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

2020; Elsevier BV; Volume: 329; Linguagem: Inglês

10.1016/j.jconrel.2020.12.003

1873-4995

Kevin Liaw, Rishi Sharma, Anjali Sharma, Sebastián Salazar, Santiago Appiani La Rosa, Rangaramanujam M. Kannan,

Histone Deacetylase Inhibitors Research

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.