Nanotherapeutic treatment of the invasive glioblastoma microenvironment

胶质母细胞瘤（GBM）是最常见、最致命的原发性脑胶质瘤， 癌症，是将治疗剂递送到手术安全区域之外的脑侵入肿瘤细胞 的拔除.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 脑侵入GBM区域，并经常成为肿瘤支持细胞。制定有效的战略 向肿瘤和肿瘤支持细胞的治疗递送，这有助于这种残留的侵袭性肿瘤 微环境（TME）是一个重要的未满足的临床需求。为了满足这一需求，我们开发了 可生物降解的纳米颗粒（NPs），具有专门的表面涂层，可快速扩散并靶向远端细胞 在大脑中。我们将这些粘附性降低的受体靶向纳米制剂称为“DART”。DART可以 作为先进的脑递送工具，以提高治疗效果并降低脱靶毒性- 大脑安全有效治疗的关键障碍。靶向GBM治疗的有前途的细胞门户 是TNF受体超家族成员，成纤维细胞生长因子诱导型-14（Fn 14）。Fn 14最小 在健康大脑中表达，在GBM核心中中度表达，最重要的是，在正常大脑中高度表达。 入侵大脑的胶质母细胞最近，我们发现在肿瘤的TAM上有高水平的Fn 14- 支持（M2样）特征，Fn 14表达升高导致侵袭性GBM，宿主较短 生存这些新的发现加上DART的前景，激发了本提案中的研究。我们 中心假设是Fn 14在侵袭性GBM微环境中发挥特定的肿瘤支持作用 并且Fn 14 DARTs将选择性地靶向Fn 14阳性（Fn 14+）肿瘤细胞、在其内运输并将药物递送至Fn 14阳性（Fn 14+）肿瘤细胞 和TAM。在目的1中，我们将研究Fn 14+和Fn 14- TME细胞中的DART运输和细胞动力学 为了更好地了解NP在这些细胞内的定位机制以及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，并使脱靶毒性最小化。在目标2中，我们将探讨Fn 14 DART对以下方面的潜在影响： 通过研究细胞活化表型确定TME和Fn 14相关治疗机会 和Fn 14 +/+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 通过该项目的工作来评估通过Fn 14的CED向TME细胞递送治疗剂的功效 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，并将有助于完善未来的犬和人类临床试验的方法。

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.