For people with diabetes, treatment can often mean drug injections, sometimes more than once per day. Fear of pain and needles leads some people to reduce or forgo their medication at the expense of controlling their blood glucose levels.
To make it easier for people to take their diabetes medicines, scientists have been working on oral delivery systems, notably for small peptides like insulin. Peptides typically can’t survive stomach acids, and they can’t squeeze between the cells lining the intestinal wall to reach the bloodstream. So they need specialized delivery systems to aid their passage.
Kathryn Whitehead, a drug delivery researcher at Carnegie Mellon University, thinks that negatively charged silica nanoparticles could help. Her team has demonstrated that tiny spheres of silica can shepherd insulin through the intestinal wall of diabetic and prediabetic mice, lowering their blood sugar levels (Nat. Biomed. Eng. 2019, DOI: 10.1038/s41551-019-0465-5).
Negatively charged nanoparticles seem to reduce electrical resistance across intestinal cells, temporarily relaxing the tight junctions between the cells. The particles likely achieve this effect by binding to receptors on the cells’ surfaces that are responsible for how strongly the cells stick to one another, Whitehead says. Once the particles have propped open the junctions between cells, insulin is free to pass through. The effect is almost like a slow-release insulin treatment, Whitehead adds.
Making the intestines reversibly permeable has been difficult, says drug delivery scientist Aaron Anselmo of the University of North Carolina Chapel Hill, who wasn’t involved in the new study. Many of the methods scientists have tried cause irreversible damage. He says finding a gentle way to widen and then narrow the spaces between intestinal cells is important to the field.
Also important is developing more gentle drug delivery methods for people who have to take medications frequently, Whitehead says. In addition to damaging intestinal structures, some of the polymers and hydrogels that scientists have previously tested for slipping treatments through the intestinal wall can elicit an immune response. People might accept some one-time discomfort if they have to take only a pill or two, Whitehead says, but with multiple doses, “there’s no way you want to be inducing any kind of adverse effect.”
After testing several sizes of nanoparticles, Whitehead and coworkers found that ones smaller than 100 nm improved insulin’s passage through mouse intestines. Then they fashioned a pill of nanoparticles and insulin that would survive stomach acid and make its way to the intestines. Within two hours of feeding the pill to mice, the researchers saw the animals’ blood sugar fall dramatically, and it stayed low for several hours. For a control group of diabetic mice who were given pills made without the nanoparticles, no drop in blood sugar occurred.
The team repeated the experiments with exenatide, a commercial diabetes peptide drug that’s usually administered by injection and maintains blood sugar through a different mechanism. The researchers saw similar results: the nanoparticles improved the amount of drug circulating in the bodies of diabetic mice.
Whitehead thinks what the particles are doing is binding to integrin receptors on the surface of intestinal epithelial cells. This binding event sets off a signaling system involving a protein called myosin light-chain kinase (MLCK). When activated, MLCK helps rearrange the internal scaffolding that gives cells their shape and coaxes them to hold tight against one another, as seen in places like the intestinal wall.
Anselmo says the work is exciting because it offers a reversible way to make the intestine permeable for drug delivery. Silica nanoparticles are often used in drug delivery studies because they are GRAS—generally regarded as safe—by the US Food and Drug Administration. Anselmo says the next step would be to see if the particles work in larger animals. No intestinal permeabilizers have survived clinical trials, and only recently has Rybelsus, the first GLP-1 oral diabetes drug, been approved by the FDA. Rybelsus delivers a small peptide and works similarly to exenatide.
“The work shown in this paper can open up a lot of opportunities in oral drug delivery,” Anselmo says.