Iron Oxide Nanoparticle-Mediated Radiation Delivery for Glioblastoma Treatment

项目摘要 放射治疗是构成胶质母细胞瘤治疗标准的主要组成部分。尽管取得了进展，但 随着辐射的集中投放，胶质母细胞瘤的预期寿命近年来变化不大。一种新兴的 提高外加辐射效能的技术是引入具有大原子序数的原子 在放疗前的肿瘤细胞内。这项技术的物理基础在于良好的光电性能 原子序数大的原子的吸收系数；与组成软组织的原子相比 在人体内，原子序数较高的较大原子更有可能与入射电离辐射相互作用， 发射电子。这些自由基电子促进了活性氧物种的生成，从而导致 破坏DNA和邻近的细胞结构，导致细胞死亡。 靶向纳米颗粒疗法的出现提高了准确沉积的能力 在感兴趣的亚细胞位置上的纳米级金属簇。纳米粒子可以针对分子表位 由胶质母细胞瘤细胞表达。金属核纳米颗粒不是将药物运送到肿瘤区域，而是 它们本身成为所谓的纳米粒子介导的辐射沉积(NMDR)的治疗剂。 以前对纳米粒子介导的辐射沉积的研究已经使用金和 其他以重金属为基础的技术，由于其有限的生物兼容性和生物降解性而受到阻碍。 相反，氧化铁纳米颗粒与其他金属核心纳米颗粒相比具有明显的优势，包括 由美国食品和药物管理局批准，已知的人体生物相容性和排泄物特征， 以及超顺磁性，允许磁共振成像中的可视化。这份提案描述了 纳米氧化铁对提高胶质母细胞瘤放射治疗效果的评价。具体的 这项研究的目的是(1)评估核心尺寸对NMDR的影响，(2)评估 研究氧化铁NMDR对胶质母细胞瘤肿瘤靶向治疗的效果。 这些目标将通过询问纳米颗粒设计参数来实现，包括核心尺寸和表面 暴露于γ-射线放射治疗时产生的反应性氧物种的涂层。此外，一种氧化铁 纳米颗粒将通过与肿瘤靶向多肽氯毒素结合而产生。这样做的效果是 纳米颗粒将在携带人原发胶质母细胞瘤异种移植瘤的小鼠身上进行评估。这些特定的 AIMS将提供有关临床相关放射增敏剂应用潜力的关键知识 治疗人类最常见的恶性脑瘤。从长远来看，氧化铁 如果纳米粒子能够作为放射增敏剂应用，它们可能会改善许多形式的癌症的生存结果。

Project Summary Radiation therapy is a major component constituting the standard of care in glioblastoma. Despite advances in the focused delivery of radiation, life expectancy for glioblastoma has changed little in recent years. An emerging technique to enhance the efficacy of applied radiation is the introduction of atoms with large atomic numbers within tumor cells prior to radiotherapy. The physical basis for this technique lies in the favorable photoelectric absorption coefficients of atoms with large atomic numbers; compared to the atoms composing the soft tissue of the body, larger atoms with higher atomic numbers are more likely to interact with incident ionizing radiation and emit electrons. These free radical electrons promote the generation of reactive oxygen species, which cause damage to DNA and cellular structures in their immediate vicinity, resulting in cell death. The advent of targeted nanoparticle therapeutics has resulted in an improved ability to accurately deposit nanoscale metal clusters at subcellular sites of interest. Nanoparticles can be aimed at molecular epitopes expressed by glioblastoma cells. Instead of ferrying a drug to tumor regions, metal-core nanoparticles themselves become therapeutic agents in so-called nanoparticle-mediated deposition of radiation (NMDR). Prior investigations into nanoparticle-mediated deposition of radiation have been conducted using gold and other heavy-metal based technologies which are hindered by their limited biocompatibility and biodegradability. Conversely, iron oxide nanoparticles possess distinct benefits over other metal-core nanoparticles, including approval by the U.S. Food and Drug Administration, known biocompatibility and excretion profiles in humans, and superparamagnetism that allows for visualization in magnetic resonance imaging. This proposal describes the evaluation of iron oxide nanoparticles to enhance the efficacy of radiotherapy in glioblastoma. The Specific Aims of the proposed research are to (1) evaluate the effect of core size on NMDR, (2) asses the effect of polymer coating on NMDR, and (3) investigate the efficacy of glioblastoma tumor targeting for iron oxide NMDR. These aims will be achieved by interrogating nanoparticle design parameters, including core size and surface coating on reactive oxygen species production upon exposure to γ-ray radiotherapy. Furthermore, an iron oxide nanoparticle will be created through conjugation with the tumor-targeting peptide chlorotoxin. The efficacy of this nanoparticle will be evaluated in mice bearing orthotopic human primary glioblastoma xenografts. These Specific Aims will provide crucial knowledge regarding the potential for a clinically-relevant radiosensitizer as applied towards the treatment of the most common malignant human brain tumor. In the long-term, iron oxide nanoparticles may improve survival outcomes for many forms of cancer if they can be applied as radiosensitizers.!