Combinatorial Brain Cancer Therapy through Irreversible Electroporation and Carbon Nanotubes

这项研究的目的是开发一种新的癌症治疗方法，该方法使用非热不可逆电穿孔（N-TIRE）和碳纳米管（CNTs）。N-TIRE是一种新型的微创局灶消融技术，使用低能量（强但短）电脉冲治疗目标组织约1分钟。这些脉冲杀死目标区域内的细胞而不损害周围组织。然而，由于N-TIRE是一种局灶消融技术，它不能选择性地杀死肿瘤边缘以外的浸润细胞而不影响周围组织。我们假设在N-TIRE治疗中加入碳纳米管可以对具有转移能力的浸润性细胞进行选择性治疗。当暴露于电场中时，碳纳米管在其碳纳米管尖端处放大电场。这些电场的局部扩增应该在相对较小的电场中诱导邻近细胞的N-TIRE，而不会影响周围健康的细胞。本提案将通过以下目标研究N-TIRE协议和碳纳米管特性对电场、温度分布和细胞/组织响应的影响：1)结合多种碳纳米管实施方式确定细胞对N-TIRE的反应2)创建含碳纳米管的N-TIRE多尺度、多物理场计算模型，以预测组织对N-TIRE方案和碳纳米管性质的反应3)实施最佳碳纳米管介导的N-TIRE方案，并测量脑肿瘤的体内反应。所提出的活动的智力价值将是全面理解不同N-TIRE参数与不同碳纳米管实施例结合抗体靶向对治疗效果的影响。确定N-TIRE参数与碳纳米管特性对细胞损伤之间的关系，将为指导设计更有效的癌症治疗方法提供巨大的见解，从而增强肿瘤破坏并最大限度地减少肿瘤复发。如果N-TIRE/CNT联合治疗被证明是有效的，它将比许多目前的癌症治疗具有显著的优势，这项研究将为该疗法的第一阶段发展提供必要的数据。该研究的更广泛影响包括确定最佳N-TIRE/CNT参数，以有效和选择性地治疗原发肿瘤和浸润性癌细胞，从而消除肿瘤复发和转移的可能性。虽然这种方法可以用于治疗多种癌症，包括前列腺癌、肝癌、肾癌和胰腺癌，但脑癌将作为我们的模型。本项目所包含的研究将为研究者课程中教授的相关主题提供动力，并允许有机会通过专注于电穿孔，纳米技术和生物传热等融合领域的交互式实验室组件来增强课程。这项研究将使许多学生有机会在研究生和本科生阶段获得实验设计、工程和细胞生物学方面的经验。研究人员将从未被充分代表的群体中招募学术能力较强的本科生，通过研究者指导的两个暑期项目在夏季进行研究。我们还将为生物工程专业的学生和医学专业的学生举办一个联合研讨会，讨论工程、实验生物学、兽医和临床医学的协同方面，以设计新的创新疗法。

0933335DavalosThe objective of this research is to develop a new cancer therapy that uses non-thermal irreversible electroporation (N-TIRE) with carbon nanotubes (CNTs). N-TIRE is a new, minimally invasive focal ablation technique that uses low energy (intense, but short) electric pulses to treat targeted tissue for approximately 1 minute. These pulses kill cells within the targeted area without damaging the surrounding tissue. However, since N-TIRE is a focal ablation technique, it does not selectively kill infiltrative cells beyond the tumor margin without affecting surrounding tissue. We hypothesize that incorporating CNTs into N-TIRE therapy can enable selective therapy of infiltrative cells capable of metastasis. When exposed to an electric field, CNTs amplify the field at their CNT tip. Localized amplification of these fields should induce N-TIRE in adjacent cells from relatively small electric fields, without affecting healthy surrounding cells. This proposal will investigate the impact of N-TIRE protocols and CNT properties on the electric field, temperature distribution, and cellular/tissue response through the following objectives: 1) Determine the cellular response to N-TIRE in combination with a variety of CNT embodiments 2) Create a multi-scale, multi-physics computational model of N-TIRE with CNTs to predict the tissue response to N-TIRE protocols and CNT properties 3) Implement optimal CNT-mediated N-TIRE protocols and measure the in vivo response of brain tumors. The intellectual merit of the proposed activity will be the development of a comprehensive understanding of the impact of varying N-TIRE parameters in combination with different CNT embodiments with antibody targeting on therapy effectiveness. Defining the relationship between N-TIRE parameters and CNT properties on cellular injury will provide enormous insight to guide design of more effective cancer therapies, which enhance tumor destruction and minimize tumor recurrence. If combinatorial N-TIRE/CNT therapy proves to be effective, it will possess significant advantages over many current cancer treatments and this research will provide the necessary data for first stage development of this therapy.The broader impacts of the proposed study include the determination of optimal N-TIRE/CNT parameters to effectively and selectively treat both the primary tumor and the infiltrative cancer cells, thereby eliminating the likelihood of tumor recurrence and metastasis. Although this approach could be utilized to treat a number of cancers including prostate, liver, kidney and pancreatic, brain cancer will serve as our model. Research contained in this project will provide motivation for related topics taught within the investigator's courses and permit the opportunity to augment the course with an interactive laboratory component focused on the converging fields of electroporation, nanotechnology, and bioheat transfer. This research will enable opportunities for numerous students to gain experience in experimental design, engineering, and cell biology at the graduate and undergraduate level. Scholastically strong undergraduate students from underrepresented groups will be recruited to perform research during the summer through two summer programs directed by the investigator. We will also develop a joint workshop for bioengineering students and medical students to discuss the synergistic aspects of engineering, experimental biology, and veterinary and clinical medicine to design new innovative therapies.