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

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导致的脑损伤(RIBI)和神经认知能力下降。这是一种进步 治疗相关副作用，影响儿童CNST幸存者的生活质量。因为更多的儿科 患者在癌症中存活，对RIBI预防和治疗策略的需求越来越大。慢性 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 人们正在研究氧化应激和神经炎症。使用再生的神经工程策略 修复RIBI的干细胞也在探索中。然而，延长移植的干细胞的存活时间 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。相应地，战略 提高移植的干细胞存活率的方法即将出现。为了使这些策略有效，药物递送 迫切需要能够有效地为脑损伤提供神经保护药物的系统。也很关键 对于临床翻译工作来说，方法是非侵入性地成像药物输送和组织对治疗的反应。 纳米技术与图像引导的神经介入手术相结合有望用于药物 送货。此外，抗磁化学交换饱和转移磁共振成像(CEST) 磁共振成像(MRI)是一种很有前途的磁共振成像技术，可用于有机药物的非侵入性直接成像。虽然， CEST MRI基于磁共振波谱(MRS)技术，它更敏感(~1000倍) 此外，考虑到CEST MRI信号、PH值和氧化应激之间的内在联系，它 也可以用来成像组织氧化应激的变化，以响应有效的药物输送。我们建议 目的：研制CEST磁共振热敏生物传感器及互补的CEST磁共振纳米热敏成像试剂。 RIBI的指导性综合治疗。在目标1中，神经保护药物将通过CEST MRI进行筛选，每种药物 药物作为pH依赖的CEST磁共振生物传感器的潜力将在我们的临床前进行评估 里比模型。CEST磁共振成像对活体组织氧化应激变化的成像可行性 代理也将接受评估。在目标2中，我们将开发氧化应激激活的CEST MRI纳米无感知器 生物传感器，并评估每种试剂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和 在我们的RIBI模型中，通过可持续地减少氧化应激和神经炎症，神经修复。干细胞 我们的干细胞跟踪核磁共振生物传感器将对存活进行成像，该传感器能够对干细胞进行非侵入性成像 递送、迁徙和生存。所有结果都将通过多参数磁共振成像进行验证； 神经炎症，使用转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。该项目将推动神经保护和治疗技术的发展 儿童中枢神经系统存活者RIBI的神经工程策略，最终改善他们的生活质量。

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.