Optimal DNA Brain-Penetrating Nanoparticle (DNA-BPN) Formulation for Glioblastoma (GBM) Treatment

用于胶质母细胞瘤 (GBM) 治疗的最佳 DNA 脑穿透纳米粒子 (DNA-BPN) 配方

基本信息

批准号：
9195468
负责人：
Karina Negron
金额：
$ 4.36万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2016-07-16 至 2020-05-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195468
关键词：
Adenovirus Vector Adhesives Adverse effects Behavior Blood - brain barrier anatomy Brain Brain Neoplasms Bypass Cancerous Cells Charge Chemical Structure Clinical Convection Corpus striatum structure DNA Data Disease Dose Effectiveness Engineering Ensure Esters Extracellular Matrix Formulation Gene Delivery Gene Transfer Generations Genes Glioblastoma Glioma Gold Human In Vitro Infusion procedures Injection of therapeutic agent Lead Malignant Neoplasms Methods Nature Obstruction Particle Size Penetration Plasmids Polyethylene Glycols Polymers Primary Brain Neoplasms Rattus Relapse Reporter Genes Safety Site Structure Suicide Surface System Testing Therapeutic Toxic effect Transfection Tumor Tissue Variant Virus abstracting base biodegradable polymer brain parenchyma brain tissue cancer cell experience gene therapy improved in vivo nano nanoparticle neoplastic cell particle preclinical study pressure promoter success suicide gene surface coating synthetic construct therapeutic transgene transgene expression tumor vector

项目摘要

Project Summary/Abstract This project proposal is focused on developing an optimal brain-penetrating DNA-nanoparticle formulation for gene therapy purposes in Glioblastoma treatment. Glioblastoma (GBM) is the most common and aggressive primary brain tumor, but currently available therapies have severe side effects and the disease remains uniformly lethal. Gene therapy is a potentially powerful strategy that has shown promise in preclinical studies. However, effective gene therapy has yet to be achieved in humans due in large part to an inability to achieve widespread distribution of gene vectors and yet tumor-selective gene transfer in the brain, which is required for the highly invasive nature of GBM. We have developed synthetic DNA-carrying nanoparticles capable of avoiding trapping within the brain parenchyma due to a combination of small particle size (<<100 nm) and dense PEG coatings. These systems are capable of penetrating throughout the entire striatum of the rat brain when administered by convection enhanced delivery (CED). Our pilot data further suggests that these DNA loaded brain-penetrating nanoparticles (DNA-BPN) provide much more widespread and increased transgene expression in healthy brain parenchyma and brain tumor tissue in vivo following CED compared to gold- standard DNA nanoparticles that do not efficiently penetrate beyond the site of infusion. We will develop and thoroughly test DNA-BPN formulated with multiple promising core polymers and compare their behavior in vitro, ex vivo and in vivo to gold-standard systems and leading virus-based vectors. Since the first-generation DNA-BPN already appear capable of safely transfecting a large part of the rat brain, we plan to investigate other promising polymers that may provide even higher transfection along with the use of a highly tumor- specific promoter to limit therapeutic transgene expression to cancerous cells. Our hypothesis is that this combined approach will allow all tumor cells, including highly invasive tumor cells that cause tumor relapse, to be selectively transfected, thereby minimizing potential side effects by eliminating gene transfer to healthy cells.

项目概要/摘要该项目提案的重点是开发一种最佳的脑穿透性 DNA 纳米颗粒制剂基因治疗在胶质母细胞瘤治疗中的用途。胶质母细胞瘤 (GBM) 是最常见且最具侵袭性的原发性脑肿瘤，但目前可用的疗法具有严重的副作用，并且该疾病仍然存在一致致命。基因治疗是一种潜在的强大策略，已在临床前研究中显示出前景。然而，有效的基因治疗尚未在人类中实现，这在很大程度上是由于无法实现基因载体的广泛分布以及大脑中肿瘤选择性基因转移，这是 GBM 的高度侵袭性。我们开发了携带 DNA 的合成纳米颗粒，能够由于颗粒尺寸小（<<100 nm）和致密的 PEG 涂层。这些系统能够穿透大鼠大脑的整个纹状体当通过对流增强递送（CED）给药时。我们的试验数据进一步表明这些 DNA 负载的脑穿透纳米颗粒（DNA-BPN）提供了更广泛和更多的转基因与金相比，CED 后健康脑实质和脑肿瘤组织中的表达标准 DNA 纳米颗粒无法有效渗透到输注部位之外。我们将开发和彻底测试由多种有前途的核心聚合物配制而成的 DNA-BPN，并比较它们在体外、离体和体内金标准系统和领先的基于病毒的载体。从第一代开始 DNA-BPN 已经能够安全转染大鼠大脑的大部分，我们计划进行研究其他有前途的聚合物可以提供更高的转染率以及使用高度肿瘤限制治疗性转基因在癌细胞中表达的特异性启动子。我们的假设是，这联合方法将使所有肿瘤细胞，包括导致肿瘤复发的高度侵袭性肿瘤细胞，被选择性转染，从而通过消除基因转移到健康人来最大限度地减少潜在的副作用细胞。