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）给药策略引起了人们的关注。药物或其他生物制剂可以通过鼻腔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（MSCs）对脑肿瘤的亲和性，利用这些细胞作为治疗载体有很大的兴趣。正如我们最近发表在Molecular Therapy杂志上的文章所示，表达TRAIL并被递送到鼻腔的MSCs可以在小鼠的颅内肿瘤中传播，并显著延长生存期。然而，尽管这些有希望的结果，我们的研究揭示了在这种治疗具有临床意义之前需要解决的几个限制。首先，很少有干细胞（<5%）在经鼻输送后到达大脑，大多数干细胞在肺部积聚。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体内应用至关重要。第三，很少

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.