Nanoparticle-Enhanced Radiation Therapy for DIPG

DIPG 纳米粒子增强放射治疗

基本信息

批准号：
10592202
负责人：
Peter Chiarelli
金额：
$ 19.4万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592202
关键词：
3-Dimensional Affect Alternative Therapies Animal Model Biochemical Biocompatible Materials Biological Biological Assay Biological Sciences Biology Brain Brain Diseases Brain Neoplasms Brain Stem Brain Stem Neoplasms Cells Cellular biology Characteristics Child Childhood Childhood Brain Stem Neoplasm Childhood Malignant Brain Tumor Chlorotoxin Clinical Clinical Trials Coculture Techniques Comet Assay Convection DNA Data Deposition Development Development Plans Diffuse intrinsic pontine glioma Doctor of Philosophy Dose Dose Fractionation Evaluation Excision Film Flow Cytometry Funding Gamma-H2AX Glioblastoma Glioma Goals H2AFX gene Histology Home Homing Immunohistochemistry In Vitro Injury Institution Intravenous Investigation Iron K-Series Research Career Programs Knowledge Length Location Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant neoplasm of brain Mediating Mentors Mentorship Methods Microbiology Microscopy Modeling Modernization Molecular Biology Mus Nucleosome Core Particle Oncology Operative Surgical Procedures Outcome Pediatric Neoplasm Phosphorylation Photons Physical Chemistry Pontine structure Proteins Publications Quality of life Radiation Radiation Accidents Radiation Dose Unit Radiation Induced DNA Damage Radiation Physics Radiation therapy Radiobiology Recurrence Regimen Research Research Personnel Research Project Grants Resected Resources Safety Scientist Stromal Cells Supratentorial Surface Survival Analysis Techniques Technology Testing Therapeutic Thick Thinness Tissues Training Translating Treatment Efficacy Tumor Biology Validation Work Xenograft Model Xenograft procedure aged animal imaging biological systems biomaterial compatibility career development cell killing chemotherapy clinical translation cytotoxicity design electron energy ethylene glycol fractionated radiation human disease improved in vivo interest iron oxide iron oxide nanoparticle irradiation live cell imaging materials science meetings mouse model multidisciplinary nanoparticle nanoshell neoplastic cell neuro-oncology neurosurgery new technology novel novel therapeutic intervention pre-clinical preclinical development quantitative imaging radiation effect side effect stem-like cell submicron success tissue/cell culture translation to humans translational applications treatment effect tumor two-dimensional

项目摘要

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).

抽象的 Peter Chiarelli，医学博士、哲学博士，是小儿神经外科领域的临床医生兼科学家，专注于应用光化学技术治疗人脑疾病。这位K08辅导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完善、生物测定的应用/评估以及实际应用生物系统的先进显微镜技术。弥补这一关键的培训差距将提供作为独立研究者在新技术转化应用方面取得成功的资源植根于物理化学领域。研究背景：弥漫性内质性脑桥胶质瘤 (DIPG) 是发生于儿童的脑干肿瘤，没有安全的手术切除选择，也没有目前有效的化疗策略。针对这种无法治愈的大脑的替代疗法的开发癌症是儿科神经肿瘤学联盟的优先事项。治疗 DIPG 的新方法是提出的，基于对不同的高级脑肿瘤（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）。该方法利用了已经存在的辐射对于患有 DIPG 的儿童来说是必需的，并使用目标 ~35 nm 生物相容性聚乙二醇 (PEG) 涂层氧化铁核壳纳米粒子（NP）通过诱导俄歇来改变入射辐射的影响从纳米颗粒核心发射光电子。通过纳米颗粒的生化靶向肿瘤细胞，辐射效应在距纳米粒子的亚微米距离内空间增强，从而有可能较低的总辐射剂量具有较大的肿瘤细胞毒性。该研究项目将使用可靠的 DIPG 小鼠模型，并通过两种不同的方法应用靶向氧化铁-PEG 纳米颗粒：静脉内 (IV) 输送和对流增强输送 (CED) 至大脑。机制探索 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射出发挥生物效应的程度。开发这项技术的目标是将 DIPG 转化为人类儿科临床试验，并实现首次实质性改进过去 3 个多世纪观察到的结果。职业发展计划：Chiarelli 博士将完成有关动物模型中的高级肿瘤生物学、台式分子生物学方法的课程，以及定量成像（细胞培养和组织）。本课程作业将与特定的顺序相结合目标包含在该提案中，以便培训可以直接应用于研究。跨学科团队拥有临床神经肿瘤学、活细胞成像、DIPG 生物学、生物材料专业知识的导师二维表面的设计和物理化学已经组装起来，为 Dr. 提供密切指导。 Chiarelli，以及所包含作品的临床翻译、专业演示所需的指导会议，以及独立资助的进展（R01 提交）。