Cancer treatment often involves the administration of toxic chemotherapeutic drugs, often combinations of several different agents, each with its own toxicity profile, dosing, and timing. Delivering high enough doses of these multiple drugs to kill cancer cells without damaging healthy neighboring cells can be challenging.
Enter nanotechnology. Nanoparticles loaded with cancer-fighting drugs offer a way to shuttle toxic chemicals directly to the cancer cells, while avoiding contact with healthy tissue. Much progress has been made in developing these drug-delivery vehicles. However, these approaches are limited to one or two different drug molecules.
A new approach developed by scientists at the
"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
Drug-delivering nanoparticles are most often made by one of two methods: encapsulating the drug inside of the nanoparticles, or chemically attaching the drug molecules to the nanoparticles. While these methods work well for one drug, and in some cases two, they are not amenable to the incorporation and release of more than two drugs.
Johnson and his team instead build the nanoparticles out of the drug molecules themselves using a method that involves ring-opening metathesis polymerization (ROMP) to synthesize nanoscopic brush-arm star polymers (BASPs). They first designed three building blocks: two branched macromonomers (MM) - CPT-MM and DOX-MM - and a Pt(IV) bisnorbomene complex that serves as a crosslinker. Once these building blocks are linked via ROMP, they are formed into nanoparticles.
"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," Johnson continues. "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."
The researchers synthesized the nanoparticles to carry a specific ratio of the three drugs, corresponding to the maximum tolerated dose of each drug, and designed the release of each drug to be triggered by a different mechanism. As soon as the nano- particle enters the cancer cell and is exposed to glutathione (an antioxidant present in cells), the bonds holding cisplatin (Pt) to the nanoparticle break down and it is released into the cell. Next, the particle encounters cellular enzymes called esterases, which trigger camptothecin (CPT) to flow out of the particle. Finally, upon exposure to ultraviolet light, doxorubicin (DOX) is released, leaving behind polyethylene glycol, which is biodegradable.
"This method could be applied to essentially any drug molecule that has a functional group that can be attached to our monomer," Johnson says. "Fortunately, there are enough drug molecules with these functional groups that we have plenty of structural space to explore."
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