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，以准备 哈米德·阿拉米博士的职业生涯是独立调查员。这一计划将建立在阿拉米博士的 生物工程科学家的多学科背景，受过纳米医学和基础癌症成像方面的培训，由 提供脑癌生物学方面的专业知识和利用磁粉进行脑肿瘤的影像引导治疗 成像(MPI)。PI将在斯坦福医学院由Sanjiv S.Gambhir博士(主要导师， 基础癌症生物学、癌症病理学和癌症纳米技术)，Heike Daldrup-Link(联合导师，Magic 纳米医学、成像和治疗学)，Max Wintermark(共同导师，神经成像和脑MPI)，Melanie 海登(神经外科和神经学联合导师)和鲍勃·辛克莱(纳米材料表征联合导师)。 恶性原发脑瘤，特别是多形性胶质母细胞瘤(GBM)的治疗具有挑战性，因为 对化疗和放疗耐药的基底膜。此外，还有不同类型的基底膜肿瘤 由于它们在大脑中的位置(例如，大脑深部区域)，因此可操作。此外，临床上常规的GBM成像 都是基于使用基于Gd的磁共振成像造影剂。然而，使用这些 基于Gd的造影剂引起慢性肾脏GBM患者的主要担忧 疾病，可以通过使用纳米造影剂来解决，这些造影剂没有显示任何应有的肾脏清除 变得更大了。拟议研究的总体目标是将MPI用作双臂和高分辨率 GBM更安全的成像和磁热治疗方法。四种不同类型的脑肿瘤 将对侵袭性水平进行研究，以确定所建议的方法在不同脑肿瘤中的可行性。 微环境。最近，我开发了一种方法来调节氧化铁纳米颗粒(NPs)以产生高 分辨率(即~600µm)MPI图像，超高对比剂质量灵敏度小于~550pg Fe/µL。 我使用MPI对静脉注射后的小鼠U87脑瘤进行了三维靶向成像 注射这些NPs。此外，在单独的研究中，我论证了MPI用于选择性地 磁热治疗U87肿瘤，当纳米粒子直接注射到肿瘤中。在这个项目中，我将 首先评估不同大脑深度的NPs的MPI和产热效率，以进一步确定理想的NPs 常规脑肿瘤成像或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对四种不同类型的脑内植入性肿瘤的靶向3D成像 静脉注射纳米粒后，进行纳米粒生物分布研究(目标2)。最后， 我将使用肿瘤内注射我的穿透肿瘤的纳米粒子来进行MPI引导的深部磁热治疗 脑肿瘤(不能手术的基底膜的代表性模型)，随后是深度生存和神经病理 研究(目标3)。氧化铁纳米颗粒已经被FDA批准用于几种临床应用，我们 希望这种方法最终能应用于许多其他类型的实体肿瘤。

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.