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.

项目总结/摘要 胶质母细胞瘤（GBM）仍然是一种致命的脑癌，目前尚无治愈方法。最大安全肿瘤切除 联合辅助治疗，如分次体外放射治疗（RT）和替莫唑胺 (TMZ)化学疗法，称为化学放射疗法（CRT），为GBM患者提供了最大的益处。 然而，局部复发发生在大多数患者中，由于侵入性治疗抵抗性浸润癌细胞， 肿瘤边缘磁热疗（MHT）是一种强大的基于纳米技术的治疗方法， 可以增强CRT的效果。MHT包括通过直接加热在肿瘤区域中产生局部热。 磁性氧化铁纳米颗粒（MIONP）的递送，所述磁性氧化铁纳米颗粒（MIONP）通过暴露于外部交变磁场而被激活。 磁场（AMF）对正常细胞安全。AMF与MIONP的磁偶极子相互作用， 产生局部热量和体温过高。人类临床试验已经证明了MHT的总体生存益处 复发性GBM的分次RT导致欧洲批准。然而，目前的MHT战略， 需要高浓度的非靶向MIONP（>100 mg/ml; 50- 100 mg Fe/g肿瘤）， 注射具有回漏且没有能量沉积的图像引导控制。因此，正常组织 损伤限制了MHT的有效性，浸润性肿瘤边缘的治疗定义不明确， 损害MHT功效。我们的建议旨在解决这些挑战，优化翻译 潜在的增强MHT的GBM与CRT相结合，并研究一些机制， MHT引起肿瘤细胞死亡、血脑和血肿瘤屏障通透性和免疫细胞募集 在体外和小鼠模型中单独给药和与CRT联合给药时。我们最近 在自发性犬胶质瘤中完成了一项初步研究，证明了图像引导下 MIONP单独交付。我们推测MHT将增强GBM的CRT。我们建议评估 MHT在小鼠GBM模型中使用创新的MIONP制剂增强CRT。我们有 初步数据表明，颅内高热与TMZ浓度增加3倍， GBM肿瘤，导致MHT + CRT治疗耐药性患者后的稳健抗肿瘤作用和生存期延长。 啮齿动物胶质瘤模型。