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神经外科、解剖学和神经生物学助理教授以及马里兰大学 (UM) Greenebaum 癌症中心神经外科肿瘤学主任。他于 2005 年在约翰·霍普金斯大学完成了医学院学业，并于 2012 年完成了神经外科住院医师培训。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门接受培训并担任有机化学家。他是国家癌症研究所资助的 T32 癌症医学纳米技术项目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科学家，利用手术室作为发现的门户和提供治疗的机会。他致力于推进转化神经肿瘤学，研究重点是为侵入大脑的、不受欢迎的癌细胞提供治疗方法。为了实现这一目标，他旨在通过药物配方、输送和测试方面的创新研究来改善中枢神经系统肿瘤患者的治疗结果。他将通过以下短期（3-5年）目标和目标来加强他的研究职业发展：（1）研究增强胶质母细胞瘤（GBM）治疗的细胞和结构靶向策略；具体来说，探索TWEAK-Fn14信号通路，（2）研究侵袭性脑癌的先进局部和其他递送系统；特别是，研究新的对流增强和系统方法，例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，伍德沃斯博士招募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（共同导师）和 Nhan Tran 博士（共同导师）。在整个培训期间，研究活动将得到补充，临床活动将投入50%的精力来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能够持续成长和发展，包括保持手术技能、跟上神经外科的进步和发展，以及将研究工作与当前的临床困境联系起来。神经外科的行政领导和临床合作伙伴坚定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系、医学院以及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的资助共同资助。该支持包括格林鲍姆癌症中心布雷斯勒研究大楼内新装修的 800 平方英尺的实验室空间，该实验室空间直接与马里兰大学医院主楼相连。 该项目的总体实验设计和基本原理是基于以下观察： 具有特殊设计表面涂层的超预期颗粒可以快速渗透到脑组织内。这些颗粒被称为“脑穿透纳米颗粒”（BPN），证据强烈表明这些大的、非粘附性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入大脑的癌细胞。指导团队的两名成员（JW、NT）在细胞表面受体 Fn14 方面合作多年，他们是第一个报告 Fn14 基因表达在体内入侵 GBM 细胞上调的研究人员。这些发现为开发 Fn14 靶向 BPN 创造了一个充满希望的机会，预计这些 BPN 可以改善治疗递送和疗效，同时降低毒性。总体假设是，BPN 将能够改善侵袭性脑肿瘤的治疗递送和疗效；这将使用装载有前景化疗药物的 Fn14 靶向 BPN 进行测试，通过局部对流增强方法在侵入性患者来源的异种移植模型中进行递送。该项目提出了三个具体目标：(1) 配制含有和不含 Fn14 特异性靶向剂的纳米粒子并对其进行表征，(2) 评估对流增强局部递送 (CED) 后优化纳米粒子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，评估通过 CED 施用的载药纳米粒子针对标准 GBM 化疗药物替莫唑胺并与标准 GBM 化疗药物替莫唑胺组合的治疗效果 模型。