Ivey Jill W, Latouche Eduardo L, Sano Michael B, Rossmeisl John H, Davalos Rafael V, Verbridge Scott S
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.
Sci Rep. 2015 Nov 24;5:17157. doi: 10.1038/srep17157.
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.
多形性胶质母细胞瘤（GBM）的治疗极具挑战性，因为缺乏优先靶向弥漫性浸润细胞和抗治疗性胶质瘤干细胞群体的方法。在此，我们报告一种基于细胞电破坏的物理治疗方法，其作用在很大程度上取决于细胞形态。有趣的是，数值模拟表明，虽然长脉冲（约100微秒）引起的外部脂质双分子层破坏对较大细胞有所增强，但短脉冲（约1微秒）优先在细胞内部产生高场，其强度与细胞核大小成比例。由于细胞核增大是恶性肿瘤的可靠指标，这提示了一种优先靶向恶性细胞的方法。虽然我们使用脉冲电场（PEF）治疗自发性犬GBM时证明了对正常细胞和恶性细胞均有杀伤作用，但我们提出，适当调整的PEF可能基于细胞核大小提供靶向消融。使用正常和恶性脑组织的3D水凝胶模型，其允许在治疗测试期间进行高分辨率询问，我们证实可以调整PEF以优先杀死癌细胞。最后，我们估计了PEF导致细胞死亡所需的核膜电位破坏。我们的结果可能有助于安全地靶向导致GBM肿瘤复发的抗治疗性细胞龛。
