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 language | English |
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Pages (from-to) | 520-525 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 113 |
Issue number | 3 |
DOIs | |
State | Published - Jan 19 2016 |
Externally published | Yes |
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).
Funders | Funder number |
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NIH/NCI | R1209, 1R01CA190525 |
Pollack Foundation | |
National Institutes of Health | 1K08CA157727 |
National Institutes of Health | |
Howard Hughes Medical Institute | RP140110 |
Howard Hughes Medical Institute | |
American Cancer Society | ACS-IRG-02-196 |
American Cancer Society | |
National Cancer Institute | P30CA142543 |
National Cancer Institute | |
Welch Foundation | I-1855 |
Welch Foundation | |
Mary Kay Foundation | 049-15 |
Mary Kay Foundation | |
Cancer Prevention and Research Institute of Texas | R1212 |
Cancer Prevention and Research Institute of Texas |
Keywords
- Cancer
- Dendrimers
- MiRNA