Tag Archives: BWH

Inspired by babies, scientists consider* popping nanoparticle pills and downing nanoparticle potions

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.

*  ‘consdier’ corrected to ‘consider’ on June 5, 2014.

Inflammation isn’t all bad but sometimes you need to reduce it with nanomedicines

Researchers from Brigham and Women’s Hospital (BWH), Columbia University Medical Center, Icahn School of Medicine at Mount Sinai, and Massachusetts Institute of Technology (MIT) have published about a study about their use of nano-sized particles to release therapeutic drugs that are designed to relieve chronic inflammation. From the Mar. 18, 2013 news release on EurekAlert,

Inflammation is the body’s natural defense mechanism against invading organisms and tissue injury. In acute inflammation, the pathogen or inflammatory mediators are cleared away and homeostasis is reached, however in chronic inflammatory states, this resolving response is impaired, leading to chronic inflammation and tissue damage. It is now widely believed that an impaired resolution of inflammation is a major contributing factor to the progression of a number of devastating diseases such as atherosclerosis, arthritis, and neurodegenerative diseases, in addition to cancer. Since the level of inflammation in these diseases is very high—targeted therapeutic solutions are required to help keep inflammation contained.

A new study from researchers at Brigham and Women’s Hospital (BWH), Columbia University Medical Center, Icahn School of Medicine at Mount Sinai, and Massachusetts Institute of Technology presents the development of tiny nanomedicines in the sub 100 nm range (100,000 times smaller than the diameter of a human hair strand) that are capable of encapsulating and releasing an inflammation-resolving peptide drug. The authors showed that these nanoparticles are potent pro-resolving nanomedicines, capable of selectively homing to sites of tissue injury in mice, and releasing their therapeutic payload in a controlled manner over time. Uniquely, these nanoparticles are designed to target the extracellular microenvironment of inflamed tissues. The particles then slowly release their potent inflammation-resolving payload such that it can diffuse through the inflamed tissue. There the drug binds to receptors on the plasma membrane of activated white blood cells and causes them to become more quiescent.

The research will be published some time this week (week of Mar. 18, 2013) by the Proceedings of the National Academy of Science. The news release offers more detail about the work,

“The beauty of this approach is that it takes advantage of nature’s own design for preventing inflammation-induced damage, which, unlike many other anti-inflammatory strategies, does not compromise host defense and promotes tissue repair,” said Ira Tabas, MD, PhD, physician-scientist at Columbia University Medical Center and co-senior author of this study.

“The development of self-assembled targeted nanoparticles which are capable of resolving inflammation has broad application in medicine including the treatment of atherosclerosis,” said Omid Farokhzad, MD, physician-scientist at BWH, and a co-senior author of this study.

Polymers consisting of three chains attached end-to-end were developed as building blocks for the engineering of self-assembled targeted nanoparticles; one chain enabled the entrapment and controlled release of the therapeutic payload, in this case a peptide which mimics the pro-resolving properties of the Annexin A1 protein. Another chain conferred stealth properties to the nanoparticles, enabling their long-circulation after systemic administration. Yet a third chain gave homing capability to the nanoparticles to target the collagen IV protein to the vascular wall. As such these nanoparticles are capable of selectively sticking to injured vasculature allowing their therapeutic anti-inflammatory cargo to be released where it is needed to effectively promote inflammation resolution in a deliberate and targeted manner.

“These targeted polymeric nanoparticles are capable of stopping neutrophils, which are the most abundant form of white blood cells, from infiltrating sites of disease or injury at very small doses. This action stops the neutrophils from secreting further signaling molecules which can lead to a constant hyper-inflammatory state and further disease complications,” said Nazila Kamaly, PhD, a postdoctoral fellow at BWH and co-lead author of this study.

“Nanoparticles that selectively bind to injured vasculature could have a profound impact in prevalent diseases, such as atherosclerosis, where damaged or comprised vasculature underlie the pathology. This work offers a novel targeted nanomedicine to the burgeoning field of inflammation-resolution, a field previously pioneered by BWH’s Dr. Charles Serhan,” said Gabrielle Fredman, PhD, a post-doctoral fellow at Columbia University Medical Center and co-lead author of this study.

These new developments have led the researchers to start investigating the potential of these pro-resolving nanomedicines for their effects on shrinking atherosclerotic plaques, and these studies are currently underway.

This news release does not offer any information as to what type of studies might be underway. My guess is that we are still years away from human clinical trials. Azonano also features this work in a Mar. 19, 2013 news item.