Staggered Nano-delivery destroys Cancer Tumor Cells

A unique cancer chemotherapy that wipes out tumor cells by initially neutralizing their defenses, then destroying them with a lethal dose of DNA damage has been developed by researchers at MIT. The double punch relies on a nanoparticle that carries two drugs and releases them at different times, to significantly shrink lung and breast cancer tumors.

“I think it’s a harbinger of what nanomedicine can do for us in the future,” says team co-lead Paula Hammond. “We’re moving from the simplest model of the nanoparticle — just getting the drug in there and targeting it — to having smart nanoparticles that deliver drug combinations in the way that you need to really attack the tumor.”

Rewiring Chemotherapy Combinations

Cancer patients are often given two or more different chemotherapy drugs in anticipation that a multipronged attack will be more successful than a single drug. Various studies have pointed to drugs that work well together, but a 2012 paper from co-lead Michael Yaffe’s lab was the first to show that timing of drug administration can very much influence the outcome.

In the 2012 study, which focused on a type of breast cancer cell known as triple negative, Yaffe and his team found they could weaken cancer cells by giving the drug erlotinib. Erlotinib shuts down one of the pathways that promote uncontrolled tumor growth.

The pretreated tumor cells were dramatically more vulnerable to treatment with a DNA-damaging drug called doxorubicin over cells given both drugs at once.

“It’s like rewiring a circuit,” said Yaffe. “When you give the first drug, the wires’ connections get switched around so that the second drug works in a much more effective way.”

Staggering Erlotinib and Doxorubicin

Erlotinib, targets the protein called epidermal growth factor (EGF) receptor, found on tumor cell surfaces. It is approved by the FDA to treat pancreatic cancer and some types of lung cancer.

Doxorubicin is used to treat various cancers, including lymphoma, leukemia, and lung, bladder, breast, and ovarian tumors.

Staggering these drugs proved especially powerful against triple-negative breast cancer cells, which don’t have overactive estrogen, progesterone, or HER2 receptors. Triple-negative tumors, which account for about 16 percent of breast cancer cases, are much more aggressive than other types and tend to strike younger women.

The finding was exciting, but there was a problem. How do you translate it into something you can actually give a cancer patient?

Liposomes to the Rescue

Yaffe joined with Hammond, a chemical engineer who has previously designed several types of nanoparticles that can carry two drugs at once.

For this project, Hammond came up with dozens of candidate particles. The most effective were a type of particle called liposomes. A liposome is a spherical droplet surrounded by a fatty outer shell.

The MIT team’s liposomes were designed to carry doxorubicin inside the particle’s core, with erlotinib embedded in the outer layer.

The particles are coated with a polymer called PEG, which protects them from being broken down in the body or filtered out by the liver and kidneys. Another tag, folate, helps direct the particles to tumor cells, which express high quantities of folate receptors.

When the nano- particles reach a tumor they are taken up by cells, and the particles begin to break down. The Erlotinib carried in the outer shell, is released first, but doxorubicin release is delayed and takes more time to seep into cells, giving erlotinib time to weaken the cells’ defenses.

“There’s a lag of somewhere between four and 24 hours between when erlotinib peaks in its effectiveness and the doxorubicin peaks in its effectiveness,” Yaffe said.

Tumours Shrank Significantly

The particles were tested in mice implanted with two types of human tumors, triple-negative breast tumors and non-small-cell lung tumors. Both types shrank significantly.

Additionally, packaging the two drugs in liposome nanoparticles made them much more effective than the traditional forms of the drugs, even when those drugs were given in a time-staggered order.

Image Credit: Stephen Morton