Nanotherapeutic treatment of the invasive glioblastoma microenvironment

侵袭性胶质母细胞瘤微环境的纳米治疗

基本信息

批准号：
10543096
负责人：
Graeme F Woodworth
金额：
$ 39.9万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543096
关键词：
Address Adhesives Animal Model Animals Area Binding Blood - brain barrier anatomy Brain Brain region Bypass Canis familiaris Cells Clinical Clinical Trials Convection Coupled Data Diffuse Drug Carriers Encapsulated Engineering Equilibrium Excision Fibroblast Growth Factor Formulation Fusion Toxin Future Glioblastoma Human Intracranial Neoplasms Invaded Investigation Knockout Mice Laboratories Ligands Link Liposomes Macrophage Malignant neoplasm of brain Mediating Microglia Microscopy Modification Operative Surgical Procedures Particulate Pathogenicity Pathway interactions Penetration Phagocytes Pharmaceutical Preparations Phenotype Play Polymers Population Primary Brain Neoplasms Publishing Rattus Residual state Role Signal Transduction Solid Neoplasm Supporting Cell Surface Techniques Testing Therapeutic Therapeutic Intervention Toxic effect Treatment Efficacy Tumor Cell Invasion Tumor Necrosis Factor Receptor Tumor-associated macrophages Variant Work brain tissue design effective therapy efficacy evaluation human model immune cell infiltrate improved in vivo local drug delivery member nanoformulation nanoparticle nanotherapeutic neoplastic cell new therapeutic target novel novel therapeutics receptor surface coating therapeutic target therapeutically effective tool trafficking treatment strategy tumor tumor microenvironment

项目摘要

A long-standing problem in the treatment of glioblastoma (GBM), the most common and deadly primary brain cancer, is delivery of therapeutics to brain-invading tumor cells outside of the area that is safe for surgical removal. Recent evidence indicates that reactive macrophages, microglia, and other immune cells infiltrate brain-invaded GBM regions and frequently become tumor-supporting cells. Establishing strategies for effective therapeutic delivery to the tumor and tumor-supporting cells, which contribute to this residual, invasive tumor microenvironment (TME) is an important unmet clinical need. To address this need, we have developed biodegradable nanoparticles (NPs) with specialized surface coatings that diffuse rapidly and target remote cells within the brain. We call these decreased adhesivity receptor-targeted nano-formulations, ‘DARTs’. DARTs can serve as advanced brain delivery tools to improve therapeutic efficacy and decrease off-target toxicities – both critical hurdles for safe, effective treatments in the brain. A promising cell portal for targeted GBM therapeutics is the TNF receptor superfamily member, fibroblast growth factor inducible-14 (Fn14). Fn14 is minimally expressed in the healthy brain, moderately expressed in the GBM core and most importantly, highly expressed in the brain-invading GBM cells. More recently, we have discovered high levels of Fn14 on TAMs with tumor- supporting (M2-like) features, and elevated Fn14 expression leads to aggressive GBMs with shorter host survival. These new findings coupled with the promise of DARTs, motivate the studies in this proposal. Our central hypothesis is that Fn14 plays specific tumor-supporting roles in the invasive GBM microenvironment and Fn14 DARTs will selectively target, traffic within, and deliver drugs to Fn14-positive (Fn14+) tumor cells and TAMs. In Aim 1, we will investigate DART trafficking and cellular dynamics in Fn14+ and Fn14- TME cells to better understand the mechanisms governing NP localization within these cells and distribution in specific cell populations. This information will help us optimize the DART formulations to improve selectivity, cellular retention, and minimize off target toxicities. In Aim 2, we will explore the potential impact of Fn14 DARTs on the TME and Fn14 related therapeutic opportunities through investigations of cellular activation phenotypes and functional variations present in Fn14+/+ or -/- tumor-host pairings. In Aim 3, we will couple our ongoing efforts with work from this project to evaluate the efficacy of therapeutic delivery to TME cells via CED of Fn14 DARTs. This project will develop a new anti-GBM therapeutic strategy designed to address the invasive GBM microenvironment, and will help refine the approach for future canine and human clinical trials.

胶质母细胞瘤（GBM）治疗的长期问题，这是最常见和致命的原发性大脑癌症是在该区域以外的脑部肿瘤细胞中提供治疗的治疗最近的证据表明，反应性巨噬细胞，小胶质细胞和其他免疫细胞浸润脑摄入的GBM区域，经常成为肿瘤支持的细胞。建立有效的策略肿瘤和肿瘤支撑细胞的治疗递送，这有助于这种残留的侵入性肿瘤微环境（TME）是重要的未满足的临床需求。为了满足这种需求，我们已经发展了可生物降解的纳米颗粒（NP），具有专门的表面涂层，可快速扩散并靶向远程细胞在大脑内。我们称这些减少的依从性受体靶向的纳米形成为“飞镖”。飞镖可以用作提高治疗效率并降低脱靶毒性的先进脑输送工具 - 既在大脑中安全有效治疗的关键障碍。有希望的针对目标GBM治疗的细胞门户网站是TNF受体超家族成员，成纤维细胞生长因子诱导14（FN14）。 FN14最少在健康的大脑中表达，以GBM核心中等表达，最重要的是，高度表达在脑介入的GBM细胞中。最近，我们发现在肿瘤的TAM上发现了高水平的FN14 支持（类似于M2的）功能和升高的FN14表达会导致较短的主机具有侵略性的GBM 生存。这些新发现以及飞镖的承诺，激励该提案中的研究。我们的中心假设是FN14在侵入性GBM微环境中扮演特定的肿瘤支持角色 FN14飞镖将有选择地靶向，在内部交通并将药物输送到FN14阳性（FN14+）肿瘤细胞和tams。在AIM 1中，我们将研究FN14+和FN14-TME细胞中的DART运输和细胞动力学更好地了解管理这些单元内NP定位并在特定中分布的机制细胞种群。这些信息将帮助我们优化DART公式以提高选择性，蜂窝保留，并最大程度地减少目标毒性。在AIM 2中，我们将探讨FN14飞镖对通过研究细胞激活表型，TME和FN14相关的治疗机会 FN14+/+或 - / - 肿瘤宿主配对中存在的功能变化。在AIM 3中，我们将融入我们正在进行的该项目的工作努力通过FN14的CED评估向TME细胞的治疗递送的有效性飞镖。该项目将开发一种新的抗GBM热策略，旨在解决侵入性GBM 微环境，并将有助于完善未来犬和人类临床试验的方法。