Nanofiber matrices to improve neural stem cell-mediated cancer therapy

纳米纤维基质改善神经干细胞介导的癌症治疗

基本信息

批准号：
9282732
负责人：
Shawn Hingtgen
金额：
$ 32.43万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282732
关键词：
Address Adherence Affect Allografting Alpha Cell Animals Apoptotic Biochemical Biological Assay Biophysics Blood Brain Caliber Cell Survival Cell Therapy Cell Transplants Cells Chemotherapy-Oncologic Procedure Clinic Clinical Coculture Techniques Cues Deposition Dextrans Engineering Enzyme-Linked Immunosorbent Assay Excision Fiber Gelatin Genetic Engineering Glioblastoma Growth Homing Human Immune Immune system In Vitro Injection of therapeutic agent Malignant neoplasm of brain Mechanics Mediating Mesenchymal Stem Cells Methods Modeling Movement Mus Oncogenes Operative Surgical Procedures Patients Penetration Pharmaceutical Preparations Polyesters Polymers Postoperative Period Property Reaction Time Recurrence Resected Residual state Safety Seeds Solid Solvents Stem cells Surgically-Created Resection Cavity System TNF-related apoptosis-inducing ligand TNFSF10 gene Testing Therapeutic Tissues Translating Transplantation Tumor Debulking Weight Xenograft procedure biodegradable polymer bioluminescence imaging brain tissue cancer cell cancer invasiveness cancer therapy cell behavior cell type cytotoxic design gene product immunocytochemistry improved in vivo killings migration mouse model nano nanofiber neoplastic cell nerve stem cell novel novel therapeutics permissiveness prevent response scaffold stem cell therapy tumor

项目摘要

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.

项目摘要/摘要基因设计的肿瘤神经干细胞（TNSC）是一种有前途的疗法高度侵略性的脑癌胶质母细胞瘤（GBM）。设计的TNSC具有独特的肿瘤的能力使他们能够将抗癌基因产品直接输送到本地和侵入性GBM焦点。我们最近发现聚合物支架显着增加了GBM切除腔中治疗性干细胞的存活，仍然允许干细胞肿瘤归巢，并明显延长了生存具有术后GBM的小鼠。但是，脚手架设计的限制可能会阻止脚手架/TNSC治疗在临床环境中的有效应用。另外，调节TNSC治疗的基质特性未知，以防止优化脚手架参数是为了开发有效的脚手架/TNSC处理针对患者的手术后GBM。我们的结果表明，改变纤维直径和支架内的明胶掺杂可改善TNSC移植。这使我们可以假设优化脚手架的设计特征将有效地抑制后 TNSC治疗的手术GBM。我们建议确定脚手架功能通过使用具有不同生物物理和不同的脚手架来促进TNSC癌症治疗生化特征已知会影响干细胞依从性，运动和分化。然后，我们将确定脚手架的能力结合了多个优化的特征，使用患者的手术切除模型改善TNSC治疗免疫缺乏的小鼠中的人异种移植物和同种异体同种异体移植物中的同种异体移植物免疫能力动物。我们建议实现以下目标：1）并表征具有不同的地形，机械，机械，和生化特性； 2）确定调节的脚手架设计参数用于术后GBM的TNSC治疗； 3）研究的功效和安全性 GBM切除/复发的免疫能力模型中的肿瘤性TSC治疗。这我们的研究结果将产生能够的治疗性TNSC/支架移植策略可用于人类患者测试的强大GBM杀戮。它也会发现调节TNSC不同方面的脚手架特征，使我们能够调节 TNSC癌症治疗通过基质设计。