Treatment of glioblastoma using chain-like nanoparticles

 描述（由申请人提供）：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，目前的治疗仅提供姑息治疗，并伴有显著的毒性。目前用于治疗胶质瘤的方法在其有效性方面是有限的，因为脑肿瘤具有弥漫性、高度侵袭性、非局部性的特征，并且大多数药物穿过血液肿瘤屏障（BTB）的药物渗透性较差。除了有限的药物输送，脑肿瘤 细胞往往特别耐药，特别是在肿瘤复发后。为了解决药物递送和耐药性的挑战，该提案的目标是将链状纳米颗粒的独特特征与互补药物的适当组合相结合，以有效治疗侵袭性脑肿瘤。为了解决药物递送问题，我们开发了一种多组分的柔性链状纳米颗粒，称为nanochain，其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体组成。纳米链的多组分性质导致协同促进难以治疗的GM的有效治疗的两个特征。首先，椭圆形的柔性纳米链具有独特的能力，通过血管靶向在胶质瘤部位的血管壁上寻找并快速存款。第二，在纳米链从血流中滑落并停靠在GBM的血管床上之后，外部低功率射频（RF）场远程触发快速药物释放，这是由于脂质体膜的机械破坏促进了广泛且有效的药物递送到GBM中。为了解决耐药性问题，我们已经确定了神经胶质瘤干细胞（GSC）的具体监管机构服从药理学靶向。我们最近发现，诱导型一氧化氮合酶（iNOS）是一个独特的信号调节GSC。由于在纳米链内装载各种类型药物的灵活性;纳米链将装载标准化疗和iNOS抑制剂，其消除了一小部分具有抗性的GBM细胞，并且可以迁移导致肿瘤复发。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递送到胶质瘤部位将促进有效治疗，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肿瘤的靶向功效 脑肿瘤的研究，并在小鼠CNS-1神经胶质瘤模型中评估穿过BTB的药物递送。具体目标2。确定（A）iNOS抑制对GBM肿瘤生长和GBM干细胞亚群的影响和（B）iNOS抑制剂经由纳米链和RF有效递送至GBM异种移植物。具体目标3。评价负载有化疗剂和iNOS抑制剂的纳米链在高度侵袭性脑肿瘤的GBM异种移植物中的治疗功效。

 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.