Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

Kejin Zhou, Liem H. Nguyen, Jason B. Miller, Yunfeng Yan, Petra Kos, Hu Xiong, Lin Li, Jing Hao, Jonathan T. Minnig, Hao Zhu, Daniel J. Siegwart

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC50 < 0.02 mg/kg siRNA against FVII (siFVII)] in dose-response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer's own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs.

Original languageEnglish (US)
Pages (from-to)520-525
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 19 2016


  • Cancer
  • Dendrimers
  • MiRNA

ASJC Scopus subject areas

  • General


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