Drugs delivered by nanoparticles hold promise for targeted treatment of many diseases, including cancer. However, the particles have to be injected into patients, which has limited their usefulness so far.
Now, researchers from MIT and Brigham and Women’s Hospital (BWH) have developed a new type of nanoparticle that can be delivered orally and absorbed through the digestive tract, allowing patients to simply take a pill instead of receiving injections.
In a paper appearing in the Nov. 27 online edition of Science Translational Medicine, the researchers used the particles to demonstrate oral delivery of insulin in mice, but they say the particles could be used to carry any kind of drug that can be encapsulated in a nanoparticle. The new nanoparticles are coated with antibodies that act as a key to unlock receptors found on the surfaces of cells that line the intestine, allowing the nanoparticles to break through the intestinal walls and enter the bloodstream.
This type of drug delivery could be especially useful in developing new treatments for conditions such as high cholesterol or arthritis. Patients with those diseases would be much more likely to take pills regularly than to make frequent visits to a doctor’s office to receive nanoparticle injections, say the researchers.
“If you were a patient and you had a choice, there’s just no question:
Patients would always prefer drugs they can take orally,” says Robert Langer, the David H. Koch Institute Professor at MIT, a member of MIT’s Koch Institute for Integrative Cancer Research, and an author of the Science Translational Medicine paper.
Lead authors of the paper are former MIT grad student Eric Pridgen and former BWH postdoc Frank Alexis, and the senior author is Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at BWH. Other authors are Timothy Kuo, a gastroenterologist at BWH; Etgar Levy-Nissenbaum, a former BWH postdoc; Rohit Karnik, an MIT associate professor of mechanical engineering; and Richard Blumberg, co-director of BWH’s Biomedical Research Institute.
No more injections
Several types of nanoparticles carrying chemotherapy drugs or short interfering RNA, which can turn off selected genes, are now in clinical trials to treat cancer and other diseases. These particles exploit the fact that tumors and other diseased tissues are surrounded by leaky blood vessels. After the particles are intravenously injected into patients, they seep through those leaky vessels and release their payload at the tumor site.
For nanoparticles to be taken orally, they need to be able to get through the intestinal lining, which is made of a layer of epithelial cells that join together to form impenetrable barriers called tight junctions.
“The key challenge is how to make a nanoparticle get through this barrier of cells. Whenever cells want to form a barrier, they make these attachments from cell to cell, analogous to a brick wall where the bricks are the cells and the mortar is the attachments, and nothing can penetrate that wall,” Farokhzad says.
Researchers have previously tried to break through this wall by temporarily disrupting the tight junctions, allowing drugs through.
However, this approach can have unwanted side effects because when the barriers are broken, harmful bacteria can also get through.
To build nanoparticles that can selectively break through the barrier, the researchers took advantage of previous work that revealed how babies absorb antibodies from their mothers’ milk, boosting their own immune defenses. Those antibodies grab onto a cell surface receptor called the FcRN, granting them access through the cells of the intestinal lining into adjacent blood vessels.
The researchers coated their nanoparticles with Fc proteins — the part of the antibody that binds to the FcRN receptor, which is also found in adult intestinal cells. The nanoparticles, made of a biocompatible polymer called PLA-PEG, can carry a large drug payload, such as insulin, in their core.
After the particles are ingested, the Fc proteins grab on to the FcRN in the intestinal lining and gain entry, bringing the entire nanoparticle along with them.
“It illustrates a very general concept where we can use these receptors to traffic nanoparticles that could contain pretty much anything. Any molecule that has difficulty crossing the barrier could be loaded in the nanoparticle and trafficked across,” Karnik says.
The researchers’ discovery of how this type of particle can penetrate cells is a key step to achieving oral nanoparticle delivery, says Edith Mathiowitz, a professor of molecular pharmacology, physiology, and biotechnology at Brown University.
“Before we understand how these particles are being transported, we can’t develop any delivery system,” says Mathiowitz, who was not part of the research team.
Breaking through barriers
In this study, the researchers demonstrated oral delivery of insulin in mice. Nanoparticles coated with Fc proteins reached the bloodstream 11-fold more efficiently than equivalent nanoparticles without the coating. Furthermore, the amount of insulin delivered was large enough to lower the mice’s blood sugar levels.
Good News on the Alzheimer’s Epidemic: Risk for Older Adults on the Decline NEJM perspective highlights effects of education, health and other changes in behavior on dementia and Alzheimer’s disease Source Newsroom: University of Michigan Health System
People are less likely to experience dementia and Alzheimer's disease today than they were 20 years ago – and those who do may be developing it later in life – says a new perspective article in the New England Journal of Medicine that examines the positive trends in dementia.
Authors examined five recent studies that suggest a decrease in the prevalence of dementia, crediting the positive trend to improvements in education levels, health care and lifestyle.
“We’re very encouraged to see a growing number of studies from around the world that suggest that the risk of dementia may be falling due to rising levels of education and better prevention and treatment of key cardiovascular risk factors such as high blood pressure and cholesterol,”
says co-author Kenneth Langa, M.D., Ph.D., a professor of Internal Medicine at the U-M Medical School and research investigator at the Center for Clinical Management Research (CCMR), VA Ann Arbor Healthcare System.
“Our findings suggest that, even if we don't find a cure for Alzheimer's disease and dementia, there are social and lifestyle factors we can address to decrease our risk.”
Authors also include Eric B. Larson, M.D., M.P.H., executive director of Group Health Research Institute and Group Health’s vice president for research; and Kristine Yaffe, M.D., a professor of psychiatry, neurology, and epidemiology and biostatistics at the University of California, San Francisco. Larson is also an adjunct professor at the University of Washington Schools of Medicine and Public Health.
Authors point to two key factors that may explain the decreased risk of dementia over the last few decades: People are completing more years of school, which helps the brain fight off dementia; and there’s more awareness and focus on preventing heart disease, another big risk factor for Alzheimer’s.
“The growing number of older adults in the U.S. and around the world means we will undoubtedly see a significant growth in the number of people with dementia, however the good news is they appear to be living longer without experiencing it,” says Langa, who is also a member of the U-M Institute for Social Research, Institute of Gerontology and Institute for Healthcare Policy and Innovation.
“We are seeing a positive trend that suggests that improving our physical and mental health go hand in hand with fighting off this devastating condition.”
In 2008, Langa and Larson reported one of the first studies suggesting a decline in U.S. dementia rates, using information from the U.S. Health and Retirement Study. They found that decline tracked with education and improvements in health care and lifestyle. Since then, several studies in Europe have confirmed this trend—and the reasons behind it.
Other research has also shown that other factors decreasing risk include early and ongoing education, physical activity, retiring later, educated parents (especially an educated mother), maintaining social activities and getting treatment for depression.