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Drug Delivery

Temperature-sensitive materials offer a quick off switch for drug delivery

GI tract devices stop releasing drug when hit with a sip or spray of warm water

by Alla Katsnelson, special to C&EN
April 18, 2019 | APPEARED IN VOLUME 97, ISSUE 16

09716-scicon5-figure2.jpg
Credit: Sci. Transl. Med
A device modeled on a blooming flower unfolds in the esophagus to deliver drugs through drug-loaded microneedles, and then refolds when its nitinol springs encounter warm water.

A cup of hot tea brings comfort on a cold evening, but less than a half cup of warm water might one day help deliver actual medicine. So say researchers who have created two different devices for delivering drugs to the gastrointestinal (GI) tract, using biomaterials that change their shape or properties when they come into contact with warm fluids (Sci. Transl. Med. 2019, DOI: 10.1126/scitranslmed.aau8581). Scientists seek better ways to control how drugs and therapeutic devices, like stents, do their job in the GI tract. For example, devices that release drugs slowly over time would be especially helpful for people who need long-term treatments, but the methods for regulating where and when the drugs get released and how the drug-carrying devices get eliminated safely from the body are limited. “We had this idea that we can use ingested warm water as a trigger for medical devices,” explains Sahab Babaee, a postdoctoral scholar in the lab of Robert Langer at the Massachusetts Institute of Technology.

To see if their plan would work, the researchers first characterized how heat dissipates in pigs’ GI tracts, which are similar to those of humans. With the animals seated upright, like how humans sit, the team used thermocouple probes to test how different volumes of water at 55 °C changed local temperatures at different points in the GI tract. Fluid holds heat well in the esophagus, they found, but dissipates by the time it gets to the stomach.

Using this information, the team designed two devices. The first one, based on the concept of a blooming flower, consists of four arms made of poly(e-caprolactone) (PCL), each harboring a tiny drug-loaded needle. These arms are connected with coils to a PCL core. In the esophagus, the coils spring open, activating the device and allow the needles to inject a drug into the esophageal wall. In experiments with esophageal tissue removed from the animal, the scientists demonstrated that the needle penetrated the tissue and delivered the asthma drug budesonide into it.

09716-scicon5-figure4.jpg
Credit: Sci. Transl. Med
A device made of foldable material travels down the esophagus in a compressed state, then opens up in the stomach for long-term drug delivery. Its thermoresponsive linkers disintegrate when sprayed with warm water.

The coils contain springs made of nitinol, a nickel-titanium alloy that changes shape at 55 °C. When ingested warm water hits the capsule-sized device, the nitinol pulls the arms back into the core, closing the device so that it can continue through the GI tract for elimination. Creating the device required carefully characterizing the number of coils and the coil diameter needed to generate the force necessary for them to open and close properly, says Giovani Traverso, a gastroenterologist at Brigham and Women’s Hospital, who co-led the work,

Delivery to the esophagus is important for conditions such as eosinophilia esophagitis, as well as certain types of cancers and infection. But “this is a region where it’s very hard to deliver drugs, and this is a really intriguing and smart approach to do it,” says Edith Mathiowitz, a biomedical engineer at Brown University, who wasn’t involved in the study.

The group designed their second device to sit in the stomach and deliver a steady dose of medicine over weeks or months. The researchers created a highly foldable structure that—with the help of gelatin capsules at each end—would remain compressed into a narrow cylinder as it traveled down the esophagus “That’s one of the biggest challenges for gastric devices—how do you get them there?” Traverso says. The gelatin quickly dissolves in stomach acid, allowing the device to open up into a cuboidal shape once it arrives in the stomach.

The device, made of PCL and other materials, consists of drug-loaded segments held together with thermoresponsive linkers that soften and disintegrate at about 55 °C. Most drug-delivery devices can carry a few hundred milligrams of a drug, but the researchers loaded this device with 3 g of the epilepsy drug carbamazepine, and found that the device released the drug steadily over two weeks in pigs’ stomachs. Finally, in a simple endoscopic operation, in which they inserted a tube down a pig’s esophagus into its stomach, they sprayed the device with warm water, causing it to break up into small pieces that could safely be eliminated through the GI tract.

Traverso hopes that other researchers will explore using temperature-responsive materials for drug delivery and other applications, such as biosensors or other types of medical devices.

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