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

134 Scopus citations

Abstract

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
Pages (from-to)520-525
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number3
DOIs
StatePublished - Jan 19 2016
Externally publishedYes

Funding

D.J.S. gratefully acknowledges financial support from the Cancer Prevention and Research Institute of Texas (CPRIT) (R1212), The Welch Foundation (I-1855), the American Cancer Society (ACS-IRG-02-196), and The Mary Kay Foundation (049-15). L.H.N. was supported by a Howard Hughes Medical Institute (HHMI) Predoctoral International Student Fellowship. J.B.M. was supported by a CPRIT Fellowship (RP140110). H.Z. was supported by the Pollack Foundation, an NIH K08 Grant (1K08CA157727), an NIH/NCI R01 Grant (1R01CA190525), a Burroughs Wellcome Career Medical Award, and CPRIT (R1209).

FundersFunder number
NIH/NCIR1209, 1R01CA190525
Pollack Foundation
National Institutes of Health1K08CA157727
National Institutes of Health
Howard Hughes Medical InstituteRP140110
Howard Hughes Medical Institute
American Cancer SocietyACS-IRG-02-196
American Cancer Society
National Cancer InstituteP30CA142543
National Cancer Institute
Welch FoundationI-1855
Welch Foundation
Mary Kay Foundation049-15
Mary Kay Foundation
Cancer Prevention and Research Institute of TexasR1212
Cancer Prevention and Research Institute of Texas

    Keywords

    • Cancer
    • Dendrimers
    • MiRNA

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