Delivering drugs that can knock out tumor cells within the body, without causing adverse side effects, is a tricky busines. It's why scientists have taken to engineering new and creative types of nanoparticles that do the job. Increasing a nanoparticle's ability to carry more drugs expands treatment options, but creating nanoparticles capable of delivering more than one or two drugs has proven difficult – until now. Scientists at MIT report creating a revolutionary building block technique that's enabled them to load a nanoparticle with three drugs. The approach, they say, could be expanded to allow a nanoparticle to carry hundreds more.
Typical nanoparticle designs don't allow for scaling, since they call for building a nanoparticle first and then encapsulating the drug molecules within it, or chemically attaching the molecules to the nanoparticle. Attempting to add more drugs into the structure makes assembling the final nanoparticle exponentially more difficult.
To overcome these limitations, Jeremiah Johnson, an assistant professor of chemistry at MIT, created nanoparticle building blocks that already included the desired drug. Called "brush first polymerization," the approach allows the researchers to incorporate many drugs within a single nanoparticle and control the precise amounts of each.
"This is a new way to build the particles from the beginning," Johnson says. "If I want a particle with five drugs, I just take the five building blocks I want and have those assemble into a particle. In principle, there’s no limitation on how many drugs you can add, and the ratio of drugs carried by the particles just depends on how they are mixed together in the beginning."
In addition to the drug, each tiny building block contains a linking unit enabling it to easily connect to other blocks, and a protective compound to ensure that the drug stays intact until it enters the cell. The approach not only allows different drug-containing blocks to be assembled into specific structures, but it also enables each drug to be released separately via different triggers.
The team has tested its triple threat nanoparticles, containing drugs typically used to treat ovarian cancer (such as doxorubicin, cisplatin and camptothecin), against lab-grown ovarian cancer cells. The results demonstrated the new nanoparticles' ability to destroy cancer cells at a higher rate than those carrying fewer drugs.
"We think it’s the first example of a nanoparticle that carries a precise ratio of three drugs and can release those drugs in response to three distinct triggering mechanisms," says Johnson.
In this case, the cisplatin in the triple threat nanoparticle is delivered the instant the particle enters the cell, as it reacts to the presence of an antioxidant found in the cells called glutathione. When the nanoparticle encounters a cellular enzyme called esterases it releases the second drug, camptothecin. Shining ultraviolet light triggers the release of the remaining doxorubicin, leaving behind only the biodegradable remnants of the nanoparticle.
The researchers believe this approach can potentially be used to link hundreds of building blocks to create multidrug-carrying nanoparticles, and pave the way for entirely new types of cancer treatments, free from the damaging side effects that accompany traditional chemotherapy. The MIT team is currently working on making nanoparticles that can deliver four drugs, and are also engaged in tests that treat tumor cells in animals.
A paper describing the team's research was published recently in the Journal of the American Chemical Society.
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