Optimization of Heating Pattern in Magnetic Nanoparticle Hyperthermia: Compuational and in vivo Experimental Study

在现有的癌症治疗方法中，磁性纳米粒子热疗因其实施简单、成本低、并发症少而成为一种极具前景的治疗方法。在这个过程中，磁性颗粒被输送到组织或血管中，当暴露在交变磁场中时，就会引起加热。这种局部热产生导致肿瘤的热损伤。纳米颗粒的使用可以在肿瘤组织内产生足够的热量，而不需要热穿透皮肤表面，从而消除了随之而来的过度附带热损伤的副作用。尽管磁性纳米粒子热疗在治疗深部/不规则形状肿瘤方面的多功能性是传统非侵入性加热方法所无法超越的，但由于缺乏对过程中温度升高的控制，这种方法受到严重限制。肿瘤组织的温度分布不均匀和温度升高不充分可能导致杀死肿瘤细胞和/或损害健康组织。纳米颗粒的多位点注射有很大的潜力在整个肿瘤区域实现理想的温度升高，但需要优化注射策略，包括注射部位、注射量和注射速度。因此，本研究将对植入小鼠体内的肿瘤进行磁性纳米颗粒热疗的体内实验研究，并对纳米颗粒在生物组织中的转运进行多尺度计算研究，以进一步了解纳米流体在肿瘤中的转运，并量化纳米颗粒在不同治疗条件下诱导的加热模式。这个项目的最终结果是一个全球性的方法学的发展，为不规则形状的肿瘤设计个性化的治疗方案。智力优势：本研究的发现将(1)显著推进对纳米颗粒在组织中的转运和磁性纳米颗粒诱导的加热模式在癌症热疗治疗中的理解；(2)提供一个平台，在此平台上可以测试颗粒特性、组织微观结构和注射策略对颗粒迁移和肿瘤加热模式的影响；(3)建立描述热影响区与注射参数依赖关系的数据库；(4)制定多部位注射的优化治疗策略。量化纳米颗粒在肿瘤中的诱导加热模式的能力是一项重要的进步，它将治疗计划从几乎经验的试错方法转变为基于科学的工程方法。更广泛的影响：建议的研究将纳入我们的研讨会系列和课程，以传播生物纳米技术，并在跨学科的环境中教育和培训学生。这两个pi都有致力于促进STEM领域中代表性不足的少数民族学生的记录。这笔资金将为来自不同背景的学生提供充足的研究机会，参与体验式培训。变革性本质：这项研究将为设计一种优化的、针对患者的磁性纳米粒子热疗治疗方案提供一种全球性的方法，并在临床应用中获得最大的治疗效果。磁性纳米粒子热疗的成功将为癌症患者提供一种低成本的治疗方法，具有高的肿瘤细胞杀伤潜力和最小的并发症。此外，研究纳米颗粒在组织中的迁移将有利于纳米毒理学和使用纳米材料的位点特异性药物递送的研究。该项目由热传输过程（TTP）计划、生物医学工程（BME）计划和流体动力学（FD）计划以及工程理事会（ENG）内的化学、生物工程、环境和运输系统（CBET）部门共同资助。

CBET-0828728MaAmong available therapeutic methods in cancer treatment, magnetic nanoparticle hyperthermia emerges as a highly promising approach due to its simple implementation, low cost, and few complications. In this process, magnetic particles delivered to tissue or blood vessels induce heating when exposed to alternating magnetic fields. This localized heat generation leads to thermal damage to the tumor. The employment of nano-sized particles enables adequate amount of heat to be generated within tumor tissue without necessitating heat penetration through the skin surface, thus eliminating the consequent side effects of excessive collateral thermal damage. Although the versatility of magnetic nanoparticle hyperthermia in treating deep-seated/irregular shaped tumors is unsurpassed by traditional non-invasive heating approaches, this method is severely limited by the lack of controlling the temperature elevations during the process. The non-homogeneous temperature distribution and inadequate temperature elevation in tumor tissue may lead to inadequacy in killing tumor cells and/or damage to healthy tissue. Multiple-site injection of nanoparticles has great potential for achieving a desired temperature elevation throughout the entire tumor region, but requires optimized injection strategy including injection sites, injection amount, and injection rate. Therefore, in the proposed study an in vivo experimental study of magnetic nanoparticle hyperthermia on tumors implanted on mice and a multi-scale computational study of nanoparticle transport in biological tissue will be performed with the aims of advancing understanding of nanofluid transport in tumor and quantifying the heating patterns induced by these nanoparticles under various therapeutic conditions. The ultimate outcome of this project is the development of a global methodology for designing individualized treatment protocol for irregular shaped tumors. Intellectual Merit: The findings of this study will (1) significantly advance understanding of nanoparticle transport in tissue and magnetic nanoparticle-induced heating pattern in hyperthermia treatment of cancer; (2) provide a platform on which the effect of particle properties, tissue microstructures, and injection strategy on the migration of particles and heating patterns in tumors can be tested; (3) establish a database describing the dependence of thermally affected region on injection parameters; and (4) develop of an optimized treatment strategy using multi-site injection. The capability of quantifying the induced heating pattern by nanoparticles in tumors is an important advance that moves the treatment planning from an almost empirical trial-and-error approach to a science-based engineering methodology. Broader Impact: The proposed study will be integrated into our seminar series and curricula for disseminating bio-nanotechnology as well as educating and training students in an interdisciplinary setting. Both PIs have established track records of commitment for promoting underrepresented minority students in STEM fields. The funding will provide our students from diverse backgrounds with ample research opportunities to engage in experiential training. Transformative essence: This study will lead to a global methodology for designing an optimized, patient-specific treatment protocol for magnetic nanoparticle hyperthermia with maximum treatment outcomes in clinical applications. The success of magnetic nanoparticle hyperthermia will offer cancer patients a low cost treatment method that has high tumor cell-killing potential and minimal complications. In addition, the study of nanoparticle migration in tissue will benefit the study of nanotoxicology and site-specific drug delivery using nanomaterials. This project is jointly funded by the Thermal Transport Processes (TTP) Program, the Biomedical Engineering (BME) Program, and the Fluid Dynamics (FD) Program, all of the Chemical, Bioengineering, Environmental, and Transport Systems (CBET) Division within the Directorate for Engineering (ENG).