In Vitro and Numerical Support for Combinatorial Irreversible Electroporation and Electrochemotherapy Glioma Treatment
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Irreversible electroporation (IRE) achieves targeted volume non-thermal focal ablation using a series of brief electric pulses to kill cells by disrupting membrane integrity. Electrochemotherapy (ECT) uses lower numbers of sub-lethal electric pulses to disrupt membranes for improved drug uptake. Malignant glioma (MG) brain tumors are difficult to treat due to diffuse peripheral margins into healthy neural tissue. Here, in vitro experimental data and numerical simulations investigate the feasibility for IRE-relevant pulse protocols with adjuvant ECT drugs to enhance MG treatment. Cytotoxicity curves were produced on two glioma cell lines in vitro at multiple pulse strengths and drug doses with Bleomycin or Carboplatin. Pulses alone increased cytotoxicity with higher pulse numbers and strengths, reaching >90% by 800 V/cm with 90 pulses. Chemotherapeutic addition increased cytotoxicity by >50% for 1 ng/mL concentrations of either drug relative to 80 pulses alone with J3T cells at electric fields ≥400 V/cm. In addition to necrosis, transmission electron microscopy visualizes apoptotic morphological changes and Hoescht 33342 staining shows apoptotic cell fractions varying with electric field and drug dose relative to controls. Numerically simulated treatment volumes in a canine brain show IRE combined with ECT expands therapeutic volume by 2.1–3.2 times compared to IRE alone.
KeywordsCombined therapy Non-thermal focal ablation Brain cancer IRE ECT Numerical modeling Minimally invasive surgery Multimodality oncology Targeted therapy
This work was supported by the Coulter Foundation, NSF CAREER Award CBET-1055913, and Whitaker International Scholars Program. The authors thank Kathy Lowe for assistance with cell morphology and histology work.
Conflict of Interest
REN, JHR, PAG, RVD, JLR: Patent holders of “Irreversible Electroporation to Treat Aberrant Masses,” and have pending patents in the area of irreversible electroporation in general, but which does not directly relate to the content submitted here. RVD provides minimal consulting and has received research funding in the area of numerical modeling of electric fields. This manuscript has not been previously published, in whole or in part, nor is it concurrently under consideration elsewhere.
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