Nanoparticle-based Sensitizer for Radiation Therapy of Glioblastoma

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是一种高度侵袭性的恶性脑肿瘤，众所周知是缺氧，缺氧是GBM治疗反应差的重要因素。GBM最常见的治疗方法是手术切除，然后分次放疗+化疗。尽管如此，经过治疗后，GBM患者的平均存活时间仅为12个月左右。一种安全、有效的技术可以提高肿瘤的氧分压，并且可以在放射治疗的每一次治疗中使用，应该会改善接受放射治疗的GBM患者的结果。这项提议旨在开发这样一种技术。NVX-108是十二氟戊烷(DDFPe)的纳米乳液。与单独使用Carbogen相比，低剂量的NVX-108使肿瘤的PO2增加了400%，逆转了放射抵抗，并增加了接受RT治疗的动物的存活率。在注射NVX-108后，肿瘤的氧分压持续上升长达两个小时；这种物质相对较快地从体内清除，便于重复给药。NVX-108是一种稳定的DDFPe配方，此前曾作为超声造影剂(USCA)在2000名患者中进行测试，是安全的。FDA认为DDFPe是可以批准的，但由于USCA市场规模较小，它从未推出。NuvOx与FDA进行了IND前的会议；FDA同意NuvOx可以参考之前对DDFPe的研究，以支持NVX-108的临床试验。这项建议旨在开发生物标记物成像，可用于验证GBM中的肿瘤再氧合，以及在两个相关的GBM临床前模型中确认有效性。这项研究的数据将被用来支持美国的IND对接受RT+NVX-108治疗的GBM患者进行临床试验。在这项建议中开发的生物标记物成像方法将被纳入临床试验的研究设计中，以证实GBM患者的肿瘤重新充氧。这项建议有两个主要目标：1)用成像生物标志物验证NVX-108对肿瘤的复氧作用；2)确认NVX-108+RT+Carbogen治疗GBM的疗效。在第一个目标中，我们将研究NVX-108在大鼠C6脑胶质瘤模型中的肿瘤再氧合作用，并用18F-EF5PET验证TELD MRI的疗效。在第二个模型中，我们将研究NVX-108在小鼠GL261胶质瘤模型中的肿瘤复氧作用，并用HypoxiSense荧光成像和生物发光进行验证。在第二个目标中，我们将确认NVX-108+RT+Carbogen在这两个GBM模型中的有效性。在小鼠模型中，我们还将治疗中度和重度肿瘤缺氧的动物。我们假设NVX-108无论肿瘤缺氧程度如何，都会逆转辐射抵抗。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a highly aggressive, malignant brain tumor widely known to be hypoxic and hypoxia is an important factor in the poor response of GBM to treatment. The most common therapy for GBM is surgical excision followed by fractionated RT + chemotherapy. Still, after treatment, GBM patients only survive, on average, about 12 months. A safe, effective technology that raised tumor pO2 and could be administered during each fraction of RT should improve outcomes in GBM patients treated with RT. This proposal is directed to developing such a technology. NVX-108 is a nano-emulsion of dodecafluoropentane (DDFPe). Low doses of NVX-108 raise tumor pO2 by 400% compared to carbogen alone, reverse radiation resistance and increase survival in animals treated with RT. Tumor pO2 continues to rise for up to two hours following administration of NVX-108; the material clears from the body relatively rapidly facilitating repeat administration. NVX-108, a stable formulation of DDFPe, was previously tested as an ultrasound contrast agent (USCA) in 2,000 patients and was safe. The FDA deemed DDFPe approvable but it was never launched due to small size of USCA market. NuvOx had pre-IND meetings with the FDA; the FDA agreed that NuvOx could reference the prior studies of DDFPe in support of clinical trials of NVX-108. This proposal is designed to develop biomarker imaging that can be used to validate tumor re- oxygenation in GBM as well as to confirm efficacy in two relevant preclinical models of GBM. The data from this study will be used to support an IND in the US for a clinical trial in GBM patients treated with RT + NVX-108. The biomarker imaging method developed in this proposal will be incorporated into the study design of the clinical trial to confirm tumor re-oxygenation in the GBM patients. There are two principle objectives to this proposal: 1) to validate tumor re-oxygenation with NVX-108 with imaging biomarkers and 2) to confirm efficacy of NVX-108 + RT + carbogen in treating GBM. In the first objective we will study tumor re-oxygenation with NVX-108 in the C6 glioma model in rats and validate efficacy of TOLD MRI with 18F-EF5 PET. In the second model we will study tumor re- oxygenation with NVX-108 in the GL261 glioma mode in mice and validate TOLD with HypoxiSense" fluorescence imaging and bioluminescence. In the second objective we will confirm efficacy of NVX-108 + RT + carbogen in these two GBM models. In the mouse model we will also treat animals with moderate and severe levels of tumor hypoxia. We hypothesize that NVX-108 will reverse radiation resistance regardless of the level of tumor hypoxia.