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Targeted Nanoparticle Tested in Patients with Cancer
The first trial to test a targeted nanoparticle capable of controlling a drug's release is now under way in humans. By packaging molecules of the chemotherapy drug docetaxel in nanoparticles, researchers aim to deliver a higher dose of the drug directly to tumors and to reduce the toxicity to patients.
In animal studies performed before the trial, the nanoparticle delivered a greater amount of the drug to tumor cells than could be achieved with the unpackaged (or free) drug. In addition, the nanoparticle did not show any more toxicity than docetaxel on its own.
Researchers from the Massachusetts Institute of Technology (MIT), Brigham and Women's Hospital, Harvard Medical School, BIND Biosciences, Inc., and their colleagues reported the development of the nanoparticle, called BIND-014, in the April 4 Science Translational Medicine.
"Normally, when you give cancer drugs they go through the whole body, and they cause really bad side effects. And only a certain amount goes to the tumor," said Dr. Robert Langer of MIT, one of the senior authors of the study. "This trial has given us an initial indication that this nanoparticle approach is safer and much more efficacious."
In a mouse xenograft model studied before the trial, the amount of docetaxel delivered to tumors was seven times higher in mice infused with the nanoparticle compared with mice that received unpackaged docetaxel. In addition, the researchers saw a greater reduction in tumor mass in mice that received the targeted nanoparticle compared with mice that received a nontargeted version of the nanoparticle. The reduction in tumor mass seen with the targeted nanoparticle was even greater when compared with free docetaxel. Side effects were no worse with the nanoparticles than with the unpackaged chemotherapy drug.
In other animal studies, the researchers found that docetaxel packaged in nanoparticles circulated in the bloodstream much longer than the unpackaged drug, and the drug remained safely encapsulated inside its shell while in the bloodstream. Also, BIND-014 did not accumulate in the liver, an unwanted occurrence that is almost always seen with other nanoparticles.
Based on these promising results in animals, the researchers have launched the phase I clinical trial to find the maximum tolerated dose in people with solid tumors that have not responded to a range of other chemotherapies. Although the trial is ongoing, the researchers reported initial clinical results in the Science Translational Medicine paper and provided additional data for the first 17 patients in a poster presented April 4 at the American Association for Cancer Research annual meeting.
Early data from the trial show that BIND-014 exhibits antitumor activity and is generally well-tolerated. Of note, tumors shrank in a patient with metastatic bile duct cancer and a patient with tonsillar cancer. Both responses occurred at doses substantially lower than those given for unpackaged docetaxel, which is consistent with the preclinical finding that BIND-014 can accumulate in tumors more effectively. Another patient with cervical cancer had a durable reduction in tumor size for more than 6 months and currently remains on the treatment.
To create a nanoparticle that could safely carry docetaxel through the bloodstream and deliver the drug directly to tumors, the researchers developed a new process for designing nanoparticles. Typically, researchers have created a prototype nanoparticle and then tried to modify its characteristics by, for instance, attaching molecules known as ligands for tumor cell binding, explained Dr. Omid Farokhzad of Harvard Medical School, another senior author of the study.
The problem with this process, said Dr. Farokhzad, is an inherent lack of reproducibility for small changes in design. "You're going to get batch-to-batch variability, and with that variability we could not create nanoparticles that differed from each other very narrowly, to find the one nanoparticle that had exactly the right pharmacologic and pharmaceutical parameters we were looking for."
To address this problem, the researchers created a library of more than 100 novel self-assembling nanoparticles. These nanoparticles start out as a long string of molecules, each with different functions—for example, holding and releasing the chemotherapy drug, hiding the nanoparticle from the immune system, or binding to tumor cells.
Small changes can be made to any of the molecules in the string before self-assembly, creating subtle variations that can be screened for the desired properties of a drug-delivery vehicle. When the desired properties are added to the string, they are dropped into a water-solvent solution containing the chemotherapy drugs to create a precisely designed nanoparticle.
Since some of the molecules in the string are repelled by water and some can mix with water, the nanoparticle folds in on itself and around the drug in a predictable, reproducible fashion, creating the final product. "We can now create nanoparticles with narrowly different biophysicochemical properties in a highly reproducible way. They will look the same every time, and we can test for the best nanoparticles in this library," said Dr. Farokhzad.
"We had done a lot of self-assembly work in our lab, so to us it was a natural approach to take for making nanoparticles, though the key here was the combination of self-assembly and use of this approach to make highly reproducible libraries of nanoparticles," added Dr. Langer.
A Firm Foundation
The initial work on the library was funded by a Centers of Cancer Nanotechnology Excellence grant from NCI's Alliance for Nanotechnology in Cancer. Hoping to rapidly advance their work to the clinic, in 2007 the researchers applied for and received an NCI Small Business Innovation Research grant to form BIND Biosciences, Inc., an independent company.
The scientists from BIND went on to screen their entire library in vitro to measure the rates of drug release and to test the stability of the nanoparticles. The most promising nanoparticles advanced to pharmacokinetic studies in rats. The researchers selected BIND-014 for further testing and manufacturing. (BIND-014 targets a protein called prostate-specific membrane antigen, which is found on the surface of prostate cancer cells and on the blood vessels feeding most other types of solid tumors.)
"This collaboration shows what can happen when you take nanotechnology forward and develop a really robust platform and product candidate, and get it into the clinic," said Dr. Jeffrey Hrkach, senior vice president, Pharmaceutical Sciences at BIND Biosciences and lead author of the study.
"Hopefully, nanomedicines like this will lead to more manageable and more effective chemotherapies," said Dr. Piotr Grodzinski, director of NCI's Office of Cancer Nanotechnology Research, which operates the Alliance for Nanotechnology in Cancer. "Perhaps we can even revisit drugs that failed in clinical trials in the past because they were too toxic, if nanoparticles allow us to deliver these drugs in a safer way."