Image-guided combination therapies for radiotherapy-induced neurocognitive impairment in pediatric brain tumor survivors

图像引导联合疗法治疗儿童脑肿瘤幸存者放疗引起的神经认知障碍

• 批准号: 10652561
• 负责人: Ethel Joso Ngen
• 金额: $ 57.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652561
• 关键词: Advanced Development; Biodistribution; Biosensor; Brain Injuries; Central Nervous System Neoplasms; Chemicals; Childhood; Childhood Brain Neoplasm; Childhood Central Nervous System Neoplasm; Chronic; Combined Modality Therapy; Convection; Drug Delivery Systems; Esters; Histology; Image; Immunohistochemistry; Injury; Learning; Life; Magnetic Resonance; Magnetic Resonance Imaging; Memory; Methods; Microglia; Modeling; Molecular; Nanotechnology; Neurocognitive Deficit; Neurologic Deficit; Neuroprotective Agents; Outcome; Oxidative Stress; Pharmaceutical Preparations; Positron-Emission Tomography; Procedures; Proteins; Quality of life; Radiation therapy; Reporter Genes; Signal Transduction; Site; Stem cell transplant; Survivors; Techniques; Therapeutic; Tissues; Transplantation; Treatment Side Effects; Validation; behavior test; bioluminescence imaging; biomaterial compatibility; cancer survival; clinical translation; clinically significant; drug release kinetics; experience; fluorescence imaging; image guided; imaging agent; imaging capabilities; improved; in vivo; migration; nanocarrier; nanotheranostics; nerve stem cell; neuroinflammation; neuroprotection; non-invasive imaging; non-invasive monitor; pediatric patients; pre-clinical; prevent; prophylactic; radiotracer; regenerative; repaired; response; screening; stem cell delivery; stem cell survival; stem cells; theranostics; tool; treatment response

Approximately 90% of pediatric central nervous system tumor (CNST) survivors, treated with radiotherapy, experience radiotherapy-induced brain injury (RIBI) and neurocognitive decline later in life. This is a progressive treatment-related side effect, which impacts the quality of life of pediatric CNST survivors. Since more pediatric patients are surviving cancer, there is a growing need for RIBI prophylactic and therapeutic strategies. Chronic oxidative stress and neuroinflammation are key contributors to RIBI. Thus, neuroprotective strategies to reduce oxidative stress and neuroinflammation are being explored. Neuroengineering strategies using regenerative stem cells to repair RIBI are also being explored. However, prolonging the survival of transplanted stem cells at injury sites is a challenge, partly due to chronic oxidative stress and neuroinflammation. Accordingly, strategies to improve transplanted stem cell survival are on the horizon. For these strategies to be effective, drug delivery systems capable of effectively delivering neuroprotective drugs to brain injuries are greatly needed. Also critical for clinical translation efforts are methods to noninvasively image drug delivery and tissue responses to therapy. Nanotechnology in combination with image-guided neuro-interventional procedures are promising for drug delivery. In addition, diamagnetic chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) is a promising MRI technique that can be used to noninvasively and directly image organic drugs. Although, CEST MRI is based on a magnetic resonance spectroscopic (MRS) technique, it is more sensitive (~1000 times) than MRS. Furthermore, given the inherent correlation between CEST MRI signals, pH, and oxidative stress, it can also be used to image changes in tissue oxidative stress, in response to effective drug delivery. We propose to develop CEST MRI theranostic biosensors and complementary CEST MRI nanotheranostic agents for image- guided combination therapy of RIBI. In Aim 1, neuroprotective drugs will be screened by CEST MRI, and each drug’s potential to serve as a pH-dependent CEST MRI theranostic biosensor will be evaluated in our preclinical RIBI model. The feasibility of imaging changes in tissue oxidative stress in vivo with the CEST MRI theranostic agents will also be evaluated. In Aim 2, we will develop oxidative stress-activable CEST MRI nanotheranostic biosensors and evaluate each agent’s potential to sustainably reduce oxidative stress and neuroinflammation in our RIBI model. In Aim 3, we will evaluate the feasibility of improving transplanted stem cell survival and neurorepair in our RIBI model, by sustainably reducing oxidative stress and neuroinflammation. Stem cell survival will be imaged with our stem cell tracking MRI biosensor, capable of noninvasively imaging stem cell delivery, migration and survival. All results will be validated with multi-parametric MRI; PET imaging of neuroinflammation, using the translocator protein radiotracer [(11)C]DPA-713; behavioral tests of memory and learning; histology and immunohistochemistry. This project will advance the development of neuroprotective and neuroengineering strategies for RIBI in pediatric CNS survivors, ultimately improving their quality of life.

大约 90% 的儿童中枢神经系统肿瘤 (CNST) 幸存者接受放射治疗， 在以后的生活中经历放射治疗引起的脑损伤（RIBI）和神经认知能力下降。这是一个进步的 治疗相关的副作用，影响儿科 CNST 幸存者的生活质量。由于儿科较多 随着癌症患者的生存，对 RIBI 预防和治疗策略的需求不断增长。慢性的 氧化应激和神经炎症是 RIBI 的关键因素。因此，神经保护策略可以减少 氧化应激和神经炎症正在被探索。使用再生的神经工程策略 修复 RIBI 的干细胞也正在探索中。然而，延长移植干细胞的存活时间 损伤部位是一个挑战，部分原因是慢性氧化应激和神经炎症。据此，策略 提高移植干细胞的存活率即将到来。为了使这些策略有效，药物输送 非常需要能够有效地向脑损伤提供神经保护药物的系统。也很关键 用于临床转化工作的是非侵入性成像药物输送和组织对治疗反应的方法。 纳米技术与图像引导的神经介入手术相结合在药物方面具有广阔的前景 送货。此外，抗磁化学交换饱和转移磁共振成像（CEST MRI）是一种很有前景的 MRI 技术，可用于无创地直接对有机药物进行成像。虽然， CEST MRI 基于磁共振波谱 (MRS) 技术，它更灵敏（~1000 倍） 比夫人。此外，考虑到 CEST MRI 信号、pH 值和氧化应激之间的内在相关性， 也可用于对组织氧化应激的变化进行成像，以响应有效的药物输送。我们建议 开发 CEST MRI 治疗诊断生物传感器和互补的 CEST MRI 纳米治疗诊断剂，用于图像- RIBI 指导联合治疗。在目标 1 中，将通过 CEST MRI 筛选神经保护药物，每种药物 该药物作为 pH 依赖性 CEST MRI 治疗诊断生物传感器的潜力将在我们的临床前评估中进行评估 RIBI 模型。使用 CEST MRI 治疗诊断对体内组织氧化应激的成像变化的可行性 代理商也将受到评估。在目标 2 中，我们将开发可氧化应激激活的 CEST MRI 纳米治疗仪 生物传感器并评估每种药物可持续减少氧化应激和神经炎症的潜力 我们的 RIBI 模型。在目标 3 中，我们将评估提高移植干细胞存活率的可行性以及 通过持续减少氧化应激和神经炎症，在我们的 RIBI 模型中进行神经修复。干细胞 我们的干细胞追踪 MRI 生物传感器将能够对生存进行成像，该传感器能够对干细胞进行无创成像 交付、迁移和生存。所有结果都将通过多参数 MRI 进行验证； PET 成像 神经炎症，使用易位蛋白放射性示踪剂 [(11)C]DPA-713；记忆和行为测试 学习;组织学和免疫组织化学。该项目将促进神经保护和 针对儿童中枢神经系统幸存者的 RIBI 神经工程策略，最终改善他们的生活质量。