More Effective, Less Harmful Chemotherapy

In this latest study, published in ACS Nano, scientists created a novel drug as a spherical nucleic acid (SNA), a nanostructure that embeds the drug directly into DNA strands, wrapping small spheres. This strategy transforms a poorly soluble, underperforming drug into a potent, targeted cancer killer that spares healthy cells.

After designing the new drug, the researchers tested it in a small animal model of acute myeloid leukemia (AML), a quickly progressing and hard-to-treat blood cancer.

Compared to the usual chemotherapy treatment, the SNA-based drug penetrated leukemia cells 12.5 times more efficiently, killed them up to 20,000 times more effectively, and slowed cancer progression by 59-fold. No discernible adverse effects were detected.

This discovery exemplifies the promise of structural nanomedicine, a new discipline in which researchers apply precise structural and compositional control to fine-tune the interaction of nanomedicines with the human body.

Seven SNA-based therapies are currently in clinical trials. The new technique may lead to effective vaccinations and treatments for cancer, infectious diseases, neurodegenerative disorders, and autoimmune diseases.

In animal models, we demonstrated that we can stop tumors in their tracks. If this translates to human patients, it’s a really exciting advance. It would mean more effective chemotherapy, better response rates, and fewer side effects. That’s always the goal with any sort of cancer treatment.

Chad A. Mirkin, Study Lead and George B. Rathmann Professor, Northwestern University

Mirkin and his team focused their new study on the standard chemotherapy medication 5-fluorouracil (5-Fu), which frequently fails to reach cancer cells. 5-Fu, because it affects healthy tissue, causes a variety of adverse effects, including nausea, exhaustion, and, in rare circumstances, heart failure.

Mirkin suggests that the issue is not the medicine itself but how the body processes it. 5-Fu is weakly soluble, meaning less than one percent dissolves in most biological fluids. Most medications need to dissolve in the circulation before they can enter cells. A poorly soluble medicine clumps or remains solid, preventing the body from effectively absorbing it.

We all know that chemotherapy is often horribly toxic. But a lot of people don’t realize it’s also often poorly soluble, so we have to find ways to transform it into water soluble forms and deliver it effectively.

Chad A. Mirkin, Study Lead and George B. Rathmann Professor, Northwestern University

Mirkin and his colleagues decided to use SNAs to create a more effective distribution method.SNAs are globular nanostructures with a nanoparticle core surrounded by a dense shell of DNA or RNA. In previous work, Mirkin found that cells recognize SNAs and encourage them to enter the cell.

For this new study, Mirkin invented and developed SNAs, which his team constructed by chemically incorporating chemotherapy into the DNA strands.

“Most cells have scavenger receptors on their surfaces. But myeloid cells overexpress these receptors, so there are even more of them. If they recognize a molecule, then they will pull it into the cell. Instead of having to force their way into cells, SNAs are naturally taken up by these receptors,” Mirkin added.

As Mirkin and his colleagues expected, the structural modification drastically altered how 5-Fu interacted with cancer cells. Unlike free-floating, unstructured chemotherapy molecules, myeloid cells readily identified and absorbed the SNA form. Once inside, the enzymes degraded the DNA shell, releasing medication molecules that destroyed the cancer cell from within.

In mouse experiments, the drug nearly eliminated the leukemia cells almost entirely in the blood and spleen, significantly extending life. Furthermore, because the SNAs specifically targeted AML cells, healthy tissues were unaffected.

Today’s chemotherapeutics kill everything they encounter. So, they kill the cancer cells, but also a lot of healthy cells. Our structural nanomedicine preferentially seeks out the myeloid cells. Instead of overwhelming the whole body with chemotherapy, it delivers a higher, more focused dose exactly where it’s needed.

Chad A. Mirkin, Study Lead and George B. Rathmann Professor, Northwestern University

Mirkin’s team intends to test the novel method in a larger cohort of small animal models before moving on to a larger animal model and, finally, human clinical trials, assuming funding is secured.

SNAs enter cancer cells to deliver chemotherapyPlay