One-Two Nanopunch For Difficult-To-Treat Breast Cancer

Most breast cancers overproduce at least one of three common receptor proteins: estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. The most successful chemotherapy drugs block tumor growth by targeting one of these three. But about 10 to 20% of breast cancers are triple-negative, which means their tumors don’t overexpress any of these receptors, making the cancers tougher to treat.

Scientists think weakening the defenses of tumor cells could help make chemotherapy drugs more effective. For instance, a small interfering RNA (siRNA)—a short double-stranded RNA fragment that silences certain genes in cells—could be used to switch off a gene in tumor cells that makes them chemotherapy-resistant.

But siRNAs are difficult to deliver to cells, says Paula T. Hammond of Massachusetts Institute of Technology. Inside the bloodstream, siRNAs tend to get degraded by enzymes. Also, siRNA strands are negatively charged, she says, so they get repelled by human cells, which are studded with negatively charged molecules.

To address this delivery problem, Hammond and her team developed a method of hiding an siRNA sequence inside the multilayered coating surrounding a nanoparticle. By also filling the core of this stealthy nanomedicine with a cancer drug, the group reports that it can simultaneously weaken the defenses of triple-negative breast cancer tumors and diminish the malignant lumps in mice.

The group begins its nanoparticle fabrication process with hollow lipid spheres and loads them with doxorubicin, a cancer drug used against a wide range of cancers, including triple-negative breast cancer. The researchers use a layer-by-layer assembly method to put additional coatings on the outside of the particles.

First, they add a thin layer of poly-L-arginine, which is positively charged and therefore sticks to negatively charged lipids. Then the team adds a layer of siRNA targeted at the gene for multidrug resistance protein 1, a molecular pump on tumor cells that pushes out cancer drugs to escape their toxicity.

After one more arginine layer, Hammond’s group tops off the particle with negatively charged hyaluronic acid. The compound is a structural component found in most tissues in the body, Hammond says, so putting it on the outside disguises the particles. “To other cells, these nanoparticles look like their native environment,” she adds. They slip by the immune system and siRNA-degrading enzymes and into cells.

When injected into mice with grafted triple-negative breast cancer tumors three times over 15 days, the nanoparticles released their cargo and shrunk the tumors, in some cases making them disappear. Tumors in mice given only saline solution, however, grew to four times their original volume.

Even though some big pharmaceutical companies have shied away from siRNA therapy because of the delivery challenges, it still has huge potential, especially for treating cancer, says Sei Kwang Hahn, a chemist at Pohang University of Science & Technology, in South Korea. This layer-by-layer nanoparticle, he adds, shows particular promise for siRNA and “seems feasible for further clinical development.”

According to Hammond, she and her group have patented the particle-assembly technique, and they plan next to look for other genes involved in triple-negative breast cancer that can be switched off by siRNA.