# Nanotherapeutic treatment of the invasive glioblastoma microenvironment

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $418,330

## Abstract

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.

## Key facts

- **NIH application ID:** 9890019
- **Project number:** 5R01NS107813-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Graeme F Woodworth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,330
- **Award type:** 5
- **Project period:** 2019-03-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890019

## Citation

> US National Institutes of Health, RePORTER application 9890019, Nanotherapeutic treatment of the invasive glioblastoma microenvironment (5R01NS107813-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9890019. Licensed CC0.

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