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:10084330
- 负责人:
- 金额:$ 41.22万
- 依托单位:
- 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 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesivesAnimal ModelAnimalsAreaBindingBlood - brain barrier anatomyBrainBrain regionBypassCanis familiarisCellsClinicalClinical TrialsConvectionCoupledDataDiffuseDrug CarriersEncapsulatedEngineeringEquilibriumExcisionFibroblast Growth FactorFormulationFusion ToxinFutureGlioblastomaHumanIntracranial NeoplasmsInvadedInvestigationKnock-outLaboratoriesLigandsLinkLiposomesMalignant neoplasm of brainMediatingMicrogliaMicroscopyModificationMusOperative Surgical ProceduresParticulatePathogenicityPathway interactionsPhagocytesPharmaceutical PreparationsPhenotypePlayPolymersPopulationPrimary Brain NeoplasmsPublishingRattusResidual stateRoleSignal TransductionSolid NeoplasmSupporting CellSurfaceTechniquesTestingTherapeuticTherapeutic InterventionToxic effectTreatment EfficacyTumor Cell InvasionTumor Necrosis Factor ReceptorTumor-associated macrophagesTumor-infiltrating immune cellsVariantWorkbrain tissuedesigneffective therapyefficacy evaluationhuman modelimprovedin vivolocal drug deliverymacrophagemembernanoformulationnanoparticlenanotherapeuticneoplastic cellnew therapeutic targetnovelnovel therapeuticsreceptorsurface coatingtherapeutic targettherapeutically effectivetooltraffickingtreatment strategytumortumor 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) 是最常见和致命的原发性脑病,这是治疗中长期存在的问题
癌症,是向手术安全区域之外的侵入大脑的肿瘤细胞提供治疗药物
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渗透。
大脑侵入 GBM 区域并经常成为肿瘤支持细胞。
将治疗传递至肿瘤和肿瘤支持细胞,从而导致残留的侵袭性肿瘤
微环境(TME)是一个重要的未满足的临床需求。
可生物降解的纳米颗粒 (NP) 具有特殊的表面涂层,可快速扩散并靶向远程细胞
我们将这些降低粘附性的受体靶向纳米制剂称为“DART”。
作为先进的大脑输送工具,以提高治疗效果并减少脱靶毒性 - 两者兼而有之
脑部安全、有效治疗的关键障碍。有希望的 GBM 靶向治疗的细胞门户。
是 TNF 受体超家族成员,成纤维细胞生长因子诱导型 14 (Fn14) 含量最低。
在健康大脑中表达,在 GBM 核心中适度表达,最重要的是,在 GBM 核心中高表达
最近,我们在患有肿瘤的 TAM 上发现了高水平的 Fn14。
支持(M2 样)特征,并且 Fn14 表达升高导致宿主较短的侵袭性 GBM
这些新发现加上 DART 的前景,激发了我们这项提案中的研究。
中心假设是 Fn14 在侵袭性 GBM 微环境中发挥特定的肿瘤支持作用
Fn14 DART 将选择性地靶向 Fn14 阳性 (Fn14+) 肿瘤细胞、在其中运输药物并向其递送药物
在目标 1 中,我们将研究 Fn14+ 和 Fn14- TME 细胞中的 DART 运输和细胞动力学。
更好地了解控制纳米颗粒在这些细胞内定位和特定分布的机制
这些信息将帮助我们优化 DART 配方,以提高细胞的选择性。
在目标 2 中,我们将探讨 Fn14 DART 对药物的潜在影响。
通过细胞激活表型研究发现 TME 和 Fn14 相关的治疗机会
以及 Fn14+/+ 或 -/- 肿瘤-宿主配对中存在的功能变异 在目标 3 中,我们将结合我们正在进行的研究。
该项目的工作是评估通过 Fn14 的 CED 向 TME 细胞传递治疗的功效
DARTs。该项目将开发一种新的抗 GBM 治疗策略,旨在解决侵袭性 GBM 问题。
微环境,并将有助于完善未来犬类和人类临床试验的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Graeme F Woodworth其他文献
Graeme F Woodworth的其他文献
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{{ truncateString('Graeme F Woodworth', 18)}}的其他基金
Nanotherapeutic treatment of the invasive glioblastoma microenvironment
侵袭性胶质母细胞瘤微环境的纳米治疗
- 批准号:
10543096 - 财政年份:2019
- 资助金额:
$ 41.22万 - 项目类别:
Nanotherapeutic treatment of the invasive glioblastoma microenvironment
侵袭性胶质母细胞瘤微环境的纳米治疗
- 批准号:
9890019 - 财政年份:2019
- 资助金额:
$ 41.22万 - 项目类别:
Nanotherapeutic treatment of the invasive glioblastoma microenvironment
侵袭性胶质母细胞瘤微环境的纳米治疗
- 批准号:
10326351 - 财政年份:2019
- 资助金额:
$ 41.22万 - 项目类别:
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:
9340290 - 财政年份:2014
- 资助金额:
$ 41.22万 - 项目类别:
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:
8805638 - 财政年份:2014
- 资助金额:
$ 41.22万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 41.22万 - 项目类别:
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