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

JOURNAL OF CONTROLLED RELEASE

卷:329

Article

Liaw, Kevin^1,2  Sharma, Rishi¹  Sharma, Anjali¹  Salazar, Sebastian³  La Rosa, Santiago Appiani^1,3  Kannan, Rangaramanujam M.^1,2,4 

[1] Johns Hopkins Univ, Wilmer Eye Inst, Ctr Nanomed, Sch Med,Dept Ophthalmol, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA

[3] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA

[4] Kennedy Krieger Inc, Hugo W Moser Res Inst, Baltimore, MD 21205 USA

关键词: Dendrimer;    Triptolide;    Glioblastoma;    Tumor-associated macrophages;    Targeted delivery;   

DOI  :  10.1016/j.jconrel.2020.12.003

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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