How can we get drugs to the liver to treat its dysfunction, without making it worse?
William Aryitey |
The second largest cause of cancer-related deaths worldwide is liver cancer, which has been particularly hard to treat because it destroys the body’s ability to metabolize drugs, making responses to traditional small-molecule drugs unpredictable. A paper by Daniel Siegwart and colleagues suggests nanoparticles could be one potential solution (1).
“Advanced hepatocellular carcinoma (HCC) has a very poor prognosis with few therapeutic options. Sorafenib is the only available chemotherapeutic agent for HCC, and it extends median survival by only about 2.5 months,” says Siegwart. After seeing five small-molecule drugs fail Phase III clinical trials, partly due to drug toxicity, the team decided to explore alternative options for treatment.
They focused on tumor-suppressing microRNAs (miRNAs), but needed a suitable vehicle to deliver these large molecules into liver cells, without causing increased toxicity. “The development of therapies that balance high potency and low toxicity is a vexing problem for cancer treatment, and it is particularly challenging in liver cancer,” says Siegwart. “We overcame this challenge by developing dendrimer nanoparticles that mediate miRNA delivery to late-stage liver tumors. These dendrimer carriers provide high potency in tumors without negatively affecting normal tissues, solving a critical issue in treating aggressive liver cancer." Dendrimer nanoparticles were chosen because they can be produced at high volume and purity, and at low cost, as well as avoiding potential immunogenicity.
Testing the approach in a mouse model of aggressive liver cancer, the team found that the miRNA nanoparticles inhibited tumor growth and significantly extended survival. Though Siegwart has plans to expand the work to other indications, he says it won’t be easy: “In order to use this system to treat other forms of cancer, it will be important to redirect these nanoparticles, either by changing their biodistribution after intravenous delivery, or by employing methods of local delivery.”
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- K Zhou et al., “Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model”, Proc Natl Acad Sci U S A, 113, 520–525 (2016). PMID: 26729861.