Modular Degradable Dendrimers Enable Small RNAs to Extend Survival in an Aggressive Liver Cancer Model

Authors: K. Zhou, L.H. Nguyen, J.B. Miller, Y. Yan, P. Kos, H. Xiong, L. Li, J. Hao, J.T. Minnig, H. Zhu and D.J. Siegwart

Journal: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.1520756113

Publication - Summary

January 19, 2016


Liver cancer is a deadly disease with limited intervention options. Tumour removal surgery and liver transplantation are extremely complicated and not always possible. Several small molecule drugs aimed to treat hepatocellular carcinoma (HCC) have failed in the clinical trials due to hepatotoxicity. Cancerous liver is typically more sensitive to drug toxicity and therefore, there is great need for therapeutic options that destroy tumour cells without further damaging the already inflamed tissue. The RNA interference (RNAi) technology is a potential therapeutic strategy for treatment of many diseases such as HCC. While new methods of drug delivery have greatly improved RNAi potency as a therapeutic agent, its use for HCC treatment has been hindered by the hepatotoxicity caused by majority of the common delivery methods. The Siegwart group from the University of Texas Southwestern have generated a biodegradable dendrimer that can deliver siRNA or microRNA (miRNA) to liver without hepatotoxicity. These dendrimers that are formulated into nanoparticles using the NanoAssemblrTM technology can potentially be used for treatment of liver cancers.

In their article featured in Proceedings of the National Academy of Sciences (PNAS), 2016, they describe their method to generate and formulate degradable dendrimers that can successfully deliver miRNA to liver without causing hepatotoxicity. The authors first generated a chemically diverse degradable dendrimer library using the orthogonal click chemistry synthesis method. The dendrimers were then formulated into nanoparticles that were loaded with siRNA against a reporter gene, luciferase. Over 1000 formulations were screened in vitro by monitoring luciferase and the dendrimers that lead to efficacious knockdown were then tested in vivo in healthy mice to assess in vivo delivery efficacy. A few dendrimers that had high intracellular and in vivo delivery were chosen to be tested in mice bearing aggressive MYC-driven liver cancer. The candidate dendrimers were first formulated with a control siRNA and injected i.v. into healthy mice. The nanoparticles that didn’t cause weight loss in healthy animals were injected into tumour bearing mice to see if they are as well tolerated in cancerous as in healthy liver. Surprisingly, out of the 2 dendrimers tested one caused severe toxicity in the liver and the other (5A2-SC8) was well tolerated, indicating the importance of minor chemical structure changes in toxicity. 5A2-SC8 was also shown to deliver siRNA to tumour cells as shown by confocal imaging and was therefore used to deliver the let-7 miRNA to the liver cancer mice. let-7miRNA is downregulated in HCC and therefore, restoring the miRNA levels back to normal should inhibit liver cancer development. The mice treated with let-7 5A2-SC8 dendrimer nanoparticles had significantly improved survival rate compared to the untreated group (100 days versus 60 days). These mice exhibited smaller abdomen and reduction in tumour burden without any significant toxicity outcomes.

This article demonstrates that synthesizing and screening of a dendrimer library can efficiently identify dendrimeric drug delivery vehicles capable of decreasing toxicity and side effects while not compromising efficacy. While several approaches have been shown to efficiently deliver nucleic acids to healthy liver, they have been unsuccessful in treating liver cancer because the cancerous liver is more sensitive to toxicity. The biodegradable dendrimers described in this article can be fine tuned to adjust the chemical and structural properties and therefore are great options for addressing the toxicity versus efficacy problem. The dendrimers described in this paper efficaciously delivered an miRNA mimic to liver tumor cells and led to increased survival rate and tumour burden reduction. This study highlights the close dependency of cancer biology treatment to chemical design and the benefits that can be resulted from fine tuning of drug delivery vehicles.


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.

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