Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncology

放射增敏纳米颗粒在儿科神经肿瘤学中的鞘内递送

• 批准号: 10755398
• 负责人: Rachael W Sirianni
• 金额: $ 76.22万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-02 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10755398
• 关键词: Intrathecal; delivery; radiation; sensitizing; nanoparticles

PROJECT SUMMARY / ABSTRACT Although survival rates for children diagnosed with a primary malignant brain tumor have improved, radiation induced damage to the developing nervous system remains a significant problem. Few treatment options are available once malignant cells have metastasized to the leptomeninges that surround the brain and spinal cord. Leptomeningeal metastasis (LM) cannot be surgically resected, and systemic chemotherapy is hindered by the presence of the blood-brain and blood-spinal cord barriers, leaving high dose craniospinal radiation as the only effective treatment option. Some investigators have administered therapeutics directly into the intrathecal space with the hope that locally administered drugs will better reach LM. However, action of intrathecally administered agents is limited by rapid clearance and inadequate tissue penetration as cerebrospinal fluid (CSF) turns over. Furthermore, most traditional chemotherapeutics are poorly water soluble and cannot be administered to the CSF at relevant concentrations. We have recently developed a novel approach for encapsulating the histone deacetyle inhibitor (HDACI) quisinostat within biodegradable and biocompatible NPs (QNPs). Our preliminary data demonstrate that intrathecally administered NPs distribute readily across the surfaces of the brain and spinal cord, are well retained within the subarachnoid space, and localize with lesions to slow the growth of LM in a murine model of metastatic medulloblastoma. Here, we propose a comprehensive approach for optimizing the design of radiation sensitizing NPs for intrathecal drug delivery to treat LM. These NPs serve not just as a stationary depot to prolong drug presence in the central nervous system but as mobile carriers that we predict will selectively sensitize metastatic lesions to radiation. We will, (1) engineer the surface of NPs to further improve their localization with LM, (2), determine the relationship between drug delivery and efficacy in models of medulloblastoma, and, (3), establish species scaling of direct-to-CSF nanoparticle delivery. Treatments will be evaluated in patient derived and genetically engineered models of medulloblastoma exhibiting LM. Fluorescent barcoding, matrix assisted laser desorption ionization (MALDI), and positron emission tomography (PET) imaging approaches will be used to precisely localize NP and drug delivery to LM with quantitative, cellular-level resolution. By directly pairing multiple measures of delivery, activity, and efficacy, we expect to develop a comprehensive understanding of barriers to effective drug delivery within the subarachnoid space. Most importantly, these studies will advance new nanotechnology toward the clinic for better treatment of pediatric brain tumors.

项目概要/摘要 尽管被诊断患有原发性恶性脑肿瘤的儿童的生存率有所提高，但放射治疗 对发育中的神经系统造成的损伤仍然是一个重大问题。治疗选择很少 一旦恶性细胞转移到大脑和脊髓周围的软脑膜，就可以使用。 软脑膜转移瘤（LM）无法通过手术切除，全身化疗受到阻碍 血脑和血脊髓屏障的存在，使得高剂量颅脊髓辐射成为唯一的治疗方法 有效的治疗选择。一些研究人员将治疗剂直接注入鞘内空间 希望局部用药能够更好地到达LM。然而，鞘内给药的作用 脑脊液 (CSF) 周转时，药物的清除速度受到快速清除和组织渗透不足的限制。 此外，大多数传统化疗药物的水溶性较差，无法对患者进行治疗。 相关浓度的脑脊液。我们最近开发了一种封装组蛋白的新方法 可生物降解和生物相容性纳米颗粒 (QNP) 内的脱乙酰抑制剂 (HDACI) 奎司他。我们的初步 数据表明，鞘内注射的纳米颗粒很容易分布在大脑表面，并且 脊髓，很好地保留在蛛网膜下腔内，并定位于病变以减缓 LM 的生长 在转移性髓母细胞瘤小鼠模型中。在这里，我们提出了一种综合的优化方法 用于鞘内给药治疗 LM 的放射增敏纳米粒子的设计。这些 NP 不仅充当 固定仓库可延长药物在中枢神经系统中的存在，但我们预测可作为移动载体 将选择性地使转移性病变对辐射敏感。我们将，(1) 设计纳米颗粒的表面以进一步改善 它们与 LM 的定位，(2)，确定模型中药物输送和功效之间的关系 髓母细胞瘤，(3)，建立直接向脑脊液纳米颗粒递送的物种规模。治疗将是 在表现出 LM 的髓母细胞瘤患者衍生模型和基因工程模型中进行评估。荧光 条形码、基质辅助激光解吸电离 (MALDI) 和正电子发射断层扫描 (PET) 成像方法将用于通过定量、细胞水平精确定位 NP 和向 LM 的药物递送 解决。通过直接配对交付、活动和功效的多种衡量标准，我们期望开发出一种 全面了解蛛网膜下腔内有效药物输送的障碍。最多 重要的是，这些研究将推动新的纳米技术走向临床，以更好地治疗儿科疾病 脑肿瘤。