Intranasal Stem-Cell Based Therapy for Glioblastoma

描述(由申请人提供)：鼻腔给药作为一种有前途的中枢神经系统(CNS)给药策略引起了人们的关注。药物或其他生物制剂可以通过鼻腔应用直接和局部地输送到大脑，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(MSCs)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。正如我们最新发表在《分子治疗》杂志上所显示的那样，表达TRAIL并被输送到鼻腔的MSCs可以转移到小鼠的颅内肿瘤中，并显著延长生存时间。然而，尽管有这些有希望的结果，我们的研究揭示了在该疗法临床应用之前需要解决的几个局限性。首先，很少有干细胞(5%)在鼻腔输送后到达大脑，而大多数积累在肺部。其次，干细胞疗法的成像仍处于初级阶段，FDA批准的药物的开发对体内应用至关重要。第三，很少 已知干细胞迁移的动力学和鼻腔给药后基于干细胞的治疗的量化。因此，我们建议在研究MSCs在中枢神经系统中迁移的机制路径时解决这三个问题，以检验中心假设：“MSCs的鼻腔给药可以优化临床应用，并允许在GBM的背景下安全和重复地使用生物疗法。”为了验证这一假设，我们现在建议完成以下特定目标：特定目标1：使用磁共振成像(MRI)和单光子发射显微镜(SPEM)来表征鼻腔给药后MSCs的迁移。具体目的2：探讨缺氧对骨髓间充质干细胞迁移和体内肿瘤侵袭的影响。具体目的3：评价辐射对骨髓间充质干细胞迁移和体内肿瘤侵袭的影响。特定目的4：检测表达TRAIL的MSCs在体内不同恶性胶质瘤模型中的疗效。TRAIL是一种溶瘤病毒，或者是一种pH响应性纳米颗粒。

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.