Combinatorial Brain Cancer Therapy through Irreversible Electroporation and Carbon Nanotubes

这项研究的目标是开发一种使用碳纳米管(CNT)的非热不可逆电穿孔(N-Tear)的新癌症疗法。N形轮胎是一种新的微创局部消融技术，它使用低能量(强，但短)电脉冲来治疗目标组织约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-轮胎是一种局部消融技术，它不会选择性地杀死肿瘤边缘以外的浸润性细胞，而不会影响周围组织。我们假设，将碳纳米管整合到N-Tel治疗中，可以选择性地治疗具有转移能力的浸润性细胞。当碳纳米管暴露在电场中时，它会放大碳纳米管尖端的电场。这些电场的局部放大应该会从相对较小的电场在相邻细胞中诱导N-Tell，而不会影响周围健康的细胞。这项建议将通过以下目标来研究N-轮胎协议和CNT属性对电场、温度分布和细胞/组织响应的影响：1)结合各种CNT实施例确定细胞对N-轮胎的响应2)使用CNT创建N-轮胎的多尺度、多物理计算模型，以预测组织对N-轮胎协议和CNT属性的响应3)实施最优的CNT介导的N-轮胎协议，并测量脑肿瘤的体内反应。拟议活动的智力价值将是全面了解不同的N-轮胎参数结合不同的带有抗体靶向的CNT载体对治疗效果的影响。明确N-轮胎参数与碳纳米管性质之间在细胞损伤方面的关系，将为指导设计更有效的癌症治疗方案提供巨大的启示，从而增强肿瘤的杀伤力，减少肿瘤的复发。如果N-轮胎/碳纳米管联合治疗被证明是有效的，它将拥有许多当前癌症治疗方法的显著优势，这项研究将为该疗法的第一阶段开发提供必要的数据。本研究的更广泛的影响包括确定最佳的N-轮胎/碳纳米管参数，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来治疗包括前列腺癌、肝癌、肾癌和胰腺癌在内的许多癌症，但脑癌将作为我们的模型。本项目中包含的研究将为研究人员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、纳米技术和生物热传递等汇聚领域的互动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水平上获得实验设计、工程和细胞生物学方面的经验。来自代表性不足群体的学业成绩优秀的本科生将被招募在暑期通过两个由调查员指导的暑期项目进行研究。我们还将为生物工程学生和医科学生开发一个联合工作坊，讨论工程学、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.