Gene Delivery Nanoparticles to Treat Glioblastoma

基因递送纳米颗粒治疗胶质母细胞瘤

基本信息

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
项目类别：
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

项目摘要

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.

有必要创建新的生物技术来安全有效地将miRNA传递给靶细胞对大脑感兴趣。我们建议开发增强的聚合物纳米颗粒细胞外稳定和可生物的细胞内，以实现安全有效的递送 mirna。我们将在脑癌模型中验证这些颗粒，因为这是一种致命的疾病迫切需要新疗法。特别是，我们将评估人类的处理与护理标准相比，原位模型中的胶质母细胞瘤。聚合物结构将是合成并用于制造非病毒纳米颗粒以递送到多个脑细胞包括健康细胞和癌细胞在内的类型。将开发纳米颗粒制剂在脑脊液（CSF）中保持稳定，并且可以在整个大脑中传播通过对流增强交付（CED）给药。我们将研究新型miRNA药物能够通过靶向肿瘤大脑来克服已知药物和辐射抗性癌干细胞（BCSC）。新型miRNA组合将在体外和体内评估。这将跟踪纳米颗粒以评估其细胞内和细胞外递送以及细胞特异性。 CED后通过正常和肿瘤的啮齿动物大脑运输和安全将进行分析。将在人类的原位模型中评估领先的纳米颗粒将比较使用分子和细胞生物学终点和抗肿瘤功效的胶质母细胞瘤符合护理标准以及与护理标准的结合。我们将创建一个用于miRNA传递的创新技术并在脑癌模型中验证它。