Radiation and Receptor Targeted RadioTheranostic Nanoparticles for Glioblastoma

用于胶质母细胞瘤的放射和受体靶向放射治疗纳米颗粒

• 批准号: 9118707
• 负责人: JAY FITZGERALD DORSEY
• 金额: $ 47.91万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118707
• 关键词: Accounting; Address; Adult; Adverse effects; Animals; Antigens; Area; Binding; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Blood - brain barrier anatomy; Brain Neoplasms; Caliber; Cell Death; Cell surface; Cells; Characteristics; DNA Damage; Development; Diagnostic; Dose; Drug Kinetics; Encapsulated; Evaluation; Formulation; Foundations; Generations; Glioblastoma; Glioma; Goals; Gold; Health; Human; Image; Intracranial Neoplasms; Lead; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Marshal; Mediating; Methodology; Micelles; Modeling; Molecular Target; Nanotechnology; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Permeability; Pharmacodynamics; Property; Public Health; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiobiology; Radiopharmaceuticals; Radiosensitization; Research; Research Proposals; Schedule; Site; Stem cells; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; contrast enhanced; di-block copolymer; experience; glioma cell line; improved; innovation; iron oxide; molecular imaging; mouse model; nano; nanoparticle; neoplastic cell; neuro-oncology; novel; outcome forecast; overexpression; pharmacokinetic characteristic; radiosensitizing; receptor; response; small hairpin RNA; standard care; tumor; uptake

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.

描述（由申请人提供）：WHO IV级胶质瘤：多形性胶质母细胞瘤（GBM）是成人中最常见和最致命的原发性脑癌。目前GBM的标准治疗包括手术，然后联合化疗和放疗（RT）;尽管这种积极的方法，中位生存时间仍然超过一年。因此，这项研究提案的主要目标是开发一种新的“放射治疗诊断”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IL 13 Ra 2靶向配体选择性地递送辐射增强和MR成像纳米颗粒。由于具有良好的放射性和诊断（放射治疗诊断）特性，GSM将被定制，表征和建模用于颅内肿瘤治疗和成像。分析将包括精确递送的RT在增强脑肿瘤内空间靶向GSM积累中的作用。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，我们将测试中心假设，即新型GSM制剂的施用将显著改善RT对GBM的靶向和功效，几乎没有或没有增加毒性，并实现以下具体目标。合成和表征具有互补治疗和诊断能力的GSM。目标二。确定RT和GSM给药之间的最佳时间，以实现颅内肿瘤内最大选择性GSM蓄积、MR成像和RT剂量增强。目标3。表征IL 13 Ra 2靶向的GSM用于胶质母细胞瘤的成像和治疗。我们已经组建了一个具有必要经验和专业知识的多功能团队，以成功验证我们的假设并实现我们的具体目标。这些研究应共同有助于促进GBM治疗的突破性进展，同时有助于实现GSM对这种高度顽固和致命的脑肿瘤的放射治疗潜力。