Intranasal Stem-Cell Based Therapy for Glioblastoma

描述（由申请人提供）：鼻内给药作为一种有前途的中枢神经系统（CNS）给药策略已引起关注。药物或其他生物制剂可以通过应用于鼻腔而直接和局部地递送到大脑，从而避免与BBB和侵入性手术相关的并发症。鉴于间充质干细胞（MSC）对脑肿瘤的向性，利用这些细胞作为治疗载体有很大的兴趣。正如我们最近在《分子治疗》杂志上发表的文章所示，表达TRAIL并被递送到鼻腔的MSC可以到达小鼠的颅内肿瘤，并显着延长生存期。然而，尽管这些有希望的结果，我们的研究已经揭示了一些局限性，需要解决之前，这种疗法是临床相关的。首先，在鼻内递送后，很少干细胞（<5%）到达大脑，并且大多数在肺中积累。其次，基于干细胞的治疗剂的成像仍处于起步阶段，并且FDA批准的药剂的开发对于体内应用是关键的。第三，很少 已知干细胞迁移的动力学和干细胞治疗的定量。因此，我们建议解决这三个问题，同时检查CNS中MSC迁移的机制途径，以测试中心假设：“MSC的鼻内递送可以针对临床应用进行优化，并允许在GBM的背景下安全和重复施用生物疗法。“为了验证这一假设，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）表征鼻内给药后MSC的迁移。具体目标2：确定体内缺氧对MSC迁移和肿瘤浸润的作用。具体目的3：评价放射对MSC迁移和肿瘤浸润的作用。具体目标4：本研究旨在检测表达肿瘤坏死因子相关凋亡诱导配体（TRAIL）、溶瘤病毒或pH响应性纳米颗粒的骨髓间充质干细胞在体内不同恶性胶质瘤模型中的疗效。

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.