Drug-delivery DNA aptamers provide dual action against leukemia stem cells

Drug-delivery DNA aptamers provide dual action against leukemia stem cells

DNA aptamers containing drug-carrying DNA can deliver a two-two punch to leukemia by precisely targeting the elusive cancer stem cells that seed cancer, researchers from the University of Illinois Urbana-Champaign report.

The aptamers - short, single-stranded snippets of DNA that can make molecules like larger antibodies - not only deliver cancer drugs but are themselves toxic to the cancer stem cells, the researchers said.

Led by Xing Wang, a U. of I. of I. professor of bioengineering and chemistry, the researchers documented their findings in the journalAdvanced functional materials.

This work shows a way to get to the root of leukemia. Targeted cancer treatments often have problems with toxicity or effectiveness. Our aptamers specifically seek out these stem cells and effectively kill them. “

Xing Wang, U. of I. Professor of Bioengineering and Chemistry

Leukemia and other blood cancers are more difficult to target than cancers that produce localized tumors because the cancer cells circulate throughout the body and cannot be removed surgically, said postdoctoral researcher Abhisek Dwivedy, first author of the paper. Leukemia has a high relapse rate due to its escape from stem cells. Although they make up a tiny fraction of cancerous cells, leukemia stem cells can be eliminated by chemotherapy by retreating into the bone marrow because they share markers and properties, Dwivedy said. The cancer cells can sometimes lurk for years and later multiply and migrate.

"It's important that leukemia, lymphoma or other blood cancers that we actually target and eliminate these stem cells, because as long as any remain, they can cause relapse and secondary cancers," Dwivedy said.

The researchers first created DNA aptamers that search for markers found on the surface of acute myeloid leukemia stem cells. They wanted to specifically target not just the cancer, but also the stem cells.

“One big thing we showed in this study is that two targets are better than one in terms of selectivity,” Wang said. "There are known antibody-drug conjugates for blood cancers that target a marker, but that marker is also found in many healthy cells. So there is a lot of toxicity with antibody conjugates. However, we used two targets: a combination commonly found in leukemia cancer cells and leukemia stem cells. The two together give a very specific target."

The researchers then combined their aptamers with the leukemia-fighting drug daunorubicin. The drug-loaded aptamers carry the drug to their target and release the drug once inside the cell for the drug to take effect.

"This is particularly important for drugs like daunorubicin because the drug itself cannot easily cross the cell membrane. But aptamers can carry them," Dwivedy said.

The researchers tested the drug-delivering aptamers in leukemia cell cultures and in live mice with leukemia.

After 72 hours, the aptamer alone had reduced cancer cells in culture by 40 percent, demonstrating the aptamer's toxicity to the cancer, the researchers report. When the aptamers carried the leukemia-fighting drug, the cells were wiped out with a dose 500 times smaller than the standard dose of the drug. In mice with leukemia, delivery of the drug via aptamer gave equal effectiveness at a dose ten times smaller than the clinical standard and showed that the one-two punch of the aptamer and the drug is more effective than either alone.

"This was exciting for us because in cancer research, what we see in vitro is not always what we see in the body. Nevertheless, we saw excellent survival and tumor reduction in the mice treated with our aptamer-drug conjugates at a tenth of the therapeutic dose and no off-target effects," Wang said.

The researchers said they hope to expand their suite of drug-delivering aptamers by identifying key combinations of tags for other cancers and binding the aptamers to other drugs.

"Every cancer cell has a signature in its surface biomarkers. If we can find markers that are uniquely present in cancer cells, we can target other cancers as well. Also, in my experience, it is much easier to combine a drug with the DNA molecules than proteins, so it opens up the possibilities for more drugs to spread in this way," said Dwivedy.

The National Institutes of Health and the National Science Foundation supported this work. Wang is affiliated with the Cancer Center at Illinois, the Carl R. Woese Institute for Genomic Biology and the Holonyak Micro and Nanotechnology Lab at the U. of I.

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