CHAMPAIGN, Ill. — Drug-carrying DNA aptamers can deliver a one-two punch to leukemia by precisely targeting the elusive cancer stem cells that seed cancer relapses, researchers at the University of Illinois Urbana-Champaign report.
The aptamers — short single-strand snippets of DNA that can target molecules like larger antibodies do — not only deliver cancer-fighting drugs, but also are themselves toxic to the cancer stem cells, the researchers said.
Led by Xing Wang , a U. of I. professor of bioengineering and of chemistry , the researchers documented their findings in the journal Advanced Functional Materials.
"This work demonstrates a way to get to the root of leukemia," Wang said. "Targeted cancer treatments often have problems with toxicity or efficacy. Our aptamers seek out these stem cells specifically and kill them effectively."
Leukemia and other cancers of the blood are more difficult to target than cancers that produce localized tumors because the cancerous cells circulate throughout the body and can't be surgically removed, said postdoctoral researcher Abhisek Dwivedy, first author of the paper. Leukemia has a high rate of relapse due to its evasive stem cells. Though they make up a tiny fraction of cancerous cells, leukemia stem cells have the ability to evade chemotherapy by retreating to the bone marrow, since they share markers and properties, Dwivedy said. The cancerous cells can lurk, sometimes for years, and later proliferate and migrate.
"It's important in leukemia, lymphoma or other blood cancers that we actually target and eliminate these stem cells, because as long as any are remaining, they can cause relapse and secondary cancers," Dwivedy said.
The researchers began by finding DNA aptamers that seek out markers found on the surface of acute myeloid leukemia stem cells. They wanted to target not just the cancer, but the stem cells specifically.
"A big thing we showed in this study is that having two targets is better than one in terms of selectivity," Wang said. "There are known antibody-drug conjugates for blood cancers that target one marker, but that marker is also found on a lot of healthy cells. So there is a lot of toxicity associated with antibody conjugates. But we used two targets: a combination often found in leukemia cancer cells and leukemia stem cells. The two together give a very specific target."
The researchers then paired their aptamers with the leukemia-fighting drug daunorubicin. The drug-laden aptamers carry the drug to their target, then release the drug once inside the cell so the drug can act.
"This is especially important for drugs like daunorubicin, because the drug on its own cannot cross the cell membrane easily. But aptamers can carry it in," Dwivedy said.
The researchers tested the drug-delivering aptamers in leukemia cell cultures as well as in live mice with leukemia.
After 72 hours, the aptamer alone had reduced the 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 dosage of the drug. In mice with leukemia, delivering the drug via aptamer yielded the same efficacy at a dose 10 times smaller than the clinical standard, showing that the one-two punch of the aptamer and drug is more effective than either alone.
"This was exciting to us, because in cancer research, what we see in vitro is not always what we see in the body. Yet we saw excellent survivability and tumor reduction in the mice treated with our aptamer-drug conjugates, at one-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 marker combinations for other cancers, as well as coupling the aptamers with other drugs.
"Every cancer cell has a signature in its surface biomarkers. If we can find markers that are present uniquely in cancer cells, we can target other cancer types as well. Also, in my experience, it's much easier to pair a drug with the DNA molecules than proteins, so that opens possibilities for delivering more drugs this way," Dwivedy said.
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.
