Tumor-Selective Delivery Approaches for Medulloblastoma

大多数原发性脑肿瘤导致高发病率和非常差的生存率。脑肿瘤是 现在不幸的是，它是儿童癌症相关死亡的主要原因。髓母细胞瘤是最常见的 恶性小儿脑肿瘤导致近三分之一的患病儿童死亡， 积极的治疗，包括手术切除、全脑和脊柱放射治疗以及全身治疗 化疗此外，绝大多数幸存儿童的结果很差， 由于这些疗法的毒性而导致的神经认知缺陷。改善初级保健结局的主要障碍 脑肿瘤患者是相对无效的输送治疗剂穿过血脑屏障 (BBB)特异性地针对脑肿瘤细胞而不伤害周围的正常脑组织。 因此，研究人员发现很少有机制专门针对原发性脑 肿瘤，以避免全身毒性。我们试图解决这个问题，以提高药物治疗指数， 提出了一种利用新型纳米颗粒特异性靶向治疗脑肿瘤血管系统的策略， 基于对肿瘤内内皮细胞上的P-选择素具有高亲和力的药物递送系统。我们 初步研究表明，选择性纳米颗粒外渗和靶向肿瘤通过血脑 在一个新的本土GEM髓母细胞瘤模型中的屏障。我们的团队提出了一个策略， 通过靶向治疗肿瘤上的P-选择素， 脉管系统我们将采用一种生理学和遗传学相关的小鼠模型， 髓母细胞瘤以鉴定与放射疗法在增强肿瘤选择性纳米颗粒药物中的协同作用 1）评价P-选择素介导的靶向作用， 放射治疗和髓母细胞瘤血脑屏障外渗的机制，2）为了评估放射治疗对髓母细胞瘤血脑屏障的影响， P-选择素靶向化疗/SHH通路抑制在Sonic Hedgehog驱动的小鼠中的疗效和毒性 评估原发性髓母细胞瘤的局部放射治疗效果 对P-选择素和纳米颗粒药物递送至远端软脑膜脑肿瘤转移的影响 体内中枢神经系统。我们将利用生物化学和成像方法，包括活体多光子 显微镜、共聚焦免疫荧光和免疫EM、用于骨分析的显微CT、药代动力学和 生物分布测量，以及评估纳米颗粒递送机制的分子生物学方法， 治疗效果和毒性。我们的主要终点是确定肿瘤选择性策略， 与目前髓母细胞瘤的标准治疗相一致。如果我们的结果证明是有利的，我们设想 临床适用于髓母细胞瘤和其他原发性脑肿瘤以及神经系统肿瘤患者， 已被证明具有内皮炎症的疾病，包括多发性硬化症和中风。

The majority of primary brain tumors result in high morbidity and very poor survival. Brain tumors are now unfortunately the leading cause of cancer-related death in children. Medulloblastoma is the most common malignant pediatric brain tumor resulting in the death of nearly one-third of afflicted children despite very aggressive therapies that include surgical resection, whole brain and spine radiation therapy, and systemic chemotherapy. Furthermore, the vast majority of surviving children have poor outcomes and significant neurocognitive deficits due to the toxicity of these therapies. A major barrier to improving outcomes for primary brain tumor patients is the relative ineffective delivery of therapeutic agents across the blood-brain barrier (BBB) specifically to brain tumor cells while sparing normal surrounding brain tissue. Heretofore, researchers have found few mechanisms to target therapies specifically to primary brain tumors, to avoid systemic toxicities. We seek to address this problem to improve drug therapeutic indices by proposing a strategy to target therapies specifically to brain tumor vasculature utilizing a novel nanoparticle- based drug delivery system that has high affinity to P-selectin on endothelial cells within tumors. Our preliminary studies show selective nanoparticle extravasation and targeting to tumors across the blood-brain barrier in a novel autochthonous GEM medulloblastoma model. Our team proposes a strategy to localize both conventional and precision drugs to brain tumor tissue by targeting therapies to P-selectin on tumor vasculature. We will employ a physiologically and genetically-relevant mouse model of Sonic hedgehog-driven medulloblastoma to identify synergy with radiation therapy in enhancing tumor-selective nanoparticle drug delivery, and will pursue the following specific aims: 1) To evaluate the P-selectin-mediated targeting, role of radiation, and mechanism of extravasation across the blood-brain barrier in medulloblastoma, 2) To assess the efficacy and toxicity of P-selectin-targeted chemotherapy/SHH pathway inhibition in Sonic hedgehog-driven medulloblastoma, and 3) To assess the effects of focal radiation therapy of primary medulloblastoma tumors on P-selectin and nanoparticle drug delivery to distant leptomeningeal brain tumor metastases within the central nervous system in vivo. We will utilize biochemical and imaging methods including intravital multiphoton microscopy, confocal immunofluorescence and immuno-EM, micro-CT for bone analysis, pharmacokinetic and biodistribution measurements, and molecular biology approaches to assess nanoparticle delivery mechanisms, treatment efficacy, and toxicity. Our primary endpoint is to identify tumor-selective strategies that synergize with current standard of care therapies for medulloblastoma. Should our results prove favorable, we envision clinical applicability to patients with medulloblastoma and other primary brain tumors as well as neurological diseases that have been shown to have endothelial inflammation including multiple sclerosis and stroke.