Nanoparticle-Enhanced Radiation Therapy for DIPG

摘要 Peter Chiarelli，MD DPhil，是儿科神经外科领域的临床医生兼科学家，他专注于 应用光化学技术治疗人脑疾病。K 08的职业生涯 发展奖将提供生物科学领域的高级培训和指导， 包括肿瘤模型的设计和改进、生物测定的应用/评估以及实际使用 先进的显微镜技术。补充这一关键的培训缺口将提供 作为一个独立的研究人员在新技术的转化应用取得成功的资源 在物理化学领域的基础上。研究背景：弥漫性内在脑桥胶质瘤（DIPG）是 一种发生在儿童中的脑干肿瘤，没有安全的手术切除选择， 有效的当前化疗策略。针对这种无法治愈的大脑的替代疗法的发展 癌症是儿科神经肿瘤学联盟的优先考虑。治疗DIPG的新方法是 基于对不同高级别脑肿瘤（小鼠异种移植物）的成功临床前工作， 幕上胶质母细胞瘤模型）。这种方法利用了辐射， DIPG儿童所必需的，并使用靶向~35 nm生物相容性聚乙二醇（PEG）涂层 氧化铁核-壳纳米颗粒（NPs）通过诱导俄歇来改变入射辐射的影响 光电子从纳米颗粒核中射出。通过纳米粒子对肿瘤细胞的生物化学靶向作用， 辐射的影响在距离NP亚微米距离内空间增强，允许 更低的总辐射剂量将被递送，具有更大的肿瘤细胞毒性。该研究项目将使用 可靠的DIPG鼠模型，并通过两种不同的方法应用靶向氧化铁-PEG NP： 静脉内（IV）递送和对流增强递送（CED）至脑。机械的探索 NP-俄歇效应也将使用二维薄膜进行，以更好地理解空间 光电子发射产生生物效应的程度。开发这项技术的目的是 将DIPG转化为人类儿科临床试验，并实现首次实质性改善， 在过去的30多年里观察到的结果。职业发展简介：Chiarelli博士将完成 在动物模型中的先进肿瘤生物学课程，台式分子生物学方法，以及 定量成像（细胞培养和组织）。本课程将与特定的序列相结合， 这一建议中包括的目标，使培训可以直接应用于研究。一支跨学门的研究团队 导师的专业知识涵盖临床神经肿瘤学、活细胞成像、DIPG生物学、生物材料 设计，和物理化学的2-D表面已经组装，提供密切的指导博士。 Chiarelli，并指导必要的临床翻译所包括的工作，介绍在专业 会议，以及争取独立供资的进展情况（R 01提交材料）。

ABSTRACT Peter Chiarelli, MD DPhil, is a clinician-scientist in the field of pediatric neurosurgery, who is focused on the application of photochemical techniques to treat disease of the human brain. This K08 mentored career development award will provide the advanced training and mentorship within the fields of biological sciences, including design and refinement of tumor models, application/evaluation of biological assays, and practical use of advanced microscopy for biological systems. Supplementing this critical training gap will provide the resources for success as an independent investigator in the translational application of novel technologies grounded in the realm of physical chemistry. RESEARCH CONTEXT: Diffuse intrinsic pontine glioma (DIPG) is a tumor of the brainstem that occurs in children, with no available option for safe surgical resection, and no effective current chemotherapeutic strategy. The development of alternative therapies for this incurable brain cancer is a priority among pediatric neuro-oncology consortia. A new approach for the treatment of DIPG is proposed, grounded on successful pre-clinical work with a different high-grade brain tumor (murine xenograft model of supratentorial glioblastoma). This method takes advantage of the radiation which is already necessary for children with DIPG, and uses targeted ~35 nm biocompatible poly(ethylene glycol)(PEG)-coated iron oxide core-shell nanoparticles (NPs) to modify the effects of incident radiation by inducing Auger photoelectron ejection from the nanoparticle core. Through the biochemical targeting of NPs to the tumor cells, the effect of radiation is spatially enhanced within sub-micron distances from the NP, allowing the possibility of lower overall radiation doses to be delivered with greater tumor cytotoxicity. This research project will use a reliable murine model of DIPG, and apply targeted iron oxide-PEG NPs through two different methods: intravenous (IV) delivery, and convection-enhanced delivery (CED) to the brain. A mechanistic exploration of the NP-Auger effect will also be carried out using 2-dimensional thin films, to better understand the spatial extent over which photoelectron ejection exerts a biological effect. The goal of developing this technology is the translation to human pediatric clinical trials for DIPG, and to achieve the first substantial improvement in outcome observed over the past 3+ decades. CAREER DEVELOPMENT PLAN: Dr. Chiarelli will complete coursework on the advanced tumor biology in animal models, methods in benchtop molecular biology, and quantitative imaging (cell culture and tissue). This coursework will be integrated with the sequence of specific aims included in this proposal, so that training can be directly applied to the research. An interdisciplinary team of mentors with expertise spanning clinical neuro-oncology, live-cell imaging, DIPG biology, biomaterials design, and physical chemistry of 2-D surfaces has been assembled to provide close mentorship for Dr. Chiarelli, and the guidance necessary for clinical translation of the included work, presentation at professional meetings, as well as progress towards independent funding (R01 submission).