Treatment of glioblastoma using chain-like nanoparticles

使用链状纳米颗粒治疗胶质母细胞瘤

基本信息

批准号：
9335795
负责人：
Efstathios Karathanasis
金额：
$ 61.75万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-14 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335795
关键词：
Address Animals Apoptotic Blood Blood Vessels Brain Neoplasms Cells Characteristics Chemicals Cytotoxic agent Deposition Diffuse Disease Docking Dose Drug Combinations Drug Delivery Systems Drug resistance Effectiveness Exhibits General Population Glioblastoma Glioma Human Injectable Life Ligands Link Liposomes Malignant Neoplasms Mechanics Membrane Modeling Multimodal Imaging Mus NOS2A gene Nanosphere Nature Patients Penetration Pharmaceutical Preparations Pharmacology Plasticizers Primary Neoplasm Recurrence Resistance Rodent Signal Transduction Site Specificity Standardization Stem cells Stream System Systemic Therapy Therapeutic Toxic effect Treatment Efficacy Treatment-related toxicity Xenograft Model Xenograft procedure chemotherapy cytotoxicity density effective therapy flexibility in vitro Assay in vivo indexing inhibitor/antagonist interstitial iron oxide nanoparticle neoplastic cell nerve stem cell palliation particle public health relevance radiofrequency self-renewal stem cell population success tumor tumor growth vascular bed

项目摘要

DESCRIPTION (provided by applicant): The invasive forms of brain tumors, such as glioblastoma multiforme (GBM) are recognized as one of the deadliest forms of cancer with current therapies offering only palliation complicated by significant toxicities. Current approaches for the treatment of glioma are limited in their effectiveness, because brain tumors are characteristically diffuse, highly invasive, non-localized, and drug penetration across the blood-tumor barrier (BTB) is poor for most drugs. In addition to limited drug delivery, brain tumor cells tend to be particularly resistant to drugs, especially after tumor recurrence. To address both challenges of drug delivery and drug resistance, the objective of this proposal is to integrate the unique features of a chain-like nanoparticle with the appropriate combination of complementary drugs to enable effective treatment of invasive brain tumors. To tackle the drug delivery issue, we have developed a multicomponent, flexible chain-like nanoparticle, termed nanochain, which is comprised of three iron oxide nanospheres and one drug-loaded liposome chemically linked into a linear, chain-like assembly. The multicomponent nature of nanochains results in two features that synergistically facilitate effective treatment of difficult-to-treat GMs. First, the oblong-shaped, flexible nanochain possesses a unique ability to seek and rapidly deposit on the blood vessel walls of glioma sites via vascular targeting. Second, after nanochains slip from the blood stream and dock on the vascular bed of GBMs, an external low-power radiofrequency (RF) field remotely triggers rapid drug release due to mechanical disruption of the liposomal membrane facilitating widespread and effective drug delivery into GBMs. To address the drug resistance issue, we have identified glioma stem cell (GSC)-specific regulators amenable to pharmacologic targeting. We recently showed that the inducible nitric oxide synthase (iNOS) is a unique signal regulator in GSCs. Due to the flexibility of loading various types of drugs within the nanochain; the nanochain will be loaded with standard chemotherapy and an iNOS inhibitor that eliminates the small fraction of GBM cells that are resistant, and can migrate to cause tumor recurrence. By using nanochains, we hypothesize that guaranteeing the effective and simultaneous delivery of these drugs with synergistic activity to glioma sites will facilitate effective treatment and ultimately eradication of the disease usinga safe dose. Specific Aim 1: Optimize the targeting efficacy of a chain-like nanoparticle to invasive brain tumors and evaluate drug delivery across the BTB in the CNS-1 glioma model in mice. Specific Aim 2. Determine (A) the effect of iNOS inhibition on GBM tumor growth and GBM stem cell subpopulations and (B) the effective delivery of iNOS inhibitors to GBM xenografts via nanochains and RF. Specific Aim 3. Evaluate the therapeutic efficacy of nanochains loaded with a chemotherapeutic and an iNOS inhibitor in GBM xenografts of highly invasive brain tumors.

描述（由申请人提供）：侵袭性脑肿瘤，例如多形性胶质母细胞瘤（GBM），被认为是最致命的癌症形式之一，目前治疗神经胶质瘤的方法仅提供姑息治疗，并伴有显着的毒性。其有效性有限，因为脑肿瘤具有弥漫性、高度侵袭性、非局部性的特征，并且除了有限的药物外，大多数药物穿过血肿瘤屏障（BTB）的药物渗透性较差。分娩、脑肿瘤细胞往往对药物特别耐药，特别是在肿瘤复发后，为了解决药物输送和耐药性整合的挑战，该提案的目的是将链状纳米颗粒的独特功能与互补药物的适当组合结合起来。为了有效治疗侵袭性脑肿瘤，我们开发了一种多组分、柔性链状纳米颗粒，称为纳米链，它由三个氧化铁纳米球和一个化学连接成的载药脂质体组成。线性、链状组装的纳米链具有两个特征，可以协同促进难以治疗的转基因药物的有效治疗。首先，椭圆形的柔性纳米链具有寻找并快速沉积在血液上的独特能力。其次，纳米链从血流中滑落并停靠在 GBM 的血管床上后，外部低功率射频 (RF) 场会因机械作用而远程触发药物快速释放。脂质体膜的破坏促进了药物广泛有效地输送到 GBM 中，为了解决耐药性问题，我们已经确定了适合药理学靶向的神经胶质瘤干细胞 (GSC) 特异性调节剂。是 GSC 中独特的信号调节剂，由于纳米链内装载各种类型的药物的灵活性，纳米链将装载标准化疗药物和消除一小部分的 iNOS 抑制剂。通过使用纳米链，GBM 细胞具有耐药性，并且可以迁移导致肿瘤复发，我们发现，保证这些具有协同活性的药物有效且同时递送至神经胶质瘤部位将有助于有效治疗并最终使用安全剂量根除该疾病。具体目标1：优化链状纳米颗粒对侵袭性的靶向功效。具体目标 2. 确定 (A) iNOS 抑制对 GBM 肿瘤生长和 GBM 干细胞亚群的影响，以及 (B) iNOS 的有效递送。通过纳米链和 RF 抑制 GBM 异种移植物。具体目标 3. 评估载有化疗药物和 iNOS 抑制剂的纳米链的治疗效果。高侵袭性脑肿瘤的 GBM 异种移植物。