(315d) Award Submission: Systemic Dendrimer-Mediated Delivery of Triptolide Specifically to Tumor-Associated Macrophages Improves Efficacy in Glioblastoma

Introduction: Glioblastoma is among the most severe types of cancers due to challenges with delivering therapies to the brain in addition to traditional solid tumor barriers. The blood brain barrier acts as a natural defense mechanism preventing foreign substances, including medicines, from reaching the brain. In addition, ill-developed vasculature and high interstitial pressure within tumors hampers effective drug penetration. This two-pronged barrier requires the administration of high doses of systemic therapies to achieve clinically relevant quantities in the brain tumor, resulting in significant off-target toxicities. Triptolide is a promising anti-cancer therapeutic that acts both as an immune suppressant in tumor-associated macrophages (TAMs) and as an anti-proliferative in cancer cells. However, like many potent anti-cancer drugs, its off-target activity causes significant systemic toxicities. Therefore, a platform that carries triptolide to the brain and into the brain tumor for triggered release while remaining inactive in the body provides an optimal clinical strategy.

Methods: Our group has shown that hydroxyl-terminated polyamidoamine (PAMAM) dendrimers selectively target activated microglia and macrophages in several neurodegenerative disorders, including TAMs in brain cancers. Here, we present novel PAMAM dendrimers surface modified with triptolide via ester linkages for intracellular and intratumoral triggered release (D-Trip). In vitro studies were performed in GL261 murine microglia to assess anti-proliferative activity and in BV2 murine microglia stimulated with IL-4 to explore immune-suppressant activity. In vivo experiments were performed in the GL261 mouse model of glioblastoma. Tumor-bearing mice were systemically administered 0.5 mg/kg triptolide or D-Trip daily starting day 5 post-inoculation and monitored regularly for markers of disease progression.

Results: D-Trip released triptolide in a sustained manner over two weeks under intracellular conditions while exhibiting minimal release in extracellular conditions. In vitro, D-Trip showed improved immune suppression in TAMs-like activated microglia over triptolide while both performed similarly in inducing tumor cell death. With systemic administration in mice, D-Trip treatment significantly reduced tumor burden (p = 0.04 vs. triptolide, p = 0.02 vs. control), leading to improved behavioral markers of disease (p = 0.0012 vs. triptolide in kyphosis score). D-Trip treatment also ameliorated the significant toxicity at the injection site observed in triptolide treated animals attributed to the targeting and triggered release capabilities of the dendrimer platform.

Conclusions: Here, we present a novel dendrimer-mediated triptolide targeted delivery platform that provides multiple anti-cancer functionalities for improved therapeutic efficacy. Dendrimers specifically target TAMs and release triptolide intracellularly to suppress their pro-tumor polarization. These TAMs then act as depots to release dendrimers into the surrounding tumor microenvironment to induce tumor cell death. These studies demonstrate the significant potential of PAMAM dendrimers for overcoming challenges to brain tumor drug delivery.