Electric field responsive nanotransducers for glioblastoma

Abstract

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.

Keywords: Electric fields; Glioblastoma; Inorganic nanoparticles; Tumor Treating Fields.

Fig. 1

Physico-chemical characterization of inorganic NPs (Gold – GNPs; Zinc Oxide – ZnO; Silica oxide – SiO₂). Transmission electron microscopy images of (A) GNPs, (B) SiO₂ and (C) ZnO NPs. D UV-Vis absorption spectrum of ZnO and GNPs in PBS; E FTIR spectrum of SiO₂ NPs; F Zeta potential; and G Hydrodynamic diameter obtained using DLS. Error bars represent the standard deviation of the mean n=3; N= 3

Fig. 2

In vitro toxicity of inorganic NPs on patient derived GBM cells. A GIN 28, and B GCE 28 were incubated with increasing concentration of GNPs, SiO₂ and ZnO NPs for 4 hours, before changing the media containing the NPs with fresh media. Metabolic activity was determined 48 hours after changing the media, the experiment was run in triplicate, and fluorescence at 590 nm is expressed as % of control (no NPs). Results are expressed as the mean ± S.D. *P < 0.05; **P < 0.01; ***P < 0.001; and ****P < 0.0001 obtained using 2-way ANOVA with a Tukey post-test

Fig. 3

TTFields and inorganic NPs (Gold – GNPs; Zinc oxide – ZnO; Silica oxide – SiO₂) mediated enhanced EF effects on patient-derived GBM cells. A Schematic representation of TTFields setup consisting of – a base plate containing 8 ceramic dishes is connected to TTFields generator via a flat cable. Cells were seeded on a coverslip placed within a ceramic dish. The base plate is placed inside an incubator where the cells were maintained at 37°C and 5% CO₂. B GIN 28 cells and C GCE 28 cells were treated with TTFields at 300 kHz, 1V/cm, and 48 hours at NPs concentration of 5 μg/mL. D GNPs mediated enhanced TTFields effect on GIN 28 cells at 300 kHz, 1V/cm after 48 and 72 hours at a concentration of 25 μg/mL. Error bar represents mean ± S.E.M. from triplicate or quadruplicate repeats and two independent experiments