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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.