Nano-sized 'Trojan horse' destroys drug-resistant leukemia cells

Researchers demonstrated that a DNA nanostructure loaded with a chemotherapeutic agent could invade and kill drug-resistant leukemia cells, according to a study published January 20, 2016 in the journal Small. The researchers nicknamed the DNA nanostructure “Horse” in honor of the Trojan Horse used by ancient Greek warriors to invade the city of Troy.

The study began with a pre-clinical model of acute myeloid leukemia (AML) that had developed resistance to daunorubicin. Researchers attribute this resistance to the overexpression of efflux pumps that either are present in the tumor at diagnosis or are induced following treatment. Thus, when molecules of daunorubicin enter the AML cell, the cell recognizes them and pumps them back out through the cell wall.

“Cancer cells have novel ways of resisting drugs, like these pumps, and the exciting part of packaging the drug this way is that we can circumvent those defenses so that the drug accumulates in the cancer cell and causes it to die,” said study co-author John Byrd, MD, Chair of Leukemia Research and Professor of Internal Medicine at The Ohio State University (OSU) Wexner Medical Center in Columbus, OH.

To circumvent the efflux pumps, the researchers took advantage of previous research on DNA origami, in which DNA is folded to create a rod-shaped, nanoscale scaffold—the Trojan Horse that carried the fighting force of daunorubicin.

“DNA origami nanostructures have a lot of potential for drug delivery, not just for making effective drug delivery vehicles, but enabling new ways to study drug delivery. For instance, we can vary the shape or mechanical stiffness of a structure very precisely and see how that affects entry into cells,” said Carlos Castro, PhD, Director of OSU’s Laboratory for Nanoengineering and Biodesign.

Dr. Castro’s team designed the capsules to be strong and stable so that they wouldn’t fully disintegrate and release the bulk of the drug, until it was too late for the cell to pump them back out.

Once the researchers achieved a stable design, they tagged the Horse DNA nanostructures with a fluorescent marker and observed them under a microscope. They found that the nanostructures were engulfed into the AML cells by endocytosis and entered into the endolysosomal pathway, bypassing resistance efflux pumps.

This process also allowed large amounts of the drug to enter and ultimately stay in the cell, they noted. Most AML cells died within the first 15 hours after consuming the Horse nanostructures.

If further research demonstrates that this process can be effectively translated to animal models, the technique will be effective in most any form of drug-resistant cancer, Dr. Byrd said. “Potentially, we can also tailor these structures to make them deliver drugs selectively to cancer cells, and not to other parts of the body where they can cause side effects,” he noted.