Radiation and Receptor Targeted RadioTheranostic Nanoparticles for Glioblastoma

描述(申请人提供)：世界卫生组织四级胶质瘤：多形性胶质母细胞瘤(GBM)是成人最常见和最致命的原发脑癌。目前GBM的标准治疗包括手术后化疗和放射治疗(RT)；尽管采取了这种积极的方法，中位生存期仍然只有一年多一点。因此，这项研究建议的主要目标是开发一种新的“放射热疗”方法来治疗GBM，该方法首次采用金和超顺磁性氧化铁(SPIO)纳米颗粒负载的聚合物胶束(GSM)，并利用辐射和胶质瘤限制性IL13RA2靶向配体选择性地输送辐射增强和磁共振成像的纳米颗粒。GSM具有良好的放射治疗和诊断(RadioTheranostic)特性，将为颅内肿瘤的治疗和成像定制、表征和建模。这些分析将包括精确递送的RT在增加脑瘤内空间靶向GSM蓄积方面的效果。利用我们在放射生物学、神经肿瘤学、原位和转基因胶质瘤模型、分子成像、纳米技术和生物工程方面的综合专业知识，我们将检验这一中心假设，即管理新的GSM配方将显著提高放射治疗的靶向性和对GBM的疗效，而几乎没有增加毒性，并实现以下具体目标目标1.合成和表征具有互补治疗和诊断能力的GSM。目的2.确定在放疗和GSM给药之间的最佳时机，以最大限度地选择性地在颅内肿瘤内积聚GSM、MR成像和RT剂量增强。目的3.以IL13RA2为靶点的GSM用于胶质母细胞瘤的成像和治疗。我们已经组建了一支拥有必要经验和专业知识的多才多艺的团队，以成功测试我们的假设并解决我们的具体目标。这些研究一起将有助于推动GBM治疗方面的突破性进展，同时帮助发挥GSM对这种高度顽固和致命的脑瘤的放射治疗潜力。

DESCRIPTION (provided by applicant): WHO Grade IV Glioma: Glioblastoma multiforme (GBM) is the most common and deadly form of primary brain cancer in adults. The current standard treatment of GBM consists of surgery followed by combined chemo- and radiation therapy (RT); despite this aggressive approach, the median survival time remains just over one year. The primary goal of this research proposal is to therefore develop a novel "RadioTheranostic" approach to treat GBM that employs for the first time Gold- and SuperParamagnetic Iron Oxide (SPIO)-nanoparticle loaded polymeric Micelles (GSMs) and utilizes Radiation and a Glioma-restricted IL13Ra2-targeting ligand to selectively deliver radiation-enhancing and MR-imagable nanoparticles. With well aligned radiotherapeutic and diagnostic (RadioTheranostic) properties, GSMs will be customized, characterized and modeled for intracranial tumor treatment and imaging. The analyses will include the effects of precisely delivered RT in augmenting spatially targeted GSM accumulation within brain tumors. Leveraging our combined expertise in radiobiology, neuro-oncology, orthotopic and transgenic glioma models, molecular imaging, nanotechnology and bioengineering we will test the central hypothesis that administration of novel GSM formulations will significantly improve the targeting and efficacy of RT for GBM with little to no added toxicity and fulfill the following specific aims Aim 1. Synthesize and characterize GSMs with complementary therapeutic and diagnostic capabilities. Aim 2. Determine the optimal timing between RT and GSM administration for maximal selective GSM accumulation within intracranial tumors, MR imaging, and RT dose enhancement. Aim 3. Characterize IL13Ra2-targeted GSMs for imaging and treatment of Glioblastoma. We have marshaled a versatile team with the requisite experience and expertise to successfully test our hypothesis and address our specific aims. These studies together should together help facilitate a breakthrough advance in the treatment of GBM, while helping to fulfill the RadioTheranostic potential of GSMs for this highly intractable and deadly brain tumor.