Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncology

项目摘要/摘要 尽管被诊断患有原发性恶性脑瘤的儿童的存活率有所提高，但放射治疗 对发育中的神经系统造成的损害仍然是一个严重的问题。很少有治疗选择是 一旦恶性细胞转移到脑和脊髓周围的软脑膜，就会出现这种情况。 软脑膜转移瘤不能手术切除，全身化疗受阻于 存在血-脑和血-脊髓屏障，使高剂量颅脑辐射成为唯一 有效的治疗选择。一些研究人员已经将治疗药物直接注入鞘内间隙。 希望当地管理的药品能更好地到达路透社。然而，鞘内给药的作用 当脑脊液(CSF)翻转时，药物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很差，不能用于 相应浓度的脑脊液。我们最近开发了一种新的方法来包封组蛋白 去乙酰基抑制剂(HDACi)在可生物降解和生物相容的纳米粒(QNPs)中使用喹诺酮。我们的预赛 数据显示，鞘内给药的NPs很容易分布在大脑表面和 脊髓被很好地保留在蛛网膜下腔内，并与病变一起定位以减缓LM的生长 在转移性髓母细胞瘤的小鼠模型中。在这里，我们提出了一种全面的优化方法 用于鞘内给药治疗LM的放射增敏纳米粒的设计。这些NP不仅仅是作为一个 固定仓库，以延长药物在中枢神经系统中的存在，但作为移动载体，我们预测 会选择性地使转移性病变对辐射敏感。我们将，(1)对NPs的表面进行工程处理，以进一步改善 它们与LM的定位，(2)，决定了药物释放和疗效之间的关系 髓母细胞瘤，以及，(3)，建立直接向脑脊液纳米粒输送的种类标度。治疗将是 在表现为LM的髓母细胞瘤患者来源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) 成像方法将被用来以定量的、细胞水平的方式精确定位NP和药物输送到LM 决议。通过直接配对交付、活动和有效性的多个衡量标准，我们预计将开发一种 全面了解蛛网膜下腔内有效给药的障碍。多数 重要的是，这些研究将把新的纳米技术推向临床，以更好地治疗儿科疾病 脑瘤。

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.