Potential of Ultrashort Pulsed Electric Fields to Disrupt Dense Structure in Glioma Tumors.

Abstract

Two major reasons why chemotherapy and immunotherapy have limited efficacy in treating gliomas are the blood-brain barrier and the dense, solid structure of the glioma. Pulsed electric fields have been a powerful tool for ablating solid tumors, and narrowing pulse duration can improve the field homogeneity penetrating into the tumor. In this study, we used multicellular tumor spheroids (MCTSs) as a model to explore the potential of ultrashort nanosecond pulses to inhibit tumor cell activity while disrupting their dense drug-resistant barriers. Exposure to ultrashort pulsed electric fields can significantly inhibit the viability of U-87 MG, C6, and GL261 spheroids, as indicated by reduced intracellular ATP content. Meanwhile, the proliferative abilities of tumor cells were suppressed, as evidenced by reduced Ki67 protein expression. In addition, it is notable that, after exposure to electric fields, the volume of spheroids increased dramatically. We hypothesize that ultrashort pulsed electric fields can reduce tumor compactness, thereby facilitating drug delivery for immunotherapy and chemotherapy. Immunofluorescence results showed that the cell-cell junction was broken by ultrashort pulsed electric fields with lower expression of adherens junction protein N-cadherin and tight junction protein ZO-1. It is evidenced that the capability of ultrashort pulsed electric fields to downregulate the intercellular adherence, as well as suppress the epithelial-mesenchymal transition, a key process of metastasis of cancer cells. At last, aqueous fluorescent nanoparticles were applied to simulate the anticancer drug or therapeutic antibodies. Under the supervision of fluorescence microscopy, the degree of nanoparticles penetrating into the spheroids was positively related to the number of ultrashort pulsed electric fields, marked with a higher fluorescent signal from the inner quiescent zone or a necrotic core. In conclusion, we emphasize that ultrashort pulsed electric fields could be promising for downgrading the compactness of glioma tumors, being a powerful assisted therapy for the delivery of anticancer drugs and therapeutic antibodies.