Magnetic Particle Imaging (MPI) for Imaging and Magnetothermal Therapy of Brain Tumors

项目概述：本提案描述了一个为期五年的研究和职业发展计划， 博士Hamed Arami作为独立调查员的职业生涯。这个项目将建立在阿拉米博士的 作为一名生物工程科学家，具有多学科背景，接受过纳米医学和基本癌症成像方面的培训， 提供脑癌生物学和使用磁性粒子的脑肿瘤图像引导治疗的专业知识 成像（MPI）。PI将在斯坦福大学医学院接受Sanjiv S. Gambhir（主要导师， 基础癌症生物学，癌症病理学和癌症纳米技术），海克Daldrup-Link（共同导师，磁 纳米医学，成像和治疗学），Max Wintermark（共同导师，神经成像和脑MPI），Melanie Hayden（共同导师，神经外科和神经病学）和Bob Sinclair（共同导师，纳米材料表征）。 恶性原发性脑肿瘤，特别是多形性胶质母细胞瘤（GBM）的治疗具有挑战性，因为 GBM对化疗和放疗的抵抗。此外，还有不同类型的GBM肿瘤， 由于它们在大脑中的位置（例如，脑深部区域）而可操作。此外，临床常规GBM成像 基于使用钆基磁共振成像造影剂。然而，使用这些 钆基造影剂引起了患有慢性肾脏病的GBM患者的主要担忧 疾病，这可以通过使用纳米颗粒造影剂解决，这些造影剂不显示任何肾脏清除， 到他们更大的尺寸。所提出的研究的总体目标是使用MPI作为双臂和高分辨率 更安全的成像和GBM的磁热疗法的方法。四种不同类型的脑肿瘤 将研究攻击性水平以确定所提出的方法在不同脑肿瘤中的可行性 微环境最近，我开发了调整氧化铁纳米颗粒（NPs）的方法， 分辨率（即~600 µm）的MPI图像，超高造影剂质量灵敏度小于~ 550 pg Fe/µL。 我已经使用MPI对静脉注射后的小鼠U87脑肿瘤进行了三维靶向成像。 注射这些NP。此外，在单独的研究中，我证明了MPI用于选择性 当NP被直接注射到肿瘤中时，U87肿瘤的磁热疗法。在这个项目中，我将 首先评估在不同脑深度的NP的MPI和产热效率，以进一步识别理想的NP 一般脑肿瘤成像或MPI局部磁热治疗的设计和成像标准（目标1）。 然后，我将评估MPI对四种不同类型颅内植入脑肿瘤的靶向3D成像 静脉注射纳米颗粒后，接着进行纳米颗粒生物分布研究（目的2）。最后， 我将使用肿瘤内注射我的肿瘤穿透纳米粒子的MPI引导下的深部磁热疗法 脑肿瘤（不能手术的GBM的代表性模型），然后是深度生存和神经病理学 研究（目标3）。氧化铁纳米颗粒已被FDA批准用于几种临床应用， 希望这种方法最终能应用于许多其他类型的实体瘤。

Project Summary: This proposal describes a five-year research and career development program to prepare Dr. Hamed Arami for a career as an independent investigator. This program will build upon Dr. Arami’s multidisciplinary background as a bioengineer scientist, trained in nanomedicine and basic cancer imaging, by providing expertise in brain cancer biology and image-guided therapy of brain tumors using Magnetic Particle Imaging (MPI). The PI will be mentored at Stanford Medical School by Drs. Sanjiv S. Gambhir (Main mentor, basic cancer biology, cancer pathology and cancer nanotechnology), Heike Daldrup-Link (co-mentor, magnetic nanomedicine, imaging and therapeutics), Max Wintermark (co-mentor, neuroimaging and brain MPI), Melanie Hayden (co-mentor, neurosurgery and neurology) and Bob Sinclair (co-mentor, nanomaterials characterization). Treatment of malignant primary brain tumors particularly glioblastoma multiforme (GBM) is challenging because of GBM resistant to chemotherapy and radiotherapy. Also, there are different types of GBM tumors that are not operable due to their locations in the brain (e.g. deep brain regions). In addition, routine GBM imaging in clinics are based on using gadolinium-based magnetic resonance imaging contrast agents. However, using these gadolinium-based contrast agents raises major concerns for GBM patients suffering from chronic kidney disease, which can be resolved by using nanoparticle contrast agents that do not show any renal clearance due to their larger size. The overall goal of the proposed research is to use MPI as a two-armed and high-resolution approach for safer imaging and magnetothermal therapy of the GBM. Four types of brain tumors with different levels of aggressiveness will be studied to identify the feasibility of the proposed method in different brain tumor microenvironments. Recently, I developed methods for tuning iron oxide nanoparticles (NPs) to generate high resolution (i.e. ~600 µm) MPI images with ultra-high contrast agent mass sensitivity of less than ~550pg Fe/µL. I have used MPI for three-dimensional targeted imaging of the U87 brain tumors in mice after intravenous injection of these NPs. Additionally, in separate studies, I demonstrated the feasibility of the MPI for selective magnetothermal therapy of the U87 tumors, when NPs were directly injected into tumors. In this project, I will first evaluate MPI and heat generation efficiency of the NPs at different brain depths to further identify ideal NPs design and imaging criteria for general brain tumor imaging or local magnetothermal therapy with MPI (Aim 1). Then, I will evaluate MPI for targeted 3D imaging of four different types of intracranially implanted brain tumors after intravenous injection of the nanoparticles, followed by nanoparticle biodistribution studies (Aim 2). Finally, I will use intratumoral injection of my tumor-penetrating NPs for MPI-guided magnetothermal therapy of the deep brain tumors (representative models for inoperable GBM), followed by in-depth survival and neuropathological studies (Aim 3). Iron oxide nanoparticles have been approved by FDA for several clinical applications and we hope that this method will ultimately find applications to many other types of solid tumors.