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In a first, MIT scientists have designed nanoparticles that can deliver three cancer drugs at a time. Such particles could be designed to carry even more drugs, allowing researchers to develop new treatment regimens that could better kill cancer cells while avoiding the side effects of traditional chemotherapy. "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," said Jeremiah Johnson, an assistant professor of chemistry at Massachusetts Institute of Technology (MIT) and the senior author of a new paper published in the Journal of the American Chemical Society. The researchers said that the triple-threat nanoparticles could kill ovarian cancer cells more effectively than particles carrying only one or two drugs, and they have begun testing the particles against tumours in animals. The new approach overcomes the inherent limitations of the two methods most often used to produce drug-delivering nanoparticles: encapsulating small drug molecules inside the particles or chemically attaching them to the particle. Combining these two approaches - encapsulating one drug inside a particle and attaching a different one to the surface - has had some success, but is still limited to two drugs. Johnson set out to create a new type of particle that would overcome those constraints, enabling the loading of any number of different drugs. Instead of building the particle and then attaching drug molecules, he created building blocks that already include the drug. These building blocks can be joined together in a very specific structure, and the researchers can precisely control how much of each drug is included. Each building block consists of three components: the drug molecule, a linking unit that can connect to other blocks, and a chain of polyethylene glycol (PEG), which helps protect the particle from being broken down in the body. Hundreds of these blocks can be linked using an approach Johnson developed, called "brush first polymerisation." In the study, researchers created particles that carry the drugs cisplatin, doxorubicin, and camptothecin, which are often used alone or in combination to treat ovarian cancer. Each particle carries the three drugs in a specific ratio that matches the maximum tolerated dose of each drug, and each drug has its own release mechanism. Cisplatin is freed as soon as the particle enters a cell, as the bonds holding it to the particle break down on exposure to glutathione, an antioxidant present in cells.
Camptothecin is also released quickly when it encounters cellular enzymes called esterases. The third drug, doxorubicin, was designed so that it would be released only when ultraviolet light shines on the particle. Once all three drugs are released, all that is left behind is PEG, which is easily biodegradable.