Treatment of glioblastoma using chain-like nanoparticles

 描述(申请人提供)：侵袭性形式的脑肿瘤，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，目前的治疗方法只提供缓解和显著的毒性。目前治疗脑胶质瘤的方法效果有限，因为脑肿瘤具有弥漫性、高侵袭性、非局部性的特点，而且大多数药物对血-肿瘤屏障(BTB)的药物渗透性很差。除了有限的药物输送外，脑瘤 细胞往往对药物特别耐药，特别是在肿瘤复发后。为了应对药物输送和耐药性方面的挑战，这项提议的目标是将链状纳米颗粒的独特特性与适当的补充药物组合结合起来，以实现对侵袭性脑肿瘤的有效治疗。为了解决药物输送问题，我们开发了一种多组分的柔性链状纳米颗粒，称为纳米链，它由三个氧化铁纳米球和一个载药脂质体化学连接成线性链状组装而成。纳米链的多组分性质导致了两个特征，它们协同促进了难以治疗的转基因生物的有效治疗。首先，这种椭圆形、柔性的纳米链具有独特的能力，可以通过血管靶向寻找并快速沉积在胶质瘤部位的血管壁上。其次，在纳米链从血液中滑落并停靠在基底膜的血管床上后，外部低功率射频(RF)场远程触发快速药物释放，因为脂膜的机械破坏促进了广泛而有效的药物向基底膜的输送。为了解决耐药性问题，我们已经确定了胶质瘤干细胞(GSC)特异性调节因子，适用于药物靶向。我们最近发现诱导型一氧化氮合酶(INOS)是GSCs中独特的信号调节因子。由于在纳米链内装载各种药物的灵活性；纳米链将装载标准化疗和iNOS抑制剂，以消除一小部分具有耐药性的GBM细胞，并可能迁移导致肿瘤复发。通过使用纳米链，我们假设，保证这些具有协同活性的药物有效和同时输送到胶质瘤部位将有助于有效治疗并最终使用安全剂量根除疾病。具体目标1：优化链状纳米颗粒对侵袭性的靶向性 并在小鼠CNS-1脑胶质瘤模型中评估跨血脑屏障的药物释放。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)通过纳米链和RF将iNOS抑制剂有效地输送到GBM异种移植瘤中。具体目的3.评价载药纳米链和诱导型一氧化氮合酶抑制剂对高侵袭性脑肿瘤GBM移植瘤的治疗效果。

 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.