Nanoparticle-based Sensitizer for Radiation Therapy of Glioblastoma

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种高度侵袭性的恶性脑肿瘤，众所周知是缺氧的，缺氧是GBM对治疗反应不良的重要因素。GBM最常见的治疗方法是手术切除，然后进行分次RT +化疗。尽管如此，治疗后，GBM患者平均只能存活12个月左右。一个安全，有效的技术，提高肿瘤pO 2，并可以在RT的每个部分管理应改善与RT治疗GBM患者的结果。这项建议是针对开发这样的技术。NVX-108是十二氟戊烷（DDFPe）的纳米乳液。与单独的carbogen相比，低剂量的NVX-108使肿瘤pO 2升高400%，逆转辐射抗性并增加用RT治疗的动物的存活率。在给予NVX-108后，肿瘤pO 2持续升高长达两小时;该物质相对快速地从体内清除，促进重复给药。NVX-108是DDFPe的一种稳定制剂，先前在2,000名患者中作为超声造影剂（USCA）进行了测试，并且是安全的。FDA认为DDFPe是可以批准的，但由于USCA市场规模小，它从未上市。NuvOx与FDA进行了IND前会议; FDA同意NuvOx可以参考DDFPe的先前研究，以支持NVX-108的临床试验。该提案旨在开发生物标志物成像，其可用于验证GBM中的肿瘤再氧合以及确认GBM的两个相关临床前模型中的疗效。本研究的数据将用于支持在美国进行的IND，用于在接受RT + NVX-108治疗的GBM患者中进行临床试验。本提案中开发的生物标志物成像方法将纳入临床试验的研究设计中，以确认GBM患者的肿瘤复氧。该提议有两个主要目的：1）用成像生物标志物验证用NVX-108的肿瘤再氧合，和2）确认NVX-108 + RT + carbogen在治疗GBM中的功效。在第一个目标中，我们将研究在大鼠的C6胶质瘤模型中用NVX-108进行的肿瘤再氧合，并验证用18F-EF 5 PET进行的TOLD MRI的功效。在第二个模型中，我们将在小鼠中的GL 261胶质瘤模式中研究用NVX-108进行的肿瘤再氧合，并用HypoxiSense荧光成像和生物发光验证TOLD。在第二个目的中，我们将证实NVX-108 + RT + carbogen在这两种GBM模型中的功效。在小鼠模型中，我们还将治疗具有中度和重度肿瘤缺氧水平的动物。我们假设，无论肿瘤缺氧水平如何，NVX-108都将逆转辐射抗性。

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.