Article

Annals of Biomedical Engineering

, Volume 42, Issue 3, pp 475-487

In Vitro and Numerical Support for Combinatorial Irreversible Electroporation and Electrochemotherapy Glioma Treatment

  • R. E. NealIIAffiliated withBioelectromechanical Systems Lab, Virginia Tech – Wake Forest School of Biomedical Engineering and SciencesRadiology Research Unit, The Alfred Hospital Email author 
  • , J. H. RossmeislJr.Affiliated withNeurology/Neurosurgery Service and Center for Comparative Oncology, VA-MD Regional College of Veterinary Medicine
  • , V. D’AlfonsoAffiliated withNeurology/Neurosurgery Service and Center for Comparative Oncology, VA-MD Regional College of Veterinary Medicine
  • , J. L. RobertsonAffiliated withCancer Engineering Group, Virginia Tech – Wake Forest School of Biomedical Engineering and Sciences
  • , P. A. GarciaAffiliated withBioelectromechanical Systems Lab, Virginia Tech – Wake Forest School of Biomedical Engineering and Sciences
  • , S. ElankumaranAffiliated withDepartment of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine
  • , R. V. DavalosAffiliated withBioelectromechanical Systems Lab, Virginia Tech – Wake Forest School of Biomedical Engineering and Sciences

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Abstract

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.

Keywords

Combined therapy Non-thermal focal ablation Brain cancer IRE ECT Numerical modeling Minimally invasive surgery Multimodality oncology Targeted therapy