Systemic dendrimer delivery of triptolide to tumor-associated macrophages improves anti-tumor efficacy and reduces systemic toxicity in glioblastoma.

Novel delivery strategies are necessary to effectively address glioblastoma without systemic toxicities. Triptolide is a therapy derived from the thunder god vine that has shown potent anti-proliferative and immunosuppressive properties but exhibits significant adverse systemic effects. Dendrimer-based nanomedicines have shown great potential for clinical translation of systemic therapies targeting neuroinflammation and brain tumors. Here we present a novel dendrimer-triptolide conjugate that specifically targets tumor-associated macrophages (TAMs) in glioblastoma from systemic administration and exhibits triggered release under intracellular and intratumor conditions. This targeted delivery improves phenotype switching of TAMs from pro- towards anti-tumor expression in vitro. In an orthotopic model of glioblastoma, dendrimer-triptolide achieved significantly improved amelioration of tumor burden compared to free triptolide. Notably, the triggered release mechanism of dendrimer-mediated triptolide delivery significantly reduced triptolide-associated hepatic and cardiac toxicities. These results demonstrate that dendrimers are a promising targeted delivery platform to achieve effective glioblastoma treatment by improving efficacy while reducing systemic toxicities.

Dendrimer-Mediated Targeted Delivery of Rapamycin to Tumor-Associated Macrophages Improves Systemic Treatment of Glioblastoma.

Glioblastoma exhibits high mortality rates due to challenges with drug delivery to the brain and into solid tumors. This two-pronged barrier necessitates high doses of systemic therapies, resulting in significant off-target toxicities. Recently, dendrimer-nanomedicines (without ligands) have shown promise for targeting specific cells in brain tumors from systemic circulation, for improved efficacy and amelioration of systemic toxicities. A dendrimer-rapamycin conjugate (D-Rapa) is presented here that specifically targets tumor-associated macrophages (TAMs) in glioblastoma from systemic administration. D-Rapa improves suppression of pro-tumor expression in activated TAMs and antiproliferative properties of rapamycin in glioma cells in vitro. In vivo, D-Rapa localizes specifically within TAMs, acting as depots to release rapamycin into the tumor microenvironment. This targeted delivery strategy yields improved reduction in tumor burden and systemic toxicities in a challenging, clinically relevant orthotopic syngeneic model of glioblastoma, demonstrating the significant potential of dendrimers as targeted immunotherapies for improving glioblastoma treatment, still an unmet need.