Translational Application of Magnetic Hyperthermia Therapy with Adjuvant Therapies for Glioblastoma

磁热疗法与辅助疗法在胶质母细胞瘤中的转化应用

• 批准号: 10599714
• 负责人: Constantinos George Hadjipanayis
• 金额: $ 5.61万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599714
• 关键词: Address; Adjuvant Therapy; Blood; Brain; Canis familiaris; Cell Death; Cells; Clinical Trials; Data; Deposition; Effectiveness; European; Excision; Exposure to; External Beam Radiation Therapy; Formulation; Generations; Glioblastoma; Glioma; Human; Hyperthermia; Immune; In Vitro; Injections; Magnetism; Malignant Neoplasms; Malignant neoplasm of brain; Modeling; Mus; Nanotechnology; Normal Cell; Normal tissue morphology; Patients; Permeability; Pilot Projects; Radiation therapy; Recurrence; Rodent; Treatment Efficacy; antitumor effect; base; blood-brain tumor barrier; cancer cell; chemoradiation; chemotherapy; design; fractionated radiation; hyperthermia treatment; image guided; innovation; iron oxide nanoparticle; magnetic dipole; magnetic field; mouse model; nanoparticle delivery; neoplastic cell; radiation effect; recruit; safety and feasibility; temozolomide; therapy resistant; tissue injury; translational applications; translational potential; tumor

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.

项目摘要/摘要 胶质母细胞瘤（GBM）仍然是致命的脑癌，无法治愈。最大安全肿瘤切除 结合辅助疗法，例如分离的外束辐射疗法（RT）和替莫唑胺 （TMZ）化学疗法，称为化学放疗（CRT），为GBM患者提供了最大的好处。 但是，由于抗侵入性治疗的浸润性癌细胞，大多数患者发生局部复发 肿瘤边缘。磁性高温治疗（MHT）是一种强大的基于纳米技术的治疗方法 可能会增强CRT的影响。 MHT包括直接在肿瘤区域的局部热量产生 通过暴露于外部交流而激活的磁氧化铁纳米颗粒（MIONPS） 对正常细胞安全的磁场（AMF）。 AMF与Mionps的磁偶极子相互作用 产生局部热量和热疗。人类临床试验表明MHT的总体生存益处 复发性GBM的RT分数导致了欧洲的批准。但是，当前的MHT策略， 需要高浓度的非靶向MIONP（> 100 mg/ml; 50-100mg Fe/g的肿瘤） 注射泄漏，没有图像引导的能量沉积控制。结果，正常组织 损伤限制了MHT的有效性和渗透性肿瘤边缘的治疗，定义很差，这 损害了MHT功效。我们的建议旨在应对这些挑战，优化翻译 与CRT结合使用GBM增强MHT的潜力，并研究了一些机制 MHT调用肿瘤细胞死亡，血脑和血肿瘤屏障的渗透性以及免疫细胞募集 当单独施用并与CRT在体外和小鼠模型中结合使用时。我们最近有 完成了自发犬神经膜瘤的试点研究，证明了图像引导的可行性和安全性 单独交付MIONP。我们假设MHT将增强GBM的CRT。我们建议评估 具有创新的MIONP公式的小鼠GBM模型中MHT对CRT的增强。我们有 初步数据证明了颅内高温，TMZ浓度增加了3倍 GBM肿瘤，导致强大的抗肿瘤作用，在耐治疗中MHT + CRT后的存活率增加 啮齿动物神经胶质瘤模型。