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Dendrimer-Transported MicroRNA Shown Effective in Treating Mice with Late-Stage Liver Cancer

By LabMedica International staff writers
Posted on 10 Feb 2016
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Image: Schematic diagram of dendrimer structure (Photo courtesy of the University of California, Irvine).
Image: Schematic diagram of dendrimer structure (Photo courtesy of the University of California, Irvine).
Cancer researchers have used nanocarriers called dendrimers to transport a specific tumor growth-inhibiting microRNA (miRNA) to the livers of mice with late-stage liver cancer.

MicroRNAs are a class of about 20 nucleotides-long RNA fragments that block gene expression by attaching to molecules of messenger RNA (mRNA) in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA. With their capacity to fine-tune protein expression via sequence-specific interactions, miRNAs help regulate cell maintenance and differentiation. A particular miRNA, let-7, is closely associated with human cancer and acts as a tumor suppressor.

A dendrimer consists of a core, repeated iterations surrounding the core called dendrons, and the periphery groups that can be modified for ligand attachment. Dendrimers are attractive for drug delivery use because the carrier can improve solubility, increase circulation half-life, and increase drug transit across biological barriers.

The poorly functioning condition of the liver with late-stage disease amplifies drug toxicity. MicroRNAs present a promising alternative treatment strategy but require development of delivery vehicles that can avoid this cancer-induced dysfunction, which exacerbates toxicity. Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) overcame this challenge by developing dendrimer nanoparticles that mediated miRNA delivery to late-stage liver tumors with low liver toxicity.

Over the course of this study 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, loaded with less than 0.02 milligrams/kilogram of let-7 miRNA provided a broad therapeutic window. These carriers were identified as potent in dose–response experiments in vitro and were well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven liver tumors.

Results published in the January 4, 2016, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) revealed that delivery of let-7 miRNA inhibited tumor growth and dramatically extended survival. The effectiveness of this treatment was attributed to a combination of a potent small RNA growth inhibitor together with the dendrimer’s own negligible toxicity.

"We have synthesized highly effective dendrimer carriers that can deliver drugs to tumor cells without adverse side effects, even when the cancerous liver is consumed by the disease," said senior author Dr. Daniel Siegwart, assistant professor of biochemistry at the University of Texas Southwestern Medical Center. "We found that efficacy required a combination of a small RNA drug that can suppress cancer growth and the carrier, thereby solving a critical issue in treating aggressive liver cancer and providing a guide for future drug development."

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University of Texas Southwestern Medical Center


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