Treatment of glioblastoma using chain-like nanoparticles

使用链状纳米颗粒治疗胶质母细胞瘤

• 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
• 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

 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（由适用提供）：脑肿瘤的侵入性形式，例如多形胶质母细胞瘤（GBM）被认为是最致命的癌症形式之一，当前的疗法仅提供严重毒性的抑制作用。当前的治疗神经胶质瘤的方法在其有效性上受到限制，因为大多数药物的脑肿瘤特征是弥漫性，高度侵入性，非定位的特征，药物渗透在血液肿瘤屏障（BTB）上很差。除药物递送有限外，脑肿瘤 细胞往往特别抗药，尤其是在肿瘤复发之后。为了应对药物输送和耐药性的挑战，该提案的目的是将链状纳米颗粒的独特特征与适当的互补药物结合在一起，以有效治疗侵入性脑肿瘤。为了解决药物输送问题，我们开发了一种多组分，柔性链状纳米颗粒，称为纳米链，该纳米素纳米座，该纳米素构成了三个氧化铁纳米球和一个装载的脂质体，该脂质体将化学链接到线性的，链状的组件中。纳米句的多组分性质产生了两种特征，可以协同有效地处理难以治疗的GMS。首先，长方形，柔性纳米方蛋白具有独特的能力，可以通过血管靶向在神经胶质瘤部位的血管壁上迅速沉积。其次，在纳米句从血流和码头滑落在GBMS的血管床上后，由于机械破坏脂质体膜的机械破坏，脂质体膜的机械破坏支持宽度宽度和有效的药物为GBMS，因此外部低功率射频（RF）场远程触发了迅速的药物释放。为了解决耐药性问题，我们已经确定了可与药物靶向的特异性调节剂。我们最近表明，诱导型一氧化氮合酶（INOS）是GSC中的独特信号调节剂。由于将各种类型的药物加载到纳米方链中的灵活性；纳米方蛋白将装有标准化疗和iNOS抑制剂，以消除抗性的GBM细胞的小部分，并可以迁移以引起肿瘤复发。通过使用纳米句，我们假设可以保证具有与神经胶质瘤部位协同活性的这些药物的有效和简单递送，将促进有效的治疗，并最终使用安全剂量对疾病进行放射。特定目标1：优化链状纳米颗粒的靶向效率以侵入性 脑肿瘤并评估小鼠CNS-1神经瘤模型中BTB的药物递送。具体目的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）通过纳米句和RF有效地递送iNOS抑制剂向GBM Xenographings。具体目的3。评估纳米座的治疗有效性，该纳米量载有化学治疗和iNOS抑制剂的GBM Xenographictic中高度浸润性脑肿瘤的效果。