temperature and impedance variations should be accounted for to improve the accuracy of computational results when investigating TTFields.

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“…Encouraged by the optimal biocompatibility of ZnO NPs (≤ 5 μg/mL), GNPs (≤ 50 μg/mL) and SiO 2 (≤ 50 μg/mL), we then investigated the role of these inorganic NPs in enhancing EF effects in patient derived GBM cells. Dielectric properties of tissues, as well as intracellular machinery, play an important role in determining the efficacy of TTFields as they are known to inhibit the proliferation of cancer cells by inducing DEP of proteins involved in the cell division process (Hershkovich et al, 2019 ; Wenger et al, 2015 ). Therefore, we hypothesised that by introducing NPs of different electrical conductivity (dielectric properties), the impedimetric properties of the cells can be modified, allowing further insights into the EF mediated cellular response.…”

Section: Resultsmentioning

confidence: 99%

Electric field responsive nanotransducers for glioblastoma

et al. 2022

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Background Electric field therapies such as Tumor Treating Fields (TTFields) have emerged as a bioelectronic treatment for isocitrate dehydrogenase wild-type and IDH mutant grade 4 astrocytoma Glioblastoma (GBM). TTFields rely on alternating current (AC) electric fields (EF) leading to the disruption of dipole alignment and induced dielectrophoresis (DEP) during cytokinesis. Although TTFields have a favourable side effect profile, particularly compared to cytotoxic chemotherapy, survival benefits remain limited (~ 4.9 months) after an extensive treatment regime (20 hours/day for 18 months). The cost of the technology also limits its clinical adoption worldwide. Therefore, the discovery of new technology that can enhance both the therapeutic efficiency and efficacy of these TTFields will be of great benefit to cancer treatment and decrease healthcare costs worldwide. Methods In this work, we report the role of electrically conductive gold (GNPs), dielectric silica oxide (SiO2), and semiconductor zinc oxide (ZnO) nanoparticles (NPs) as transducers for enhancing EF mediated anticancer effects on patient derived GBM cells. Physicochemical properties of these NPs were analyzed using spectroscopic, electron microscopy, and light-scattering techniques. Results In vitro TTFields studies indicated an enhanced reduction in the metabolic activity of patient-derived Glioma INvasive marginal (GIN 28) and Glioma contrast enhanced core (GCE 28) GBM As per our journal style, article titles should not include capitalised letters unless these are proper nouns/acronyms. We have therefore used the article title “Electric field responsive nanotransducers for glioblastoma” as opposed to “Electric Field Responsive Nanotransducers for Glioblastoma” as given in the submission system. Please check if this is correct.cells in groups treated with NPs vs. control groups, irrespective of NPs dielectric properties. Our results indicate the inorganic NPs used in this work enhance the intracellular EF effects that could be due to the virtue of bipolar dielectrophoretic and electrophoretic effects. Conclusions This work presents preliminary evidence which could help to improve future EF applications for bioelectronic medicine. Furthermore, the merits of spherical morphology, excellent colloidal stability, and low toxicity, make these NPs ideal for future studies for elucidating the detailed mechanism and efficacy upon their delivery in GBM preclinical models.

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The dielectric properties of skin and their influence on the delivery of tumor treating fields to the torso: a study combining in vivo measurements with numerical simulations

Cited by 23 publications

References 39 publications

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Temperature and Impedance Variations During Tumor Treating Fields (TTFields) Treatment

Electric field responsive nanotransducers for glioblastoma

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