Electrolytic ablation enables cancer cell targeting through pH modulation

Nicholas R Perkons,Roni Itkin-Ofer,Joseph C Wildenberg,Michael C Soulen,Kamiel Saleh,Terence P Gade,Daniel Ackerman,Elliot J Stein,Stephen J Hunt,Chike Nwaezeapu,Gregory J Nadolski

doi:10.1038/s42003-018-0047-1

Nicholas R Perkons, Roni Itkin-Ofer + Show 9 more

Open Access

https://doi.org/10.1038/s42003-018-0047-1

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Abstract

Minimally invasive ablation strategies enable locoregional treatment of tumors. One such strategy, electrolytic ablation, functions through the local delivery of direct current without thermal effects, facilitating enhanced precision. However, the clinical application of electrolytic ablation is limited by an incompletely characterized mechanism of action. Here we show that acid and base production at the electrodes precipitates local pH changes causing the rapid cell death that underlies macroscopic tumor necrosis at pH > 10.6 or < 4.8. The extent of cell death can be modulated by altering the local buffering capacity and antioxidant availability. These data demonstrate that electrolytic ablation is distinguished from other ablation strategies via its ability to induce cellular necrosis by directly altering the tumor microenvironment. These findings may enable further development of electrolytic ablation as a curative therapy for primary, early stage tumors.

Highlights

Invasive ablation strategies enable locoregional treatment of tumors
To evaluate the mechanism of cell death in electrolytic ablation, we developed an in vitro cell encapsulation assay in which hepatocellular carcinoma (HCC) cells (Huh-7, unless otherwise specified) were embedded in low melting temperature agarose (Fig. 1a)
Electrolytic ablation was performed by applying a direct current between two inert needle electrodes placed 1.5 cm apart within encapsulation assays prepared in 6 cm tissue culture dishes

Summary

Introduction

Invasive ablation strategies enable locoregional treatment of tumors. One such strategy, electrolytic ablation, functions through the local delivery of direct current without thermal effects, facilitating enhanced precision. The extent of cell death can be modulated by altering the local buffering capacity and antioxidant availability These data demonstrate that electrolytic ablation is distinguished from other ablation strategies via its ability to induce cellular necrosis by directly altering the tumor microenvironment. Among the thermal-dependent modalities, the majority (radiofrequency ablation, microwave ablation, laser interstitial therapy, and high-intensity focused ultrasound) deposit energy, which causes hyperthermia and subsequent cell death through direct and indirect injury. Vessels traversing an ablation zone serve as heat sinks or sources, which can distort the temperature gradients within the ablation zone and lead to undesirable treatment margins[3,4] This imprecision, in combination with safety considerations stemming from off-target toxicity, emphasizes the importance of developing non-thermal ablation strategies to treat cancer

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