Gene Delivery Nanoparticles to Treat Glioblastoma

基因递送纳米颗粒治疗胶质母细胞瘤

• 批准号: 10058249
• 负责人: Jordan Green
• 金额: $ 36.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-16 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058249
• 关键词: Affect; Animal Cancer Model; Astrocytes; Biological; Biological Models; Biomedical Engineering; Biotechnology; Brain; Cancer Model; Cations; Cells; Cerebrospinal Fluid; Clinic; Clinical; Convection; Cytosol; DNA delivery; Development; Disease; Drug resistance; Electrostatics; Endosomes; Engineering; Epigenetic Process; Evaluation; Formulation; Gene Delivery; Glioblastoma; Health; Human; In Vitro; Label; Malignant Neoplasms; Malignant neoplasm of brain; Messenger RNA; MicroRNAs; Microglia; Modeling; Molecular; Nuclear; Pharmaceutical Preparations; Polymers; Property; Radiation; Regenerative Medicine; Research Proposals; Rod; Rodent; Rodent Model; Role; Safety; Site; Specificity; Structure; Surface; Technology; Therapeutic; Time; Translating; Untranslated RNA; brain cell; cancer cell; cancer stem cell; cancer therapy; cell type; chemical property; chemotherapy; crosslink; cytotoxicity; design; extracellular; flexibility; genetic technology; human disease; in vivo; innovative technologies; interest; nanobiotechnology; nanoparticle; nanoparticle delivery; nervous system disorder; neuroregulation; novel; novel therapeutics; particle; physical property; plasmid DNA; radiation resistance; standard of care; stem cell biology; stem cells; technology validation; temozolomide; therapeutically effective; tumor; uptake

There is a need to create new biotechnology to safely and effectively deliver miRNA to target cells of interest in the brain. We propose to develop enhanced polymeric nanoparticles designed to be stable extracellularly and bioreducible intracellularly, to enable safe and effective delivery of miRNA. We will validate these particles in models of brain cancer as it is a deadly disease that is in critical need of new therapies. In particular, we will evaluate treatment of human glioblastoma in orthotopic models compared to the standard of care. Polymer structures will be synthesized and utilized to fabricate non-viral nanoparticles for delivery to multiple brain cell types including healthy cells and cancer cells. Nanoparticle formulations will be developed that remain stable in cerebrospinal fluid (CSF) and that can spread throughout the brain following administration by convection-enhanced delivery (CED). We will investigate novel miRNA drugs capable of overcoming known drug and radiation resistances by targeting tumor-propagating brain cancer stem cells (BCSCs). Novel miRNA combinations will be evaluated in vitro and in vivo. The nanoparticles will be tracked to evaluate their intracellular and extracellular delivery and cell specificity. Transport and safety through normal and tumor- bearing rodent brains following CED will be analyzed. Leading nanoparticles will be evaluated in an orthotopic model for human glioblastoma using molecular and cell biological endpoints and anti-tumor efficacy will be compared to the standard of care as well as in combination with the standard of care. We will create an innovative technology for miRNA delivery and validate it in models of brain cancer.

有必要创造新的生物技术来安全有效地将miRNA输送到靶细胞 对大脑有兴趣。我们建议开发增强型聚合物纳米颗粒，旨在 稳定的细胞外和细胞内可生物还原，以实现安全和有效的递送 MiRNA。我们将在脑癌模型中验证这些颗粒，因为它是一种致命的疾病， 迫切需要新的治疗方法。特别是，我们将评估对人类 比较胶质母细胞瘤原位模型的护理标准。聚合物结构将是 合成并用于制备非病毒纳米粒以输送到多个脑细胞 类型包括健康细胞和癌细胞。将开发纳米颗粒配方，以 在脑脊液(CSF)中保持稳定，并可在以下情况下扩散到整个大脑 通过对流增强输送(CED)给药。我们将研究新的miRNA药物 能够通过靶向肿瘤扩散的脑来克服已知的药物和辐射抗性 癌症干细胞(BCSC)新的miRNA组合将在体外和体内进行评估。这个 将对纳米颗粒进行跟踪，以评估其细胞内和细胞外的递送和 专一性。CED后正常和荷瘤鼠脑的转运和安全性 将会被分析。领先的纳米粒子将在人体原位模型中进行评估 利用分子和细胞生物学终点对胶质母细胞瘤的抗肿瘤疗效进行比较 符合护理标准以及与护理标准相结合。我们将创建一个 创新的miRNA传递技术，并在脑癌模型中进行验证。