New Nanotech Design Improves Drug Efficacy, Lowers Toxicity
Researchers at the Massachusetts Institute of Technology (MIT) and Brigham and Women's Hospital have revealed a nanoscale molecular design that increases the efficacy of the chemotherapy agent docetaxel against prostate tumors while reducing its toxic side effects in mice. The study, which appeared April 18 in the Proceedings of the National Academy of Sciences and was funded in part by NCI, is the first case where aptamers - short strands of nucleic acids - have been used successfully for the targeted delivery of a cancer drug in vivo.
"The greatest advantage of our study is in the combination of materials that we used," says Dr. Robert Langer of MIT, who directed the project with Dr. Omid Farokhzad of Harvard Medical School. Their team chose prostate cancer because it is often diagnosed early, when treatment prognosis is good, hoping that a need for safer localized treatments may facilitate the translation of their work to patient care. They designed their drug-delivery vehicle from poly (D,L-lactic-co-glycolic acid) (PLGA) because of the material's demonstrated safety in other FDA-approved medical devices, such as sutures.
To help the vehicles find their targets, the team coated their surfaces with aptamers that bind to a membrane protein found on prostate cancer cells. Aptamers have an advantage over antibody-targeted systems because they can be manufactured independently of biological systems, with less variability. The team added polyethylene glycol to the surface, helping the particles resist the body's efforts to break them down and flush them out. Dr. Farokhzad describes the resulting bioconjugates as "very small tennis balls - small enough that you could put 500 of them side-by-side to span the cross section of a piece of human hair - with molecules on the surface that look like pins."
The addition of aptamers to these nanoparticles gave promising results: in vitro, the bioconjugates killed about 30 percent more tumor cells than when docetaxel was given via aptamer-free particles. When mice xenografted with prostate cancer were given just one injection of the bioconjugate at their tumor site, their lesions shrank significantly, and in five of seven mice, the tumors disappeared within 6 weeks. Mice in the comparison groups saw less shrinkage and, in some cases, died.
All of the mice that received the bioconjugates survived the full length of the 109-day study and also maintained their body weight better than those that received straight docetaxel, indicating that the bioconjugate design may have shielded them from toxic side effects of the drug.
"The real advantages here are that the design gets the drug to the right place, and appears to avoid the toxicities and metabolic effects that have hampered some chemotherapy agents up to this point," says Dr. Gregory Downing, director of NCI's Office of Technology and Industrial Relations.
Dr. Farokhzad's group plans to continue their research with aptamer bioconjugates in larger animal models, and he projects human clinical studies in as little as 2 years. His team is pursuing bioconjugates that target atherosclerotic plaques for treatment of cardiovascular disease as well. Other research with aptamers has shown that they can be used to carry imaging agents, which may eventually be used to visualize the location and concentration of drugs at the subcellular level.
By building their bioconjugates from material known to be safe in humans, Dr. Downing says the MIT-Harvard researchers may have an advantage when it comes to eventual clinical testing and regulation. "But there are quite a number of questions that will need to be addressed," he says.
"At the nanoscale level, the fundamental properties of materials change," he continued. "The laws of pharmacokinetics are redefined, and the ability of these things to transfer across biological membranes, self-assemble, or take over molecular functions isn't really known yet."
This research was conducted in laboratories that are funded as the MIT-Harvard Center of Cancer Nanotechnology Excellence, part of NCI's Alliance for Nanotechnology in Cancer initiative that accelerates the application of promising nanotechnology to cancer.
By Brittany Moya del Pino