Iron Oxide Nanoparticle-Mediated Radiation Delivery for Glioblastoma Treatment

氧化铁纳米粒子介导的放射治疗用于胶质母细胞瘤治疗

• 批准号: 9811784
• 负责人: Richard Aaron Revia
• 金额: $ 3.32万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-28 至 2020-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811784
• 关键词: Affect; Asses; Biological; Blood - brain barrier anatomy; Brain Neoplasms; Carbon; Cell Death; Cells; Cellular Structures; Chlorotoxin; Clinic; Clinical; Communities; Cyclophosphamide; DNA; DNA Structure; Deposition; Disease; Disease Progression; Distant; Drug Delivery Systems; Electrons; Epitopes; Evaluation; Excision; Excretory function; Exhibits; Exposure to; Formulation; Free Radicals; Gamma Rays; Gene Delivery; Generations; Glioblastoma; Goals; Gold; Heavy Metals; Human; Imagery; In Vitro; Investigation; Ionizing radiation; Iron; Knowledge; Life Expectancy; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of central nervous system; Mediating; Medical; Membrane Lipids; Metals; Modeling; Modernization; Molecular; Mus; Neoplasm Metastasis; Neoplasms; Nitrogen; Operative Surgical Procedures; Outcome; Oxygen; Patients; Penetration; Peptides; Pharmaceutical Preparations; Polymers; Probability; Production; Property; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Reactive Oxygen Species; Research; Research Project Grants; Research Technics; Resistance development; Risk; Site; Surgical Management; Techniques; Technology; Testing; Therapeutic Agents; Tissues; Toxic effect; Translating; Treatment Efficacy; United States Food and Drug Administration; Work; World Health Organization; Xenograft procedure; absorption; base; biomaterial compatibility; chemotherapy; clinical translation; clinically relevant; contrast enhanced; design; fight against; improved; in vivo; interest; iron oxide; iron oxide nanoparticle; nanoparticle; nanoscale; neoplastic cell; radiation delivery; soft tissue; standard of care; superparamagnetism; surface coating; survival outcome; therapeutic nanoparticles; tumor; uptake

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.!

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， 近年来，随着放射线的集中输送，胶质母细胞瘤的预期寿命几乎没有变化。一个新兴 一种提高应用辐射效率的技术是引入具有大原子序数的原子 在放射治疗之前的肿瘤细胞内。这种技术的物理基础在于有利的光电效应。 具有大原子序数的原子的吸收系数;与构成软组织的原子相比， 在身体中，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活性氧物质的产生， DNA和细胞结构在其附近的损害，导致细胞死亡。 靶向纳米颗粒治疗剂的出现导致了准确存款的能力的提高 纳米级金属簇在亚细胞网站的兴趣。纳米颗粒可以瞄准分子表位 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， 它们本身在所谓的纳米粒子介导的辐射沉积（NMDR）中成为治疗剂。 对纳米颗粒介导的辐射沉积的先前研究已经使用金和 其他基于重金属的技术，这些技术受到其有限的生物相容性和生物降解性的阻碍。 相反，氧化铁纳米颗粒具有优于其他金属核纳米颗粒的明显益处，包括 经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特征， 和超顺磁性，这使得磁共振成像可视化。该提案描述了 评价氧化铁纳米颗粒增强胶质母细胞瘤放射治疗的疗效。具体 本研究的目的是：（1）评估核尺寸对NMDR的影响，（2）评估 聚合物涂层在NMDR上的作用，以及（3）研究胶质母细胞瘤肿瘤靶向氧化铁NMDR的功效。 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 涂层对暴露于γ射线放射治疗后活性氧产生的影响。此外，一种氧化铁 纳米颗粒将通过与肿瘤靶向肽氯毒素缀合而产生。这种药物的功效 将在携带原位人原发性胶质母细胞瘤异种移植物的小鼠中评价纳米颗粒。这些具体 目的将提供有关临床相关放射增敏剂应用潜力的关键知识 用于治疗最常见的人类恶性脑瘤。从长远来看，氧化铁 如果纳米粒子可以作为放射增敏剂应用，那么它们可以改善许多形式癌症的生存结果。