Triple-negative breast cancer: Nanodelivery of new drug shows promise

Using nanoparticles to deliver an experimental drug directly into triple-negative breast cancer cells could be an effective way to fight this very aggressive cancer, which has very few treatment options. The drug is a peptide that is unstable, and delivering it directly into cells means that it can reach its target before degrading.

So concludes a study led by Mohamed El-Tanani, a professor in the Institute for Cancer Therapeutics at the University of Bradford in the United Kingdom. He and his colleagues report their findings in the International Journal of Pharmaceutics.

The new drug - discovered by El-Tanani - is a protein fragment, or peptide, that blocks a cell-regulation protein called RAN, which promotes cancer cell division and proliferation.

The researchers note that high levels of RAN are linked to aggressive tumor growth and spread (metastasis), resistance to chemotherapy, and poor outcomes in several cancers, including triple-negative breast cancer.

Around 10-20 percent of breast cancers are diagnosed as triple negative.

The term "triple negative" means that tumors test negative for the three most common receptors that drive the majority of breast cancers: human epidermal growth factor receptor 2, progesterone receptors, and estrogen receptors.

Nanoparticle capsule prevents degrading of unstable peptide

The lack of all three receptors limits the options for treating this highly aggressive cancer, resulting in poorer outcomes for patients and an increased risk of recurrence.

The new study builds on previous work by Prof. El-Tanani and colleagues, in which they showed that blocking RAN can prevent and perhaps even reverse chemotherapy resistance in small cell lung cancer.

When they ran tests in the laboratory, the researchers found that the drug was not as effective as predicted using computer models of cell processes, as Prof. El-Tanani explains:

"We knew we'd need a novel delivery mechanism for this drug because peptides on their own are unstable and they can degrade too quickly to be effective. Using a nanoparticle as a delivery mechanism was the perfect solution."

Medical researchers are increasingly turning to nanotechnology to develop new treatments because it allows them to work with and control molecules at a scale that is smaller than cells.

Two thirds of cancer cells died within 24 hours

For the new study, the team used a biodegradable polymer to make a nanoparticle that encapsulates the peptide. They tested a number of materials before they found one that effectively sustained the integrity and stability of the peptide.

When they tested nanoparticles charged with the peptide on triple-negative cancer cells in the laboratory, the researchers found that the cells actively took them in, reduced their growth rate, and stopped replicating. Within 24 hours, around two thirds of the cells were dead.

Adding either the peptide on its own, or the nanoparticle without the peptide load, had no such effects.

On closer examination, the researchers found that the peptide was killing the cancer cells in the same way as the computer models predicted - it was preventing RAN activation by silencing a gene called regulator of chromosome condensation 1, or RCC1.

The Bradford team is already testing the nanoparticle delivery method in a model of triple-negative breast cancer and considering how to progress toward clinical trials.

They are also looking at other RAN inhibitor candidates. One of these is a "repurposed" drug that they say has passed preclinical tests of breast and lung cancer and is ready for clinical trials, for which they are seeking funding.

"By developing a nanoparticle that can help this peptide enter triple-negative breast cancer cells and block RAN we've brought this potential new treatment a step closer to the clinic."

Prof. Mohamed El-Tanani

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