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，优化翻译 GBM与CRT联合应用增强MHT的可能性，并研究其作用机制 MHT引起肿瘤细胞死亡、血脑和血肿瘤屏障通透性以及免疫细胞募集 在体外和小鼠模型中单独和与CRT联合给药时。我们最近做了 完成了对自发性犬脑胶质瘤的初步研究，证明了图像引导的可行性和安全性 MIONP单独交付。我们推测MHT能增强GBM的CRT。我们建议评估 用创新的MIONP配方增强MHT对小鼠GBM模型CRT的影响。我们有 初步数据显示，在TMZ浓度增加3倍的情况下，颅内温度过高 GBM肿瘤，导致强大的抗肿瘤作用与增加生存期后MHT+CRT在一种治疗耐药 鼠脑胶质瘤模型。

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, optimize the translational potential for enhanced MHT of GBM in combination with CRT, and study some of the mechanisms by which MHT invokes tumor cell death, blood-brain and blood-tumor barrier permeability, and immune cell recruitment when administered alone and in combination with CRT in vitro and in a mouse model. We have recently completed a pilot study in spontaneous canine gliomas demonstrating feasibility and safety of image-guided MIONP delivery alone. We hypothesize that MHT will enhance CRT of GBM. We propose to evaluate the enhancement of CRT by MHT in mouse GBM models with an innovative MIONP formulation. 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.