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
基本信息
- 批准号:10308036
- 负责人:
- 金额:$ 67.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdjuvant TherapyAftercareAnimal ModelAnimalsAutopsyBrainBrain NeoplasmsCanis familiarisCell DeathClinicalClinical ResearchClinical TrialsComputer ModelsDNA Double Strand BreakDataDepositionDoseEffectivenessEuropeanExcisionExposure toExternal Beam Radiation TherapyFinite Element AnalysisFormulationFoundationsGenerationsGlioblastomaGliomaHeat shock proteinsHeatingHistopathologyHumanHyperthermiaImageInjectionsIronMagnetic Resonance ImagingMagnetismMalignant NeoplasmsMalignant neoplasm of brainMeasuresMethodologyModelingMusNanotechnologyNormal CellNormal tissue morphologyOral AdministrationOryctolagus cuniculusPatientsPenetrationPilot ProjectsPrognosisRadiation therapyRecurrenceRodentSafetySolidStudy of magneticsTechnologyTemperatureTissuesToxic effectTreatment EfficacyTumor DebulkingWorkantitumor effectbasebioluminescence imagingbrain tissuecancer cellchemoradiationchemotherapyclinical translationclinically relevantdesigneffective therapyfractionated radiationhyperthermia treatmenthyperthermia tumor treatmentimage guidedimaging modalityimprovedinnovationiron oxide nanoparticlemagnetic dipolemagnetic fieldnanoparticle deliveryneoplastic cellradiation effectsafety and feasibilitytemozolomidetherapy resistanttissue injurytooltranslation to humanstranslational applicationstranslational potentialtreatment planningtreatment responsetumortumor microenvironment
项目摘要
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.
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肿瘤内的浓度,导致强大的抗肿瘤作用,并增加了MHT+CRT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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Constantinos George Hadjipanayis其他文献
Constantinos George Hadjipanayis的其他文献
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{{ truncateString('Constantinos George Hadjipanayis', 18)}}的其他基金
dMRI-guided pre-operative planning for supra-total resection of high-grade gliomas
dMRI引导的高级别胶质瘤超全切除术前规划
- 批准号:
10635099 - 财政年份:2023
- 资助金额:
$ 67.49万 - 项目类别:
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:
10737738 - 财政年份:2019
- 资助金额:
$ 67.49万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 67.49万 - 项目类别:
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:
9916087 - 财政年份:2019
- 资助金额:
$ 67.49万 - 项目类别:
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:
10054965 - 财政年份:2019
- 资助金额:
$ 67.49万 - 项目类别:
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:
10730272 - 财政年份:2019
- 资助金额:
$ 67.49万 - 项目类别:
Improving extent of glioblastoma resection by combining volumetric MRSI and 5-ALA
结合体积 MRSI 和 5-ALA 提高胶质母细胞瘤切除范围
- 批准号:
8699970 - 财政年份:2014
- 资助金额:
$ 67.49万 - 项目类别:
HSV-Mediated Chemoradiosensitivity Human Glioma Model
HSV介导的化学放射敏感性人类神经胶质瘤模型
- 批准号:
7263982 - 财政年份:2006
- 资助金额:
$ 67.49万 - 项目类别:
HSV-Mediated Chemoradiosensitivity Human Glioma Model
HSV介导的化学放射敏感性人类神经胶质瘤模型
- 批准号:
7145786 - 财政年份:2006
- 资助金额:
$ 67.49万 - 项目类别:
HSV-Mediated Chemoradiosensitivity Human Glioma Model
HSV介导的化学放射敏感性人类神经胶质瘤模型
- 批准号:
7503347 - 财政年份:2006
- 资助金额:
$ 67.49万 - 项目类别:
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