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.
Highlights
Adopt a different mechanical phenotype to accomplish invasion[11]
It should be noted that the maximum transmembrane potential (TMP) reached by both cell types when exposed to high-frequency irreversible electroporation (HFIRE) pulses is significantly lower than the TMP for irreversible electroporation (IRE) pulses
Though malignant glioblastoma cells (Fig. 5e) were ablated with IRE treatment (Fig. 5f), so too is the stromal cytoarchitecture. Based on these in vivo results demonstrating the relatively non-selective nature of IRE ablation in canine glioblastoma multiforme (GBM), combined with our in vitro studies demonstrating statistically significant yet small differences in IRE threshold based on cell size, we focused on the potential for pulsed electric fields to exert cell-specific targeting
Summary
Adopt a different mechanical phenotype to accomplish invasion[11]. The extension of tumor cells into the surrounding brain parenchyma contributes significantly to the failure of surgery as a treatment method, there is no method to target these infiltrative cells preferentially without damaging critical surrounding structures such as astrocytes, neurons and blood vessels[12]. If the TMP breaches a critical threshold, transient nanoscale pores form in the plasma membrane, which allow large molecules to traverse across the lipid bilayer[13] This phenomenon, known as reversible electroporation[14], is a well-established method used in aiding drug delivery, or for delivery of genetic material[15,16]. Beyond another critical TMP threshold, typically 1 V, irreparable damage occurs, preventing the resealing of these pores, which leads to cell death. Using 3D micro-engineered mimics of normal and malignant brain tissues, with experimentally defined ECM composition, we investigated cell-specific response to a range of pulse frequencies, to determine the extent to which either IRE or HFIRE can target specific morphological cellular characteristics within a heterogeneous microenvironment
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