Reducing Drug Side Effects with Nanoparticles
Researchers at the Massachusetts Institute of Technology (MIT) and Brigham and Women's Hospital have shown that they can deliver the cancer drug cisplatin much more effectively and safely in a form that has been encapsulated in a nanoparticle targeted to prostate tumor cells. Using the new particles, the researchers were able to successfully shrink tumors in mice, using only one-third the amount of conventional cisplatin needed to achieve the same effect. Such a dose reduction, should these results hold in human clinical trials, could help reduce cisplatin's potentially severe side effects, which include kidney damage and nerve damage.
In 2008, this research team, headed by Stephen Lippard and Omid Farokhzad, a member of the MIT-Harvard Center of Cancer Nanotechnology Excellence (CCNE) funded by the National Cancer Institute, showed that the nanoparticles worked in cancer cells grown in a lab dish. Now that the particles have shown promise in animals, the team hopes to move on to human tests. "At each stage, it's possible there will be new roadblocks that will come up, but you just keep trying," says Dr. Lippard. The results of these investigations were published in the Proceedings of the National Academy of Sciences.
Cisplatin, which doctors began using to treat cancer in the late 1970s, destroys cancer cells by damaging their DNA, which ultimately triggers cell death. Despite its adverse side effects, which also include nausea, about half of all cancer patients receiving chemotherapy are taking platinum drugs. And in addition, cisplatin suffers from other problems that ultimately limit the utility of this potent tumor-killing agent. One problem with the drug is that conventional cisplatin remains in the bloodstream for only a short period of time. In fact, only about one percent of the dose given to a patient ever reaches the tumor cells' DNA, with about half of any given dose being excreted from the body within an hour of treatment.
To prolong the time in circulation, Drs. Lippard and Farokhzad and their collaborators decided to encase a derivative of cisplatin in a hydrophobic (water-repelling) nanoparticle. First, the researchers modified the drug, which is normally hydrophilic (water-attracting), with two hexanoic acid units — organic fragments that repel water. That modification enabled them to encapsulate the resulting prodrug — a form that is inactive until it enters a target cell — in a nanoparticle.
Using this approach, far more of the drug reaches the tumor. The researchers found that the nanoparticles circulated in the bloodstream for about 24 hours, at least 5 times longer than un-encapsulated cisplatin. They also found that it did not accumulate as much in the kidneys as conventional cisplatin, which could reduce the dose-limiting kidney toxicity that limits the duration of cisplatin treatment today. To help the nanoparticles reach their target, the researchers also coated them with molecules that bind to prostate specific membrane antigen (PSMA), a protein found on most prostate cancer cells.
After showing that nanoparticles improved ciplatin's lifetime in the blood stream, the researchers tested their effectiveness by treating mice implanted with human prostate tumors. They found that the nanoparticles reduced tumor size as much as conventional cisplatin over 30 days, but with only 30 percent of the dose normally required to see such a therapeutic response.
The particles tested in this paper are based on the same design as particles developed by Farokhzad and his MIT colleague Robert Langer, who is the co-principal investigator of the MIT-Harvard CCNE, to more effectively deliver the cancer drug docetaxel to tumors. A Phase I clinical trial to assess those particles, run by BIND Biosciences, commenced in January. Additional animal testing is needed before the cisplatin-carrying particles can go into human clinical trials, says Farokhzad. "At the end of the day, if the development results are all promising, then we would hope to put something like this in humans within the next three years," he says.
This work, which is detailed in a paper titled, "Targeted delivery of cisplatin prodrug for safer and more effective prostate cancer therapy in vivo," was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An abstract of this paper is available at the journal's website.