Brain-Penetrating Nanoparticle Therapeutics for Invasive Brain Cancer

描述(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Greenebaum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培训。在我接受内科和神经外科培训之前，他在塔夫茨大学和辉瑞药物发现部门接受培训并担任有机化学家。他是通过国家癌症研究所资助的癌症医学纳米技术T32计划的神经肿瘤学博士后研究员。伍德沃斯博士的长期目标是成为一名独立资助的神经外科医生兼科学家，将手术室作为一个发现发现的门户和提供治疗的机会。他正在努力推进翻译神经肿瘤学，专注于向大脑侵袭的、不受尊敬的癌细胞提供治疗方法。为了实现这一目标，他的目标是通过药物配方、给药和测试方面的创新研究，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)目标和目标加强他的研究生涯发展：(1)研究用于增强胶质母细胞瘤(GBM)治疗的细胞和结构靶向策略；具体而言，探索TWEEP-Fn14信号通路；(2)研究侵袭性脑癌的先进的局部和其他递送系统；尤其是研究新的对流增强和系统性方法，如磁共振成像引导下的聚焦超声(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，伍德沃斯博士招募了三位在这些领域拥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结合起来。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，研究活动将与临床活动相辅相成，以50%的努力照顾良性和恶性中枢神经系统肿瘤患者。临床和科学活动的这种同等贡献将使神经外科医生继续成长和发展，包括保持外科技能，与神经外科的进步和发展保持同步，并将研究努力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坚定地致力于确保这一受保护的时间。伍德沃斯博士的实验室由该部门、医学院、NIH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。该支持包括在Greenebaum癌症中心内的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理论基础是基于观察到的更大的- 具有特殊设计的表面涂层的颗粒可以快速渗透到脑组织中。这些颗粒被称为“脑穿透纳米颗粒”(BPN)，有证据有力地表明，这些大的、非粘连的颗粒将能够改善脑组织中的分散，控制药物释放，并靶向侵袭大脑的癌细胞。指导小组的两名成员(JW，NT)在细胞表面受体Fn14方面合作多年，他们是第一批报告Fn14基因在体内入侵的GBM细胞中表达上调的研究人员。这些发现为开发以Fn14为靶点的BPN创造了一个有希望的机会，有望在毒性较小的情况下改善治疗效果和疗效。总体假设是，BPN将能够改善对侵袭性脑瘤的治疗输送和治疗效果；这将使用Fn14靶向BPN进行测试，该BPN装载有希望的化疗药物，通过局部对流增强方法在侵袭性患者来源的异种移植模型中输送。本项目提出了三个具体目标：(1)制备和表征含有和不含有Fn14特异性靶向剂的纳米颗粒；(2)评估对流增强局部递送(CED)后优化纳米颗粒配方的组织分布和细胞靶向效率；(3)使用侵入性、患者来源的肿瘤模型评估通过CED给予的载药纳米颗粒与标准GBM化疗药物替莫唑胺联合使用的治疗效果。

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.