“Having the capacity to deliver macromolecules really opens up the field as to what can be explored and delivered to the gastrointestinal tract, without any significant formulation,” said senior author Giovanni Traverso at Massachusetts Institute of Technology, Cambridge, US.
Ultrasound increased absorption of the small molecule mesalamine by an order of magnitude and made possible the absorption of the macromolecule insulin to the pig. The researchers plan to target ulcerative colitis in patients initially. “Initial treatment was with mesalamine, but it would be interesting to explore other molecules to treat colitis, including monoclonal antibodies,” said Traverso.
Accelerated colitis treatment
The research began after a patient suffering from colitis questioned if it was possible to accelerate the delivery of their therapeutic. It is reported in the journal Science Translational Medicine.
Medication for inflammatory bowel disease, or chronic inflammation of the gut, is usually effective, but often poorly or too slowly absorbed by the gut. The standard of care, known as enema, requires nightly self-administration of a drug into the bowel, a demanding regimen for many patients.
“It is challenging for these patients who may be suffering from diarrhea, to hold onto these medicaitons because of their underlying disease. And in the case of macromolecules such as proteins, those are digested in the gastrointestinal tract,” Traverso said.
The sound waves from the handheld device were emitted for a minute. Mice with acute colitis treated daily with ultrasound-delivered enema recovered much faster than mice treated with enema alone.
Boosting the amount of drug reaching the colon could potentially cut down patients’ dosing frequency from once a day to every other day. A miniaturized ultrasound probe for patients or even ingestible ultrasound-emitting capsules is possible, say the researchers, to treat inflammatory bowel disease and other gut diseases.
Clinically ultrasound between 3 and 15 megahertz is used for imaging; this case the ultrasound is lower in frequency, between 20 and 100 kilohertz, so high energy. At these frequencies, ultrasound has unique properties including the ability to temporarily increase permeability in a tissue and propel therapeutic substances inside via “transient cavitation.”
Gastrointestinal delivery
Delivering drugs through the gastrointestinal tract is highly attractive because of its potential to be minimally invasive and allow for more rapid take-up. Even the delivery of small molecules can be difficult, with drugs often requiring specialized formulations to stabilize the compound and provide optimal absorption.
“Drug delivery is sometimes hindered by formulation development, which can take a significant amount of time and can be costly. Here with ultrasound we were able to deliver macromolecules across a broad range of molecule types,” says Traverso.
The paper is interesting from a conceptual point of view, but very much a work in progress, comments Hugh Mulcahy at the Centre for Colorectal Disease at St Vincent’s University Hospital, Dublin, Ireland.
“The colitis models involved ASA agents (anti-inflammatory agents) given rectally,” he noted. “This might be potentially valuable for rectal administration, but there are no data to compare with oral administration.”