Tumor-Selective Delivery Approaches for Medulloblastoma

大多数原发性脑肿瘤导致高发病率和极低的生存率。脑肿瘤是 不幸的是，现在它已成为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，尽管情况非常严重 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局不佳且严重 由于这些疗法的毒性而导致的神经认知缺陷。改善小学成绩的主要障碍 脑肿瘤患者的治疗药物穿过血脑屏障的传递相对无效 (BBB) 专门针对脑肿瘤细胞，同时不伤害周围的正常脑组织。 迄今为止，研究人员尚未发现专门针对原发性大脑的治疗机制 肿瘤，以避免全身毒性。我们寻求解决这个问题，通过以下方法提高药物治疗指数： 提出了一种利用新型纳米颗粒专门针对脑肿瘤脉管系统的治疗策略 基于药物递送系统，与肿瘤内皮细胞上的 P-选择素具有高亲和力。我们的 初步研究表明纳米颗粒选择性外渗并靶向穿过血脑的肿瘤 新型本土 GEM 髓母细胞瘤模型中的屏障。我们的团队提出了一项将两者本地化的策略 通过针对肿瘤 P-选择素的靶向治疗来治疗脑肿瘤组织的常规药物和精准药物 脉管系统。我们将采用与生理学和遗传相关的声波刺猬驱动的小鼠模型 髓母细胞瘤确定与放射治疗在增强肿瘤选择性纳米颗粒药物方面的协同作用 交付，并将追求以下具体目标：1）评估P-选择素介导的靶向作用， 放射，以及髓母细胞瘤中穿过血脑屏障的外渗机制，2) 评估 P-选择素靶向化疗/SHH通路抑制在Sonic Hedgehog驱动中的疗效和毒性 髓母细胞瘤，3) 评估原发性髓母细胞瘤局部放射治疗的效果 P-选择素和纳米颗粒药物递送至远处软脑膜脑肿瘤转移的研究 体内中枢神经系统。我们将利用生化和成像方法，包括活体多光子 显微镜、共聚焦免疫荧光和免疫电镜、用于骨分析的显微 CT、药代动力学和 生物分布测量和评估纳米颗粒输送机制的分子生物学方法， 治疗效果及毒性。我们的主要终点是确定协同作用的肿瘤选择性策略 符合现行髓母细胞瘤护理治疗标准。如果我们的结果证明是有利的，我们预计 对髓母细胞瘤和其他原发性脑肿瘤以及神经系统疾病患者的临床适用性 已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.