Brain-Penetrating Nanoparticle Therapeutics for Invasive Brain Cancer

简介（由申请人提供）：Woodworth博士目前是马里兰大学医学院神经外科、解剖学和神经生物学助理教授，也是马里兰大学格林鲍姆癌症中心神经外科肿瘤学主任。他于2005年完成医学院学业，2012年在约翰霍普金斯大学完成神经外科住院医师实习。在我接受医学和神经外科培训之前，他在塔夫茨大学（Tufts University）和辉瑞公司（Pfizer - Drug Discovery Division）担任有机化学家。他是美国国家癌症研究所资助的纳米技术癌症医学T32项目神经肿瘤学博士后研究员。Woodworth博士的长期目标是成为一名独立资助的神经外科科学家，利用手术室作为发现的门户和治疗交付的机会。他致力于推进转化神经肿瘤学，研究重点是为侵入大脑的、不受尊敬的癌细胞提供治疗方法。为了实现这一目标，他致力于通过药物配方、给药和测试方面的创新研究来改善中枢神经系统肿瘤患者的预后。他将通过以下短期（3-5年）目标和目标来加强他的研究生涯发展：(1)研究细胞和结构靶向策略，以增强胶质母细胞瘤（GBM）的治疗；(2)研究侵袭性脑癌的晚期局部及其他给药系统；特别是，研究新的对流增强和系统方法，如磁共振成像引导聚焦超声（MRgFUS），以及(3)了解和分析患者来源的异种移植和转基因啮齿动物GBM模型的相对优点和局限性。为了实现这些短期和长期的职业发展目标，Woodworth博士聘请了三位在这些领域具有专业知识的杰出导师，并计划将这些互动与相关领域的具体教育活动相结合。这些导师是：Jeff Winkles博士（主要导师），Justin Hanes博士（联合导师）和Nhan Tran博士（联合导师）。在整个培训期间，研究活动将辅以临床活动，以50%的努力照顾良性和恶性中枢神经系统肿瘤患者。这种临床和科学活动的平等贡献将使神经外科医生持续成长和发展，包括保持手术技能，保持神经外科的进步和发展，并将研究工作与当前的临床困境联系起来。神经外科的行政领导和临床合作伙伴都坚定地致力于确保这一受保护的时间。Woodworth博士的实验室由该系、医学院、美国国立卫生研究院神经外科医生研究职业发展计划和帕萨诺基金会共同资助。支持包括在Greenebaum癌症中心的Bressler研究大楼内新装修的800平方英尺的实验室空间，并直接连接到马里兰大学医院的主要建筑。这个项目的总体实验设计和基本原理是基于观察到更大的

DESCRIPTION (provided by applicant): Dr. Woodworth is currently an Assistant Professor of Neurosurgery, Anatomy and Neurobiology at the University Of Maryland School Of Medicine and the Director of Neurosurgical Oncology at the University of Maryland (UM) Greenebaum Cancer Center. He completed medical school in 2005 and neurosurgery residency in 2012, both at Johns Hopkins. Prior to my medical and neurosurgery training, he trained and worked as an organic chemist at Tufts University and Pfizer - Drug Discovery Division. He was a post-doctoral research fellow in Neuro-Oncology through the National Cancer Institute-funded T32 Program in Nanotechnology for Cancer Medicine. Dr. Woodworth's long-term goal is to become an independently- funded neurosurgeon-scientist, leveraging the operating room as a portal for discovery and an opportunity for therapeutic delivery. He is working to advance Translational Neuro-Oncology with a research focus on delivering therapeutics to brain-invading, unrespectable cancer cells. Towards this goal, he aims to improve outcomes for patients with central nervous system tumors through innovative research in drug formulation, delivery, and testing. He will enhance his research career development through the following short-term (3-5 year) goals and objectives: (1) Study the cellular and structural targeting strategies for enhancing glioblastoma (GBM) therapeutics; specifically, explore the TWEAK-Fn14 signaling pathway, (2) Investigate advanced local and other delivery systems for invasive brain cancer; particularly, examine new convection enhanced and systemic approaches, such as magnetic resonance imaging guided focused ultrasound (MRgFUS), and (3) Understand and analyze the relative merits and limitations of patient- derived xenograft and transgenic rodent GBM models. To accomplish these short- and long-term career development goals, Dr. Woodworth has enlisted three outstanding mentors with expertise in these areas and plans to integrate these interactions with specific educational activities in related areas. These mentors are: Jeff Winkles, Ph.D. (primary mentor), Justin Hanes, Ph.D. (co-mentor), and Nhan Tran, Ph.D. (co-mentor). Research activities will be complemented throughout the training period with clinical activity caring for patients with benign and malignant CNS tumors with 50% effort. This equal contribution of clinical and scientific activities will enable continued growth and evolution as a neurosurgeon including maintaining surgical skills, remaining abreast of neurosurgical advances and developments, and relating the research efforts to current clinical dilemmas. The administrative leadership of and clinical partners within the Neurosurgery Department are strongly committed to ensuring this protected time. Dr. Woodworth's laboratory is joint-funded by the department, the School of Medicine and grants from the NIH Neurosurgeon Research Career Development Program and the Passano Foundation. The support includes a newly renovated 800ft2 laboratory space in the Bressler Research Building within the Greenebaum Cancer Center and directly connected to the main University of Maryland Hospital building. The overall experimental design and rationale for this project is based on the observation that larger- than-expected particles with specially engineered surface coatings can penetrate rapidly within brain tissue. These particles have been termed 'brain-penetrating nanoparticles' (BPN) and evidence strongly suggests that these large, non-adhesive particles will enable improved dispersion in brain tissue, controlled drug release, and targeting to brain-invading cancer cells. Two members of the mentoring team (JW, NT) have worked together for a number of years on the cell-surface receptor Fn14 and they were the first investigators to report that Fn14 gene expression is upregulated on invading GBM cells in vivo. These findings create a promising opportunity to develop Fn14-targeted BPNs that are anticipated to improve therapeutic delivery and efficacy with less toxicity. The overall hypothesis is that BPNs will enable improved therapeutic delivery to and efficacy against invasive brain tumors; this will be tested using Fn14-targeted BPNs loaded with promising chemotherapeutic agents delivered via a local convection-enhanced approach in an invasive patient-derived xenograft model. Three Specific Aims are proposed for this project: (1) Formulate and characterize nanoparticles with and without Fn14-specific targeting agents, (2) Evaluate the tissue distribution and cell-targeting efficiency of optimized nanoparticle formulations following convection enhanced local delivery (CED), and (3) Assess the therapeutic efficacy of drug-loaded nanoparticles administered via CED against and in combination with the standard GBM chemotherapeutic agent temozolomide using an invasive, patient-derived tumor model.