Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncology

项目总结/摘要 尽管被诊断为原发性恶性脑肿瘤的儿童的存活率有所提高， 对发育中的神经系统的诱导损伤仍然是一个重要的问题。很少有治疗选择， 一旦恶性细胞转移到大脑和脊髓周围的软脑膜， 软脑膜转移（LM）不能手术切除，全身化疗受到肿瘤的阻碍。 血脑和血脊髓屏障的存在，使高剂量颅脊髓放射成为唯一的治疗方法。 有效的治疗选择。一些研究者已经将治疗剂直接施用到鞘内空间 希望局部给药能更好地到达LM。然而，鞘内给药 由于脑脊液（CSF）翻转，药物的快速清除和组织渗透不足，因此受到限制。 此外，大多数传统的化学治疗剂是水溶性差的，并且不能被施用至患者。 相关浓度的CSF。我们最近开发了一种新的方法来封装组蛋白 在生物可降解和生物相容性NP（QNP）中的脱乙酰基抑制剂（HDACI）quisinostat。我们的初步 数据表明鞘内给药的NP容易分布在整个脑表面， 脊髓，在蛛网膜下腔内保留良好，并与病变局部化，以减缓LM的生长 在转移性髓母细胞瘤的鼠模型中。在这里，我们提出了一个全面的优化方法， 设计用于鞘内药物递送以治疗LM的放射增敏NP。这些NP不仅仅是一个 固定的贮库，以延长药物在中枢神经系统中的存在，但作为移动的载体，我们预测 将选择性地使转移病灶对放射敏感。我们将（1）设计纳米粒子的表面，以进一步改善 它们与LM的定位，（2），确定药物递送和疗效之间的关系，在模型中， 髓母细胞瘤，和，（3），建立直接到CSF纳米颗粒递送的物种缩放。治疗将 在表现出LM的髓母细胞瘤的患者衍生和基因工程模型中进行评价。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） 成像方法将用于精确定位NP和药物递送到LM， 分辨率通过直接配对交付，活动和功效的多个措施，我们希望开发一个 全面了解蛛网膜下腔内有效药物输送的障碍。最 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.