title: Targeted cellular ablation based on the morphology of malignant cells.
abstract: Treatment of glioblastoma multiforme (GBM) is especially challenging due to a shortage of methods to preferentially target diffuse infiltrative cells, and therapy-resistant glioma stem cell populations. Here we report a physical treatment method based on electrical disruption of cells, whose action depends strongly on cellular morphology. Interestingly, numerical modeling suggests that while outer lipid bilayer disruption induced by long pulses (~100 μs) is enhanced for larger cells, short pulses (~1 μs) preferentially result in high fields within the cell interior, which scale in magnitude with nucleus size. Because enlarged nuclei represent a reliable indicator of malignancy, this suggested a means of preferentially targeting malignant cells. While we demonstrate killing of both normal and malignant cells using pulsed electric fields (PEFs) to treat spontaneous canine GBM, we proposed that properly tuned PEFs might provide targeted ablation based on nuclear size. Using 3D hydrogel models of normal and malignant brain tissues, which permit high-resolution interrogation during treatment testing, we confirmed that PEFs could be tuned to preferentially kill cancerous cells. Finally, we estimated the nuclear envelope electric potential disruption needed for cell death from PEFs. Our results may be useful in safely targeting the therapy-resistant cell niches that cause recurrence of GBM tumors.
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Tech-Wake Forest University, Blacksburg, VA, 24061.
authors.forename: Jill W
authors.initials: JW
authors.lastname: Ivey
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Tech-Wake Forest University, Blacksburg, VA, 24061.
authors.forename: Eduardo L
authors.initials: EL
authors.lastname: Latouche
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Tech-Wake Forest University, Blacksburg, VA, 24061.|Department of Radiation Oncology, Division of Radiation Physics, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sano
authors.affiliation: Neurology and Neurosurgery, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061.|Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157.
authors.forename: John H
authors.initials: JH
authors.lastname: Rossmeisl
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Tech-Wake Forest University, Blacksburg, VA, 24061.|Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157.
authors.forename: Rafael V
authors.initials: RV
authors.lastname: Davalos
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Tech-Wake Forest University, Blacksburg, VA, 24061.|Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Verbridge
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy / Q000662:veterinary*; D045744:Cell Line, Tumor; D053145:Cell Nucleus Size; D048430:Cell Shape; D002470:Cell Survival; D018920:Coculture Techniques; D004283:Dog Diseases / Q000473:pathology / Q000628:therapy*; D004285:Dogs; D018274:Electroporation; D020342:Finite Element Analysis; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy / Q000662:veterinary*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D059010:Single-Cell Analysis
chemical_list: D020100:Hydrogels