Given the choice over injections or suppositories most of us will choose to take medication orally (pills or liquids). It may be a surprise to some but with all the talk about nanomedicine there has been a problem with using nanoparticles in an oral delivery system which scientists at the Brigham and Women’s Hospital (BWH) and Massachusetts Institute of Technology (MIT) have solved. From a Nov. 27, 2013 BWH news release, on EurekAlert,
… a study led by researchers at Brigham and Women’s Hospital (BWH) and Massachusetts Institute of Technology (MIT) is the first to report in the field of nanomedicine a new type of nanoparticle that can be successfully absorbed through the digestive tract. The findings may one day allow patients to simply take a pill instead of receiving injections.
Until recently, after being injected into the body, nanoparticles travelled to their destination, such as a tumor, by seeping through leaky vessels. The research team, led by Farokhzad [Omid Farokhzad, MD, director of the BWH Laboratory of Nanomedicine and Biomaterials, senior study author] and Robert Langer, ScD of MIT, developed nanoparticles that could reach the target site without relying on injection nor leaky vessels.
For nanoparticles to be taken orally they need to cross the intestinal lining. This lining is composed of a layer of epithelial cells joined together to form impenetrable barriers called tight junctions. To ensure that the nanoparticles could cross these barriers, the researchers took a cue from research on how babies absorb antibodies from their mothers’ milk. The antibodies would grab onto a receptor, known as neonatal Fc receptors, found on the cell surface. This gave them access across the cells of the intestinal lining into neighboring blood vessels.
Based on this knowledge, the researchers decorated nanoparticles with Fc proteins that targeted and bound to these receptors, which are also found in adult intestinal cells. After attaching to the receptors, the Fc-protein-decorated nanoparticles—toting their drug payload—are all absorbed into the intestinal lining and into the bloodstream at a high concentration.
According to the researchers, these receptors can be used to transport nanoparticles carrying different kinds of drugs and other materials—a feat that combines a versatile vehicle and an easily accessible passageway across cellular barriers.
To demonstrate how transport of Fc-targeted nanoparticles could impact the clinical space, the researchers focused on a diabetes treatment scenario, showing how oral delivery of insulin via these targeted nanoparticles could alter blood sugar levels in mice.
Insulin carried in nanoparticles decorated with Fc proteins reached the bloodstream more efficiently than those without the proteins. Moreover, the amount of insulin delivered was large enough to lower the mice’s blood sugar levels. Aside from insulin, the researchers note that the nanoparticles can be used to carry any kind of drug to treat many diseases.
“Being able to deliver nanomedicine orally would offer clinicians broad and novel ways to treat today’s many chronic diseases that require daily therapy, such as diabetes and cancer,” said Langer. “Imagine being able to take RNA or proteins orally; that would be paradigm shift.”
In terms of next steps, the researchers are working to enhance the nanoparticles’ drug-releasing abilities to prepare for future pre-clinical testing with insulin and other drugs. They also plan to design nanoparticles that can cross other barriers, such as the blood-brain barrier, which prevents many drugs from reaching the brain.
The Nov. 27, 2013 MIT news release by Anne Trafton on EurekAlert provides additional insight into the difficulties of getting nanoparticles past our digestive tracts (this is a bit repetitive but there’s enough new detail to make it worth my while to include it here),,
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 [Rohit Karnik, an MIT associate professor of mechanical engineering] says.
Here’s a link to and a citation for the article,
Transepithelial Transport of Fc-Targeted Nanoparticles by the Neonatal Fc Receptor for Oral Delivery by Eric M. Pridgen, Frank Alexis, Timothy T. Kuo, Etgar Levy-Nissenbaum, Rohit Karnik, Richard S. Blumberg, Robert Langer, and Omid C. Farokhzad.
Sci Transl Med 27 November 2013: Vol. 5, Issue 213, p. 213ra167 DOI: 10.1126/scitranslmed.3007049
This article is behind a paywall.