Nanotherapeutic treatment of the invasive glioblastoma microenvironment

胶质母细胞瘤(GBM)是最常见和最致命的原发大脑，是治疗中的一个长期问题 癌症，是将治疗药物输送到手术安全的区域以外的脑侵袭性肿瘤细胞 移走。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入。 侵犯大脑的基底膜区域，并经常成为肿瘤支持细胞。制定有效的战略 对肿瘤和肿瘤支持细胞的治疗性输送，这对这种残留的侵袭性肿瘤有贡献 微环境(TME)是临床上尚未满足的重要需求。为了满足这一需求，我们开发了 具有特殊表面涂层的可生物降解纳米颗粒(NPs)，可快速扩散并靶向远程细胞 在大脑里。我们把这些粘附性降低的受体靶向纳米制剂称为‘DART’。飞镖可以 作为先进的大脑递送工具，提高治疗效果并减少非目标毒性-两者 安全、有效的大脑治疗的关键障碍。一种有前景的靶向GBM治疗的细胞门户 是肿瘤坏死因子受体超家族成员，成纤维细胞生长因子诱导因子14(Fn14)。Fn14是最小的 在健康的大脑中表达，在GBM核心中适度表达，最重要的是，高度表达 在侵袭大脑的GBM细胞中。最近，我们在患有肿瘤的TAM上发现了高水平的Fn14- 支持(类似M2的)功能和提升的Fn14表达导致具有更短主机的侵略性GBM 生死存亡。这些新的发现加上DART的前景，推动了这项提案中的研究。我们的 中心假说是Fn14在侵袭性GBM微环境中发挥特定的肿瘤支持作用 而Fn14 DART将选择性地靶向Fn14阳性(Fn14)肿瘤细胞，在其内运输药物，并将药物输送到Fn14阳性肿瘤细胞 还有塔姆斯。在目标1中，我们将研究DART在Fn14和Fn14-TME细胞中的转运和细胞动力学 为了更好地了解NP在这些细胞内定位的机制和在特定细胞中的分布 细胞群。这些信息将帮助我们优化DART配方，以提高选择性，细胞 保留，并最大限度地减少偏离目标的毒性。在目标2中，我们将探索Fn14飞镖对 通过细胞激活表型研究TME和Fn14相关的治疗机会 在Fn14/或-/-肿瘤宿主配对中存在功能变异。在《目标3》中，我们将结合我们正在进行的 与该项目合作评估通过Fn14的CED向TME细胞输送治疗性药物的效果 飞镖。该项目将开发一种新的抗GBM治疗策略，旨在解决侵袭性GBM 微环境，并将有助于完善的方法，为未来的狗和人类临床试验。

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.