MIT chemists design new nanoparticle that could help with treatment of cancer

Chemists with the Massachusetts Institute of Technology (MIT) have designed a new nanoparticle that can be loaded with multiple drugs to provide a more effective cancer treatment, according to an MIT News article published Jan. 26.

Treating cancer with different drug combinations can be more effective than using a single drug; however, learning the best combination of drugs for each situation and ensuring that all of them reach the right place has proven a challenge. 

To help resolve the issue, MIT chemists have designed a bottlebrush-shaped nanoparticle that can be loaded with multiple drugs in easy-to-control ratios. Using the particles, the researchers could calculate and deliver the optimal ratio of three cancer drugs used to combat multiple myeloma.

“There’s a lot of interest in finding synergistic combination therapies for cancer. [This means] that they leverage some underlying mechanism of the cancer cell that allows them to kill more effectively, but oftentimes we don’t know what that right ratio will be,” said MIT chemistry professor and senior study author Jeremiah Johnson.

The use of nanoparticles to deliver cancer drugs allows the drugs to build up in the tumor site and reduce toxic side effects due to the particles protecting the drugs from being released prematurely; however, only a select few nanoparticle drug formulations have been given FDA approval to treat cancer, and only one of the particles carries more than one drug.

For several years, Johnson's team has been developing polymer nanoparticles that can carry multiple drugs. In their new study, the research team focused on a bottlebrush-shaped particle. To make these particles, drug molecules are inactivated by binding to polymer building blocks and mixed together in a specific ratio for polymerization. 

This procedure forms chains that extend from a central backbone, giving the molecule a bottlebrush-like structure with inactivated drugs (prodrugs) along the backbone of the bottlebrush. The cleaving of the linker that holds the drug to the backbone releases the active agent.

"If we want to make a bottlebrush that has two drugs or three drugs or any number of drugs in it, we simply need to synthesize those different drug-conjugated monomers, mix them together, and polymerize them," Johnson said. "The resulting bottlebrushes have exactly the same size and shape as the bottlebrush that only has one drug, but now they have a distribution of two, three, or however many drugs you want within them."

In the study, the researchers first tested particles carrying only one drug: bortezomib, which is used to treat multiple myeloma. 

Bortezomib is a proteasome inhibitor, meaning it prevents cancer cells from breaking down the excess proteins that they produce. The accumulation of these proteins eventually causes the tumor cells to die. 

When the drug is administered on its own, it tends to accumulate in red blood cells, which have high proteasome concentrations. When the researchers gave the bottlebrush prodrug version of the drug to mice, however, they learned the particles primarily accumulated in plasma cells, because the bottlebrush structure protects the drug from being released immediately, allowing it to circulate long enough to reach its target.

Using the bottlebrush particles, the researchers could analyze many different drug combinations to study which among them was the most effective. They found that three-drug bottlebrushes, with a synergistic ratio, significantly inhibited tumor growth, compared to the free drugs given without the particle. 

The nanoparticle platform could potentially deliver drug combinations against multiple types of cancer.

"Whenever you are trying to develop a synergistic drug combination that you ultimately plan to administer in a nanoparticle, you should measure synergy in the context of the nanoparticle,” Johnson said. “If you measure it for the drugs alone, and then try to make a nanoparticle with that ratio, you can’t guarantee it will be as effective.”

Harvard Medical School and Dana-Farber Cancer Institute professor of medicine Irene Ghrobrial and Ceptur Therapeutics' president and former MIT Koch Institute clinical investigator P. Peter Ghoroghcian are senior authors of the paper, which was published in Nature Nanotechnology. 

Strasbourg Europe Cancer Institute's Alexandre Detappe and Hung Nguyen, a 2019 Ph.D, are the paper's lead authors.