Brain-Penetrating Nanoparticle Therapeutics for Invasive Brain Cancer

侵入性脑癌的脑穿透性纳米粒子疗法

• 批准号: 9139514
• 负责人: Graeme F Woodworth
• 金额: $ 14.91万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139514
• 关键词: Address; Advanced Development; Anatomy; Animals; Apoptosis; Apoptosis Promoter; Applications Grants; Area; Benign; Binding; Biological Assay; Brain; Brain Neoplasms; Bystander Effect; Cancer Center; Cancer Etiology; Cell Surface Receptors; Cells; Central Nervous System Neoplasms; Cessation of life; Characteristics; Chimeric Proteins; Cisplatin; Clinical; Complement; Convection; Couples; Cryoultramicrotomy; Development; Dialysis procedure; Diffuse; Doctor of Philosophy; Doxorubicin; Drug Carriers; Drug Controls; Drug Formulations; Drug or chemical Tissue Distribution; Drug resistance; Educational Activities; Enabling Factors; Encapsulated; Engineering; Ensure; Erythrocytes; Etoposide; Evolution; Excision; Experimental Designs; Fibroblast Growth Factor; Flow Cytometry; Focused Ultrasound; Formulation; Foundations; Funding; Future; Gadolinium; Gene Expression; Glioblastoma; Glioma; Goals; Grant; Growth; Health; High Pressure Liquid Chromatography; Hospitals; Human; Imaging Techniques; Invaded; Joints; Label; Laboratories; Lead; Leadership; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Maryland; Measurement; Medical; Medicine; Mentors; Mesenchymal Cell Neoplasm; Methods; Microscopic; Microscopy; Modeling; Modification; Molecular Target; Monoclonal Antibodies; Names; Nanotechnology; National Cancer Institute; Neurobiology; Neurologic; Neurosurgeon; Operating Rooms; Operative Surgical Procedures; Outcome Measure; Paclitaxel; Particulate; Patient Care; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Polymers; Postdoctoral Fellow; Property; Protein Tyrosine Kinase; Recurrence; Reporting; Research; Research Activity; Research Personnel; Residencies; Rodent; Schools; Scientist; Signal Pathway; Signal Transduction; Slice; Structure; Surface; Surface Plasmon Resonance; System; TNF gene; Technology; Testing; Therapeutic; Time; Tissue imaging; Tissues; Toxic effect; Training; Transgenic Organisms; Treatment Efficacy; Tumor Necrosis Factor Receptor; Tumor Subtype; Tumor-Derived; United States National Institutes of Health; Universities; Work; Xenograft Model; Xenograft procedure; base; brain tissue; cancer cell; career development; chemotherapeutic agent; cytokine; cytotoxic; drug discovery; drug distribution; drug efficacy; experience; gadolinium oxide; image guided; imaging agent; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; macromolecule; medical schools; member; nanoparticle; neoplastic cell; neuro-oncology; neurosurgery; non-invasive imaging; oncology; particle; prevent; primary outcome; professor; programs; receptor; secondary outcome; skills; small molecule; standard of care; surface coating; targeted agent; temozolomide; trafficking; tumor; uptake

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.

描述（由申请人提供）：Woodworth博士目前是马里兰大学医学院的神经外科，解剖学和神经生物学助理教授，也是马里兰大学（UM）Greenebaum癌症中心的神经外科肿瘤学主任。他于2005年在约翰·霍普金斯大学（Johns Hopkins）完成了医学院，并于2012年在2012年完成了神经外科住院医师。在接受医学和神经外科培训之前，他曾在塔夫茨大学和辉瑞 - 药物发现部培训并担任有机化学家。他曾是国家癌症研究所资助的纳米技术癌症医学的T32计划，曾是神经肿瘤学的博士后研究员。伍德沃思博士的长期目标是成为一名独立资助的神经外科医生，并利用手术室作为发现的门户和治疗性分娩的机会。他正在努力提高翻译神经肿瘤学，研究重点是为脑部受脑的，不可或缺的癌细胞提供治疗疗法。为了实现这一目标，他的目标是通过在药物制剂，分娩和测试方面的创新研究中改善中枢神经系统肿瘤患者的结局。他将通过接下来的短期（3 - 5年）的目标和目标来增强他的研究职业发展：（1）研究增强胶质母细胞瘤（GBM）治疗剂的细胞和结构靶向策略；具体而言，探索Tweak-FN14信号通路，（2）研究用于侵袭性脑癌的先进局部和其他递送系统；特别是，检查新的对流增强和全身方法，例如引导聚焦超声（MRGFUS）的磁共振成像，（3）理解和分析患者衍生的异种移植物和转基因啮齿动物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，伍德沃思博士在这些领域招募了三位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特定教育活动融合在一起。这些导师是：Jeff Winkles博士。 （主要导师），贾斯汀·汉斯（Justin Hanes），博士（Co-entor）和Nhan Tran博士（联盟）。在整个培训期间，研究活动将与临床活动相辅相成，照顾良性和恶性中枢神经系统肿瘤患者，并以50％的努力进行护理。临床和科学活动的同等贡献将使作为神经外科医生的持续增长和进化，包括保持手术技能，保持神经外科进步和发展以及将研究工作与当前的临床困境联系起来。神经外科部门内的行政领导和临床伙伴的行政领导力强烈致力于确保这一受保护的时间。 Woodworth博士的实验室由NIH神经外科研究职业发展计划和Passano Foundation系，医学院和赠款联合资助。支持包括在格林鲍姆癌症中心内布雷斯勒研究大楼的新近装修的800FT2实验室空间，直接连接到马里兰州主要医院大楼。 该项目的整体实验设计和基本原理是基于这样的观察结果 超过指向特殊设计的表面涂层的颗粒可以在脑组织中迅速穿透。这些颗粒已被称为“脑穿透纳米颗粒”（BPN），并且有强烈的证据表明，这些大型的非粘附颗粒将可以改善脑组织中的分散体，受控药物释放，并靶向脑侵化癌细胞。指导团队的两名成员（NT JW）在细胞表面受体FN14上共同努力了多年，他们是第一个报告的研究者，报告说FN14基因表达在体内入侵的GBM细胞上上调。这些发现创造了一个有前途的机会来开发针对FN14的BPN，这些BPN预计会以较小的毒性提高治疗递送和疗效。总体假设是，BPN可以改善对侵入性脑肿瘤的治疗递送和功效。这将使用fn14靶向的BPN进行测试，该BPN载有有前途的化学治疗剂，该化学治疗剂通过局部对流增强方法在侵入性的患者衍生的异种移植模型中进行了测试。 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使用侵入性的，患者衍生的肿瘤模型的化学治疗剂Temozolomide。