Nanofiber matrices to improve neural stem cell-mediated cancer therapy

项目摘要/摘要 基因工程抗肿瘤神经干细胞(TNSCs)是一种有前途的治疗方法 高度侵袭性脑癌胶质母细胞瘤(GBM)。经工程设计的tNSC具有独特的 肿瘤归巢能力，使他们能够将抗癌基因产品直接输送到 局灶性和侵袭性基底膜病灶。我们最近发现，聚合物支架 显著提高了治疗干细胞在GBM切除腔中的存活率， 仍然允许干细胞向肿瘤归巢，并显著延长存活时间 术后基底膜的小鼠。然而，脚手架设计的局限性可能会阻止 支架/tNSC疗法在临床环境中的有效应用。此外， 调节tNSC治疗的基质特性尚不清楚，阻碍了tNSC的优化 支架参数，以开发支架/tNSC治疗是有效的 抗术后肾小球基底膜。我们的结果表明，改变纤维直径和 支架内明胶掺杂可促进神经干细胞移植。这使我们能够假设 优化脚手架的设计特点，将有效地抑制后冲击 经tNSC治疗的脑胶质瘤外科治疗。我们建议确定脚手架的特征 用一组不同生物物理和化学成分的支架促进肿瘤细胞的治疗 已知的影响干细胞黏附、移动和 差异化。然后我们将确定结合多个 使用患者的手术切除模式改进tNSC治疗的优化功能- 免疫耗竭小鼠来源的人异种移植和同种异体GBM移植 免疫能力强的动物。我们建议承担以下目标：1)发展 以及表征一组具有不同的地形、机械 和生化特性；2)确定规范的支架设计参数 TNSC治疗肾小球基底膜的疗效和安全性观察 抗肿瘤TSC治疗免疫功能良好的基底膜切除/复发模型。这个 我们的研究结果将产生一种治疗性tNSC/支架移植策略 可以转化为人类患者测试的强大的GBM杀伤力。它还将揭开 脚手架功能调节tNSCs的不同方面，允许我们调节 TNSC通过矩阵设计治疗肿瘤。

Project Summary/Abstract Genetically engineered tumoricidal neural stem cells (tNSCs) are a promising therapy for the highly aggressive brain cancer Glioblastoma (GBM). Engineered tNSCs have unique tumor-homing capacity that allows them to deliver anti-cancer gene products directly into local and invasive GBM foci. We recently discovered that polymeric scaffolds significantly increase the survival of therapeutic stem cells in the GBM resection cavity, remained permissive to stem cell tumoritropic homing, and markedly prolong the survival of mice with post-operative GBM. Yet, limitations to scaffold design are likely to prevent the effective application of scaffold/tNSC therapy in a clinical setting. Additionally, the matrix properties that regulate tNSC therapy are unknown, preventing the optimization of scaffold parameters in order to develop a scaffold/tNSC treatment that is effective against post-surgical GBM in patients. Our results show that altering fiber diameter and gelatin doping within scaffolds improves tNSC transplant. This allows us to hypothesize that optimizing the design features of scaffolds will achieve effective suppression of post- surgical GBMs by tNSC therapy. We propose to identify the scaffold features that promote tNSC cancer therapy by using a panel of scaffolds with different biophysical and biochemical features known to influence stem cell adherence, movement, and differentiation. We will then determine the ability of scaffolds incorporating multiple optimized features to improve tNSC therapy using surgical resection models of patient- derived human xenografts in immune-depleted mice and syngeneic GBM allografts in immune-competent animals. We propose to undertake the following Aims: 1) Develop and characterize a panel of polymeric scaffolds with differing topographic, mechanical, and biochemical properties; 2) Determine the scaffold design parameters that regulate tNSC therapy for post-operative GBM; 3) Investigate the efficacy and safety of tumoricidal tSC therapy in immune-competent models of GBM resection/recurrence. The results of our study will generate a therapeutic tNSC/scaffold transplant strategy capable of robust GBM killing that can be translated for human patient testing. It will also uncover the scaffold features that regulate different aspects of tNSCs, allowing us to modulate tNSC cancer therapy through matrix design.