Combining drugs to treat cancer can be more effective than using a single drug. However, it can be difficult to determine the best combination (Targeting cancer using multi-drug nanoparticles) of drugs and to ensure that all drugs reach the right place.
To help solve these challenges, chemists at MIT designed a nanoparticle with a brush that can deliver (Targeting cancer using multi-drug nanoparticles) multiple drugs, in an easily controlled manner. Using these factors, the researchers were able to calculate and determine the optimal dose of the three cancer drugs used to treat multiple myeloma.
“There is a lot of interest in finding synergistic joint therapies for cancer, meaning they use mechanisms inside cancer cells to kill them effectively, but often we don’t know what that good is.” will be.” Jeremiah said. Johnson, a chemistry professor at MIT and one of the study’s leaders.
In a mouse study, researchers showed that nanoparticles carrying three drugs in a synergistic ratio they discovered shrank tumors more than when three drugs are delivered in the same ratio but not interested in a particle. This nanoparticle platform can be deployed to deliver drug combinations against various cancers, the researchers said.
Also lead author of the paper, which appears today in Nature Nanotechnology. Alexandre Detappe, assistant professor at the European Cancer Institute in Strasbourg, and Hung Nguyen PhD ’19 are the lead authors of the article.
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The use of nanoparticles to deliver cancer drugs allows the drugs to accumulate at the tumor site and reduce the toxic effects because the particles prevent the release of the drugs in time. However, only a few of the nanoparticle-based drugs have received FDA approval to treat cancer, and only one of those contains more than one drug.
For years, Johnson’s lab has been working on polymer nanoparticles designed to carry multiple drugs. In the new study, the research team focused on plastic bottles. To make the molecules, the drug molecules are activated by combining the polymeric building blocks and mixing them in the same amount for polymerization. This forms chains from the backbone, giving the molecule a brush-like structure with inactive drugs – prodrugs – along the backbone of the brush. The rupture of the bond that holds the drug to the spine releases the operator.
“If we want to make a bottle brush with two drugs or three drugs or any number of drugs, we just have to create these different drug monomers, mix them together, and let them polymerize. The resulting bottle brush is the same size and shape as a single-drug bottle brush, but now has the delivery of two, three, or as many drugs as you need,” Johnson says.
In this study, the researchers first tested molecules carrying one drug: bortezomib, which is used to treat multiple myeloma, a cancer that affects a type of B cell called plasma cells. . Bortezomib is a proteasome inhibitor, a type of drug that prevents cancer cells from breaking down the proteins they make. The accumulation of these proteins eventually leads to tumor cell death.
When bortezomib is given alone, the drug accumulates in red blood cells, which contain a large proteasome. However, when the researchers gave mice the drug they created with the brush, they found that the substances tended to accumulate in the plasma cells, because the structure of the brush prevented the drug from being released immediately, allowing it to distribute as long as it circulates on its own.
Social integration
Using a piece of the bottle, the researchers can also analyze several different combinations of drugs to determine the most effective. Currently, researchers are testing possible drug combinations by exposing cancer cells in laboratory dishes to a wide variety of drugs, but these results are often not translated to patients because Each drug is distributed and absorbed in different ways in the human body.
“If you inject three drugs into the body, the chances of the right amount of the drugs getting into the cancer cell at the same time can be very small. Drugs have different properties that make them go where they are. are different, which limits the translation of these drug discovery reports,” Johnson says.
However, delivering the three drugs together in one phase can overcome this obstacle and facilitate the delivery of synergistic doses. Because of the ease of creating bottle-plant seeds with different amounts of the drug, the researchers were able to compare those carrying different amounts of bortezomib with two other drugs used to treat multiple myeloma. : a drug that strengthens the immune system called pomalidomide and dexamethasone, an anti-inflammatory. medicine.
Exposure of these molecules to cancer cells in a laboratory dish showed a synergistic combination, but these combinations differed from the synergistic interactions that were detected using herbal medicine outside the bottle.
“What this tells us is that whenever you try to develop a synergistic drug combination and you end up planning to deliver a nanoparticle, you have to consider the synergy in the context of the nanoparticle,” Johnson saying. “If you measure it only for drugs and try to make a nanoparticle at that size, you can’t guarantee that it will be effective.”
A new combination
“We are pleased to note that the Bortezomib brush-to-bottle prodrug is an excellent drug in its own right, showing superior efficacy and safety over bortezomib, and this has led us to continue our efforts to bring this molecule in the clinic, as another – generation proteasome inhibitor. “, said Johnson. “It has different properties than bortezomib and gives you access to a wider range of treatments to treat cancers that are not treated with bortezomib.”
Johnson, Nguyen and Yivan Jiang PhD ’19 founded a company called Window Therapeutics, which is working to further develop these cells for trials that often fail. The company also hopes to discover other combinations of drugs that can be used against other types of cancer.
Johnson’s research lab is also working on using these materials to deliver therapeutic antibodies and drugs, as well as combining them with larger materials that can deliver messenger RNA and drug molecules. “The versatility of this platform gives us endless opportunities to create new collections,” he says.
