Combinatorial Brain Cancer Therapy through Irreversible Electroporation and Carbon Nanotubes

0933335 Davalos本研究的目的是开发一种新的癌症治疗方法，该方法使用碳纳米管（CNT）的非热不可逆电穿孔（N-TIRE）。N-TIRE是一种新的微创局灶性消融技术，使用低能量（强但短）电脉冲治疗靶组织约1分钟。这些脉冲杀死目标区域内的细胞，而不会损坏周围组织。然而，由于N-TIRE是一种局灶性消融技术，它不会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。我们假设将CNT并入N-TIRE疗法中可实现对能够转移的浸润性细胞的选择性疗法。当暴露于电场时，CNT在其CNT尖端处放大场。这些场的局部放大应该从相对小的电场诱导相邻细胞中的N-TIRE，而不影响健康的周围细胞。本提案将通过以下目的研究N-TIRE方案和CNT特性对电场、温度分布和细胞/组织反应的影响：1）结合各种CNT实施方案确定对N-TIRE的细胞响应2）创建多尺度，具有CNT的N-TIRE的多物理计算模型，以预测对N-TIRE方案和CNT性质的组织响应3）实施最佳CNT介导的N-TIRE。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发展对不同N-TIRE参数与具有抗体靶向的不同CNT实施方案组合对治疗有效性的影响的全面理解。确定N-TIRE参数和CNT特性对细胞损伤的关系将为指导设计更有效的癌症治疗提供巨大的洞察力，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，它将具有比目前许多癌症治疗方法更显著的优势，这项研究将为这种治疗方法的第一阶段开发提供必要的数据。拟议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性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许多癌症，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。本项目中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融合领域的互动实验室组件来增强课程。这项研究将使众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。来自代表性不足群体的优秀本科生将被招募，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开发一个联合研讨会，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.