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.

Modeling of Transmembrane Potential in Realistic Multicellular Structures before Electroporation

“…S10 and S11). It has been previously observed that H-FIRE treatment generates more homogenous lesions (2,24,(27)(28)(29)(30)(31) and in this article, we offer an explanation for that phenomenon.…”

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part III: Irreversible Electroporation and High-Frequency Irreversible Electroporation for the Eradication of Glioblastoma

“…Using the 3D in vitro tumor constructs, Ivey and Latouche et al experimentally validated the selectivity claim (51). In this study, U-87 human GBM cells, DBTRG human GBM cells, C6 rat GBM cells, normal human astrocytes (NHA), normal rat astrocytes D1TNC1, and undifferentiated rat neurons PC12 were cultured in collagen hydrogels and H-FIRE therapy was delivered using a 1-5-1 μs burst scheme.…”

The Feasibility of Enhancing Susceptibility of Glioblastoma Cells to IRE Using a Calcium Adjuvant

“…This technique has been used previously by Arena et al 3 and Ivey et al 24 to study the effects of IRE on different tumor cell lines using similar matrix composition and stiffness. Concentrated collagen stock solutions (10mg/mL) were created using rat tail collagen type I as described previously 3 .…”

“…A custom algorithm developed in MATLAB was used to measure lesion area (see Supplementary Material for details). Details describing the numerical model simulating collagen scaffold experiments and calculation of electric field thresholds have been previously reported 3,24 and are described in Supplementary Material.…”