Rapid Electrical Impedance Spectroscopy for Detection of High-Frequency Irreversible Electroporation Ablation Growth in a Rodent Glioma Model

多样性补充项目摘要 最常见和最具侵袭性的恶性脑瘤，多形性胶质母细胞瘤(GBM)，表现为5- 一年存活率仅为5.6%。在治疗基底膜方面出现的困难包括大分子无法 通过血脑屏障(BBB)的药物；高侵袭性的GBM细胞迁移到 实体/可见肿瘤边缘；以及大体、显微和肿瘤内遗传的异质性。绕过问题 与标准护理相关，并提高基于电穿孔的颅内治疗的多功能性 应用，我们的团队开发了一种新的肿瘤消融策略，它利用双极PEF的爆发来 非热消融肿瘤。这种称为高频IRE(H-FIRE)的第二代策略， 显示局部组织消融，周围有延伸厘米的血脑屏障破裂区(BBBD) 在非热性损伤之外。尽管电穿孔非热敏材料的发展取得了重大进展 消融疗法，在知识方面存在一些挑战和差距。消融/脉冲的测定 终点目前还没有定义，依赖于术后MRI和超声技术的成像。 因此，在家长P01拨款的基础上，这项多样性补充提案试图进行初步的 H-FIRE和傅立叶分析光谱分析消融肿瘤组织的研究 建立原位啮齿动物GBM肿瘤模型，并确定脉冲终点。本项目建议书有两个具体目标： 具体目标1：快速阻抗测量以确定脉冲的初步研究 H-Fire消融的终点。H-Fire疗法将用于消融原位GBM肿瘤组织 啮齿类动物GBM肿瘤模型。已知H-Fire烧蚀体积在设置后达到饱和 应用的脉冲数。因此，我们将利用新开发的傅里叶分析光谱学，一种快速 电阻抗频谱技术，以连续监测组织阻抗在整个H- 火疗。具体目标2：四环磷酰胺联合H-Fire治疗的初步研究。 这项初步研究将阐明一种分子佐剂增强H-Fire治疗胶质瘤的效果。H- 火介导的血脑屏障阻断促进药物向侵袭健康大脑的浸润性胶质瘤细胞的递送 薄壁组织。将使用F98啮齿动物胶质瘤模型，类似于AIM 2的模型。H-Fire疗法将是 应用生物发光成像来定量肿瘤生物发光后的独立H- 火疗和H-FIRE与新开发的四环磷酸盐的组合。

Diversity Supplement Project Summary The most common and aggressive malignant brain tumor, glioblastoma multiforme (GBM), demonstrates a 5- year survival rate of only 5.6%. Difficulties arising in the treatment of GBM include the inability of large molecular agents to permeate through the blood-brain barrier (BBB); migration of highly invasive GBM cells beyond the solid/visible tumor margin; and gross, microscopic, and genetic intratumor heterogeneity. To circumvent issues associated with standard of care and to improve the versatility of electroporation-based therapies for intracranial applications, our group has developed a novel tumor ablation strategy which utilizes bursts of bipolar PEFs to nonthermally ablate tumors. This second-generation strategy, termed high-frequency IRE (H-FIRE), demonstrates focal tissue ablation with a surrounding zone of BBB disruption (BBBD) that extends centimeters beyond the nonthermal lesion. Despite major progress in development of electroporation-based nonthermal ablation therapies, several challenges and gaps in knowledge exist. The determination of an ablation/pulsing endpoint is not currently defined and is reliant on postoperative imaging with MRI and ultrasound techniques. Therefore, building off the parent P01 grant, this Diversity Supplement proposal seeks to conduct a preliminary investigation of H-FIRE and the proposed Fourier Analysis SpecTroscopy to ablate neoplastic tissue in an orthotopic rodent GBM tumor model and determine a pulsing endpoint. This project proposal has 2 specific aims: Specific Aim 1: Preliminary investigation of FAST impedance measurements to determine a pulsing endpoint for H-FIRE ablation. H-FIRE therapy will be applied to ablate GBM tumor tissue in an orthotopic rodent GBM tumor model. It is known that the H-FIRE ablation volume reaches a saturation following a set number of bursts applied. Therefore, we will utilize the newly developed Fourier Analysis SpecTroscopy, a rapid electrical impedance spectroscopy technique, to continually monitor changes in tissue impedance throughout H- FIRE therapy. Specific Aim 2: Preliminary investigation of combinatorial H-FIRE therapy with QUAD-CTX. This pilot study will elucidate the effects of a molecular adjuvant to enhance glioma treatment with H-FIRE. H- FIRE-mediated BBB disruption facilitates enhanced drug delivery to infiltrative glioma cells invading healthy brain parenchyma. An F98 rodent glioma model, similar to that of Aim 2, will be employed. H-FIRE therapy will be administered and bioluminescent imaging used to quantify the tumor bioluminescence follow stand-alone H- FIRE therapy and combinatorial H-FIRE with newly developed QUAD-CTX.