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Targeting leptomeningeal metastasis in medulloblastoma

靶向髓母细胞瘤的软脑膜转移

基本信息

批准号：
10595323
负责人：
Rachael W Sirianni
金额：
$ 5.77万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10595323
关键词：
Address Affect Angiopoietin-2 Antibiotics Attention Bar Codes Blood Brain Brain Neoplasms Cell Culture Techniques Cells Cerebellum Cerebrospinal Fluid Childhood Malignant Brain Tumor Clinical Data Diagnosis Disease Drug Delivery Systems Drug Design Drug Targeting Encapsulated Ensure Excision Exhibits Formulation Genetic Engineering Growth Human Characteristics In Vitro Individual Infiltration Injections Intravenous Ligands Low Dose Radiation Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Meninges Metastatic Neoplasm to the Leptomeninges Methods Modeling Modification Molecular Movement Mus Neoplasm Metastasis Nervous system structure Neuraxis Operative Surgical Procedures Outcome Study Patients Pediatric Neoplasm Peptides Pharmaceutical Preparations Polymers Primary Neoplasm Prognosis Radiation Radiation Dose Unit Radiation induced damage Resolution Route Site Spinal Cord Subarachnoid Space Surface Survivors System Testing Therapeutic Time Tissues Toxic effect Treatment Efficacy Treatment Side Effects Work actinomycin aggressive therapy biocompatible polymer biodegradable polymer brain parenchyma burden of illness cancer cell chemotherapy cisterna magna clinical translation design drug action drug discovery drug efficacy effective therapy efficacy testing ethylene glycol expectation high throughput screening high-throughput drug screening human disease improved in vivo innovation interest medulloblastoma nanoparticle nanoparticle delivery nanoparticle drug nervous system disorder novel strategies poly(lactic acid)polypeptide receptor side effect small molecule targeted delivery targeted treatment therapeutic candidate therapy outcome tool treatment response tumor tumor growth

项目摘要

Medulloblastoma (MB) is the most common malignant childhood brain tumor. Even with aggressive therapy, many patients still die of their disease. Moreover, survivors suffer severe long-term side effects as a result of treatment, which are thought to result in large part from radiation-induced damage to the developing nervous system. Unlike other brain tumors, which infiltrate through the brain parenchyma, MB commonly spreads through the meninges that surround the brain and spinal cord, a phenomenon termed leptomeningeal metastasis (LM). We recently performed a high throughput drug screen to identify the polypeptide antibiotic actinomycin as a compound of interest for the treatment of MB. We developed methods to encapsulate actinomycin within biodegradable and biocompatible polymeric nanoparticles. We have also identified a peptide ligand capable of targeting receptors that are upregulated on both spinal cord vasculature and patient derived MB. Our preliminary data demonstrate that actinomycin delivered from nanoparticles is significantly more effective at treating intracranial MB than free drug when administered intravenously. Further, we demonstrate that nanoparticles administered directly to the cerebrospinal fluid (CSF) localize with malignant cells to slow the growth of LM. In this work, we will evaluate delivery strategies (presence of targeting ligand, route of administration) to optimize these new approaches in MB. Nanoparticles will be "barcoded" to fluoresce in distinct wavelengths, such that the cellular level distribution of both control and targeted nanoparticle formulations can be evaluated within a single subject to directly assess nanoparticle fate and drug action at the cellular level. We will test test these systems in patient derived and genetically engineered models of MB exhibiting LM. We hypothesize that improved, targeted nanoparticle delivery will enhance exposure of metastatic cells to drug, to improve therapeutic efficacy and reduce the radiation dose needed to achieve complete tumor therapy. To test this hypothesis, we will (1) track delivery of targeted nanoparticles to malignant cells in the brain and spinal cord; (2) evaluate delivery, activity, and toxicity of actinomycin; and (3) test efficacy of targeted therapies in combination with radiation. Our experimental approach has been designed to sequentially refine the design of drug-loaded nanoparticles to yield a better treatment for MB by directly addressing LM as a unique disease burden. We expect that the outcome of these studies will also yield new strategies for spinal cord targeted drug delivery that will be relevant to other disseminated cancers or neurological diseases affecting the spinal cord.

髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤。即使有积极的治疗，许多病人仍然死于他们的疾病。此外，幸存者遭受严重的长期副作用，治疗，这被认为是导致在很大程度上从辐射引起的损害，发展中国家的神经系统与其他脑肿瘤不同，MB通常通过脑实质浸润，通过包围大脑和脊髓的脑膜，这种现象称为软脑膜转移（LM）。我们最近进行了高通量药物筛选，以确定多肽抗生素放线菌素作为感兴趣的化合物用于治疗MB。我们开发了封装方法生物可降解和生物相容性聚合物纳米颗粒内的放线菌素。我们还发现了一个能够靶向在脊髓脉管系统和患者上上调的受体的肽配体衍生MB我们的初步数据表明，放线菌素从纳米颗粒输送，静脉给药时，治疗颅内MB的效果比游离药物更好。我们还表明直接给予脑脊液（CSF）的纳米颗粒定位于恶性肿瘤，细胞来减缓LM的生长。在这项工作中，我们将评估递送策略（靶向配体的存在，给药途径），以优化MB中的这些新方法。纳米颗粒将被“条形码”发出荧光以不同的波长，使得对照和靶向纳米颗粒的细胞水平分布可以在单个受试者中评估制剂，以直接评估纳米颗粒的命运和药物作用。细胞水平。我们将在患者来源和基因工程MB模型中测试这些系统表现出LM。我们假设，改进的靶向纳米颗粒递送将增加暴露于转移细胞的药物，以提高治疗效果，并减少所需的辐射剂量，以实现完整的肿瘤治疗。为了验证这一假设，我们将（1）跟踪靶向纳米颗粒的递送，脑和脊髓中的恶性细胞;（2）评价放线菌素的递送、活性和毒性;以及（3）测试靶向治疗与放射治疗相结合的疗效。我们的实验方法以连续地改进载药纳米颗粒的设计，从而通过直接将LM视为一种独特的疾病负担。我们预计，这些研究的结果也将产生新的脊髓靶向药物递送的策略，将与其他播散性癌症相关，或影响脊髓的神经系统疾病。