Intranasal Stem-Cell Based Therapy for Glioblastoma

鼻内干细胞治疗胶质母细胞瘤

• 批准号: 9203217
• 负责人: Irina V Balyasnikova
• 金额: $ 40.75万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203217
• 关键词: Address; Adipose tissue; Adult; Attention; Autologous; Biological Response Modifier Therapy; Blood - brain barrier anatomy; Bone Marrow; Brain; Brain Neoplasms; CXCL12 gene; Cell Therapy; Cells; Convection; Data; Development; Drug Delivery Systems; Environment; Excision; FDA approved; Failure; Glioblastoma; Glioma; Health; Hypoxia; Image; In Vitro; Infiltration; Intracranial Neoplasms; Intranasal Administration; Ischemic Brain Injury; Kinetics; Laboratories; Literature; Location; Lung; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mesenchymal Stem Cells; Methods; Microscopy; Modeling; Molecular; Multiple Sclerosis; Mus; Nasal cavity; Neuraxis; Oncolytic viruses; Operative Surgical Procedures; Parkinson Disease; Parvovirus; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Photons; Publications; Radiation; Radiation therapy; Rattus; Reporting; Role; Route; Safety; Site; Stem cells; TNFSF10 gene; Testing; Therapeutic; Therapeutic Agents; Travel; Treatment Protocols; Tropism; base; cell motility; chemotherapy; clinical application; clinical efficacy; clinically relevant; clinically significant; human disease; in vivo; infancy; interest; irradiation; migration; nanoparticle; novel; outcome forecast; preconditioning; stem cell biology; stem cell therapy; tumor

DESCRIPTION (provided by applicant): Intranasal delivery of drugs has attracted attention as a promising delivery strategy to the central nervous system (CNS). Drugs or other biologics can be delivered directly and locally to the brain by the application to the nasal cavity thereby avoiding complications associated with the BBB and invasive surgery. Given the tropism of mesenchymal stem cells (MSCs) to brain tumor, there is significant interest in utilizing these cells as therapeutic vehicles. As shown in our most recent publication in Molecular Therapy, MSCs expressing TRAIL and delivered to the nasal cavity travel to intracranial tumors in mice and significantly prolong survival. However, in spite of these promising results, our studies have revealed several limitations that need to be addressed before this therapy is clinically relevant. First, very few stem cells (<5%) reach the brain following intranasal delivery and the majority accumulate in the lungs. Second, imaging of stem cell- based therapeutics is still in its infancy and the development of FDA-approved agents is critical for in vivo applications. Third, very little is known about the kinetics of stem cell migration and quantification of stem cell- based therapies following intranasal delivery. As a result, we propose to address these three problems while examining mechanistic pathways of MSCs migration in the CNS to test the central hypothesis: "Intranasal delivery of MSCs can be optimized for clinical applications and allow for safe and repeated administration of biological therapies in the context of GBM." In order to test this hypothesis, we now propose to complete the following specific aims: Specific Aim 1: To characterize the migration of MSCs following intranasal administration using magnetic resonance imaging (MRI) and single photon emission microscopy (SPEM). Specific Aim 2: To determine the role of hypoxia on MSC migration and tumor infiltration in vivo. Specific Aim 3: To evaluate the role of irradiation on MSC migration and tumor infiltration in vivo. Specific Aim 4: T examine the efficacy of MSCs expressing TRAIL, an oncolytic virus, or a pH-responsive nanoparticle in different models of malignant glioma in vivo.

描述（由申请人提供）：鼻内递送药物作为一种有前途的中枢神经系统（CNS）递送策略而引起了人们的关注。药物或其他生物制剂可以通过鼻腔应用直接局部输送到大脑，从而避免与血脑屏障和侵入性手术相关的并发症。鉴于间充质干细胞（MSC）对脑肿瘤的趋向性，人们对利用这些细胞作为治疗载体非常感兴趣。正如我们最近在《分子治疗》杂志上发表的文章所示，表达 TRAIL 并输送到鼻腔的 MSC 可以到达小鼠的颅内肿瘤，并显着延长生存期。然而，尽管取得了这些有希望的结果，但我们的研究揭示了在这种疗法应用于临床之前需要解决的一些局限性。首先，鼻内输送后很少有干细胞（<5%）到达大脑，大部分在肺部积聚。其次，基于干细胞的成像疗法仍处于起步阶段，FDA 批准的药物的开发对于体内应用至关重要。三、很少 已知鼻内递送后干细胞迁移的动力学和基于干细胞的疗法的量化。因此，我们建议解决这三个问题，同时检查间充质干细胞在中枢神经系统中迁移的机制途径，以检验中心假设：“鼻内输送间充质干细胞可以针对临床应用进行优化，并允许在 GBM 背景下安全、重复地进行生物疗法。”为了检验这一假设，我们现在建议完成以下具体目标： 具体目标 1：使用磁共振成像（MRI）和单光子发射显微镜（SPEM）来表征鼻内给药后 MSC 的迁移。具体目标2：确定缺氧对体内MSC迁移和肿瘤浸润的作用。具体目标3：评估辐射对体内MSC迁移和肿瘤浸润的作用。具体目标 4：检查表达 TRAIL（一种溶瘤病毒或 pH 响应纳米颗粒）的 MSC 在体内不同恶性胶质瘤模型中的功效。