Translational Application of Magnetic Hyperthermia Therapy with Adjuvant Therapies for Glioblastoma

项目摘要/摘要 胶质母细胞瘤(GBM)仍然是一种致命的脑癌，目前还没有治愈的方法。最大安全的肿瘤切除 联合辅助治疗，如分次外照射(RT)和替莫唑胺 TMZ化疗，即所谓的放化疗(CRT)，为GBM患者提供了最大的好处。 然而，大多数患者的局部复发是由于侵袭治疗耐药的浸润性癌细胞 肿瘤边缘。磁热疗法(MHT)是一种基于纳米技术的强大疗法 可能会增强CRT的效果。MHT包括通过直接在肿瘤区域产生局部热 磁性氧化铁纳米颗粒(MIONPs)的输送，该纳米颗粒通过暴露在外部交变磁场中而被激活 对正常细胞安全的磁场(AMF)。AMF与MIONPs的磁偶极子相互作用 产生局部热量和体温过高。人体临床试验已经证实了MHT的总体生存益处 部分RT用于复发的GBM，导致欧洲批准。然而，目前的MHT策略， 需要高浓度的非靶向MIONPs(100毫克/毫升；50-100毫克铁/克肿瘤) 有泄漏的喷射，没有图像引导的能量沉积控制。因此，正常组织 损伤限制MHT的有效性和对浸润性肿瘤边缘的治疗定义不明确，这 损害了MHT的疗效。我们的建议旨在应对这些挑战并优化 使用小动物模型和大动物模型，结合CRT，GBM增强MHT的可能性 自发性犬脑胶质瘤的临床概念验证。我们最近完成了一项初步研究。 在自发性犬脑胶质瘤中，证明了单独使用图像引导的MIONP给药的可行性和安全性。我们 假设图像引导下的MHT能增强基底膜的CRT。我们提案的主要创新之处在于：1) 用创新的专有MIONP评价MHT对小鼠GBM模型CRT的增强作用 需要将肿瘤中铁浓度降低20倍的配方，以实现比目前更有效的治疗 批准的MIONP；2)通过计算优化图像引导的MIONP递送和MHT治疗计划 兔脑肿瘤模型的建立；3)通过以下方法加强浸润性肿瘤边缘的热疗 通过创新的AMF电源应用控制电源沉积，该应用还将限制目标加热；以及，4) 在自发性犬脑胶质瘤中完成我们的MHT手术的临床相关概念验证研究 模特。我们有初步数据显示，颅内高热导致TMZ增加3倍 在GBM肿瘤内的浓集，导致强大的抗肿瘤作用，并增加MHT CRT后的存活率 在一个耐治疗的啮齿动物胶质瘤模型中。总体而言，这项跨学科工作将为 甲基强的松龙联合CRT治疗基底膜的临床意义。与肿瘤相关的成像方法 MHT后的热分布将被开发用于移植到人类患者身上。

Project Summary/Abstract Glioblastoma (GBM) remains a fatal brain cancer for which there is no cure. Maximal safe tumor resection combined with adjuvant therapies such as fractionated external beam radiation therapy (RT) and temozolomide (TMZ) chemotherapy, known as chemoradiation (CRT), has provided the greatest benefit to GBM patients. However, local recurrence occurs in most patients due to invasive therapy-resistant infiltrating cancer cells at the tumor margin. Magnetic hyperthermia therapy (MHT) is a powerful nanotechnology-based treatment that may enhance the effects of CRT. MHT consists of local heat generation in the tumor region through direct delivery of magnetic iron-oxide nanoparticles (MIONPs) that are activated by exposure to an external alternating magnetic field (AMF) that is safe to normal cells. The AMF interacts with the magnetic dipoles of the MIONPs to generate local heat and hyperthermia. Human clinical trials have demonstrated overall survival benefits of MHT with fractionated RT in recurrent GBM resulting in European approval. Current MHT strategies, however, require high concentrations of nontargeted MIONPs (>100 mg/ml; 50-100mg Fe/g of tumor) delivered by injection with leakback and without image-guided control of energy deposition. As a result, normal tissue injury limits MHT effectiveness and treatment of the infiltrative tumor margins is poorly defined, which compromises MHT efficacy. Our proposal is designed to address these challenges and optimize the translational potential for enhanced MHT of GBM in combination with CRT using both small and large animal models, with clinical proof-of-concept demonstration in spontaneous canine gliomas. We have recently completed a pilot study in spontaneous canine gliomas demonstrating feasibility and safety of image-guided MIONP delivery alone. We hypothesize that image-guided MHT will enhance CRT of GBM. Key innovations of our proposal are to: 1) evaluate the enhancement of CRT by MHT in mouse GBM models with an innovative proprietary MIONP formulation that requires 20-fold lower Fe concentration in tumors for more effective treatment than current approved MIONPs; 2) optimize image-guided MIONP delivery and MHT treatment planning with computational modelling in a rabbit brain tumor model; 3) enhance thermal treatment at the infiltrative tumor margins by controlling power deposition with innovative AMF power application that will also limit off target heating; and, 4) complete a clinically relevant proof-of-concept study of our MHT approach in a spontaneous canine glioma model. We have Preliminary Data that demonstrate intracranial hyperthermia with a 3-fold increase in TMZ concentration within GBM tumors, leading to a robust antitumor effect with increased survival after MHT + CRT in a therapy-resistant rodent glioma model. Overall, this interdisciplinary work will provide a solid foundation for meaningful clinical translation of MHT with CRT for treatment of GBM. Imaging methods that correlate tumor heat distribution after MHT will be developed for translation to human patients.