Drug-induced aptamers target leukemia stem cells for 1-2 knockout punches

Researchers in the Urbana-Champaign Report of the University of Illinois, drug-carrying DNA aptamers can deliver a one-to-two punch to leukemia by accurately targeting elusive cancer stem cells when cancer recurs.

Apatmers sniff single-stranded snippets of DNA that can target molecules like larger antibodies – not only supplying cancer drugs, but are also toxic to cancer stem cells in their own right, the researchers said.

The researchers, led by Xing Wang, professor of bioengineering and chemistry, documented their findings in Journal Advanced Functional Materials.

“This study shows how to reach the roots of leukemia,” Wang said. “Targeted cancer treatments often have problems with toxicity and efficacy. Our aptamers seek out these stem cells specifically and effectively kill them.”

Leukemia and other blood cancers are more difficult to target than cancers that produce local tumors, as cancer cells circulate throughout the body and cannot be surgically removed, post-doctoral researchers said Dwivedy, the first author of the paper.

Leukemia has a high recurrence rate because it avoids stem cells. Although they make up a small portion of cancer cells, leukemia stem cells share markers and properties, and therefore have the ability to avoid chemotherapy by retreating into the bone marrow, Dwivedy said. Cancer cells can sometimes be lurking for years and then grow and migrate.

“It’s important in leukemia, lymphoma, or other blood cancers that actually target and eliminate these stem cells, because as long as either of them remains, it can cause recurrence or secondary cancers,” Dwivedy said.

The researchers began by finding DNA aptamers looking for markers found on the surface of acute myeloid leukemia stem cells. They wanted to specifically target stem cells, not just cancer.

“The big thing we showed in this study is that having two targets is better than one target in terms of selectivity,” Wang said. “There are known antibody drug conjugates in blood cancers that target one marker, but the markers are also found in many healthy cells. Therefore, there are many toxicities associated with antibody conjugates. However, we used two targets.

Researchers then combined aptamers with the drug donorubicin, which fights leukemia. Drug-containing aptamers carry the drug to their targets and then release the drug once within the cell so that it acts.

“This is especially important for drugs like donorubicin. Its own ability to pass through the cell membrane, so the aptamer can carry it,” Dwivedy said.

The researchers tested drug-dependent aptamers in leukemia cell cultures and live leukemia mice.

After 72 hours, only the aptamer reduces cancer cells in culture by 40%, indicating the toxicity of the aptamer against cancer, the researchers report. When aptamer carried the drug to fight leukemia, the cells were wiped off at 500 times smaller than the standard dose of the drug. In leukemia mice, supplying the drug via aptamers provides the same efficacy at doses 10 times greater than clinical standard, indicating that one punch of aptamers and drugs is more effective than either.

“This was exciting for us, because cancer studies show that what you see in vitro is not always seen in the body. However, at one tenth of the therapeutic dose, we found excellent survival and reduced tumors in mice treated with aptamer drug conjugates.

The researchers said they would like to expand the series of drug-induced aptamers by identifying key marker combinations for other cancers and concurrently binding to other drugs.

“All cancer cells have characteristics in surface biomarkers. If you can find markers present in cancer cells, you can target other types of cancer as well. In my experience, drugs can be combined with DNA molecules rather than proteins.