chemicals from Massachusetts Institute of Technology (MIT), designed in the United States brush shaped nanoparticle that can be loaded multiple drugs, In easily controllable proportions. Using these particles, the researchers calculated and administered the optimal ratio of three anticancer drugs used to treat cancer. multiple myeloma, as published in the magazineNature Nanotechnology’.
Cancer treatment with a combination of drugs may be more effective than using a drug, But it’s hard to figure out what’s the optimal combination of drugs and make sure they all get to the right places.
“There is great interest in finding synergistic combination therapies against cancer that take advantage of some of the underlying mechanisms of the cancer cell. which allows them to kill more effectivelyBut often we don’t know what that appropriate ratio would be,” says Jeremiah JohnsonMIT professor of chemistry and one of the study’s lead authors.
In a mouse study, researchers showed that Nanoparticles carrying three drugs in synergistic ratios identify highly shrunk tumors since when the three drugs were administered in the same ratio but one did not bind to the particle. He says this nanoparticle platform could be used to deliver combinations of drugs against different types of cancer.
Using nanoparticles to deliver cancer drugs Allows these to accumulate in the tumor area and minimizes toxic side effects Because the particles prevent the drugs from being released prematurely. Even then, The FDA has approved only a handful of nanoparticle formulations for cancer treatment, And only one of them has more than one drug.
laboratory of Johnson has been working for many years on polymeric nanoparticles designed for transport multiple drugs, In the new study, the research team focused on a particle Brush shaped.
to make particlesThe drug molecules are deactivated by binding to the polymer blocks and then mixed in a specific ratio for its polymerization. Thus, chains are formed that extend from a central backbone, giving molecules a bottle shaped structure With inactive drugs (prodrugs) along the spine of the bottle. sprain Releases active agent.
“If we want to make a ‘bottle brush’ with two, three or more drugs, it is sufficient to synthesize different conjugated monomers, mix them and polymerize them. The resulting brush has exactly the same size and shape is as they come. Used to be just one drug, but now they’re delivered in two, three, or whatever drugs you want,” Johnson explains.
against multiple myeloma
in this studio, The researchers first tested the particles with a single drug: bortezomib, used to treat multiple myeloma, a cancer that affects a type B lymphocytes are also known as plasma cells., It is a proteasome inhibitor, a type of drug Prevents cancer cells from breaking down extra proteins they have made, These proteins end up accumulating Causes death of tumor cells.
When bortezomib is administered alone it tends to accumulate in red blood cells, which contain high concentrations of proteasomes. However, when the researchers administered their version of the drug as a bottled prodrug to rats, They found that the particles mainly accumulate in plasma cells because the bottled structure prevents the drug from being released immediately, allowing it to circulate for a long time to reach its target.
with particles ‘bottle brush’, The researchers were also able to test several different combinations of drugs to see which were most effective.
Now, researchers are testing potential drug combinations by exposing cancer cells to in a laboratory dish for different concentrations of different drugs, but these results usually do not transfer to patients because each drug It is distributed and absorbed differently within the human body.
“If three drugs are injected into the body, it is likely that the correct proportion of those drugs will reach the cancer cell at the same time. Drugs have different properties that cause them to target different sites, making it extremely difficult to translate these identified synergistic ratios of drugs.says Johnson.
However, co-administration of three drugs in a single particle can overcome that barrier and facilitate the delivery of synergistic ratios. Thanks to the ease of creating brush-shaped particles containing different concentrations of drugs, The researchers were able to compare the particles with different ratios of bortezomib and two other drugs used in the treatment of multiple myeloma: an immunostimulatory drug called pomidolomide and dexamethasone, an anti-inflammatory.
By exposing these particles to cancer cells A lab plate synergistic combination was observedbut different from the synergistic ratios that were identified using the drugs bound to the brush.
“What this tells us is that whenever you’re trying to develop a synergistic combination of drugs that you ultimately plan to deliver in the nanoparticle, you need to measure the synergy in the context of the nanoparticle,” Johnson said. If you measure it for drugs alone and then try to make nanoparticles with that ratio, you can’t guarantee that it will be as effective.”
In tests with two mouse models of multiple myeloma, researchers found that three-drug brushes with synergistic ratios tumor growth Compared to free drug administered in the same ratio and with three different brush mixtures of the same drug.
They also found that their bortezomib-based brush was very effective at slowing tumor growth only when given in high doses. Although approved for blood cancers such as multiple myeloma, bortezomib has never been approved for solid tumors. Its limited therapeutic window and bioavailability.
“We were pleased to see that the bottlebrush prodrug of bortezomib was an excellent drug on its own, showing improved efficacy and safety compared to bortezomib, and this inspired us to attempt to bring this molecule into the clinic as a proteasome inhibitor.” inspired.” Next-gen,” Johnson says. It has completely different properties than bortezomib and gives you the potential for a broad therapeutic index to treat cancers where bortezomib hasn’t been used before.”
Johnson, Hung Nguyen y Yiwan XianGee has founded a company called Window Therapeutics, which is working on further development of these particles for testing in clinical trials. The company also hopes to explore other drug combinations. Can be used against other types of cancer.
Johnson’s lab is also working on using these particles to deliver therapeutic antibodies with drugs, as well as combining them with larger particles that can deliver messenger RNA along with drug molecules. “The versatility of this platform gives us endless opportunities to create new combinations,” confirm.
