As revolutionary as glucagon-like peptide 1 (GLP-1) drugs are, they still last for only so long in the body. Patients with diabetes typically must be injected once or twice a day (liraglutide) or once a week (semaglutide). This could hinder proper diabetes management, as adherence tends to go down the more frequent the dose.
But what if a single GLP-1 injection could last for 4 months?
Stanford engineers have developed an injectable hydrogel depot that releases GLP-1 slowly as the hydrogel gradually “melts away like a sugar cube dissolving in water, molecule by molecule,” said Eric Appel, PhD, the project’s principal investigator and an associate professor of materials science and engineering at Stanford.
So far, the team has tested the new drug delivery system in rats, and they say human clinical trials could start within 2 years.
Mathematical modeling indicated that one shot of liraglutide could maintain exposure in humans for 120 days, or about 4 months, according to their study in Cell Reports Medicine.
“Patient adherence is of critical importance to diabetes care,” said Alex Abramson, PhD, an assistant professor in the chemical and biomolecular engineering department at Georgia Tech, who was not involved in the study. “It’s very exciting to have a potential new system that can last 4 months on a single injection.”
Long-Acting Injectables Have Come a Long Way
The first long-acting injectable — Lupron Depot, a monthly treatment for advanced prostate cancer — was approved in 1989. Since then, long-acting injectable depots have revolutionized the treatment and management of conditions ranging from osteoarthritis knee pain to schizophrenia to opioid use disorder. In 2021, the US Food and Drug Administration approved Apretude — an injectable treatment for HIV pre-exposure prevention that only needs to be given every 2 months, compared with daily for the pill equivalent. Other new and innovative developments are underway: Researchers at the University of Connecticut are working on a transdermal microneedle patch — with many tiny vaccine-loaded needles — that could provide multiple doses of a vaccine over time, no boosters needed.
At Stanford, Appel’s lab has spent years developing gels for drug delivery. His team uses a class of hydrogel called polymer-nanoparticle (PNP), which features weakly bound polymers and nanoparticles that can dissipate slowly over time.
The goal is to address a longstanding challenge with long-acting formulations: Achieving steady release. Because the hydrogel is “self-healing” — able to repair damages and restore its shape — it’s less likely to burst and release its drug cargo too early.
“Our PNP hydrogels possess a number of really unique characteristics,” Appel said. They have “excellent” biocompatibility, based on animal studies, and could work with a wide range of drugs. In proof-of-concept mouse studies, Appel and his team have shown that these hydrogels could also be used to make vaccines last longer, ferry cancer immunotherapies directly to tumors, and deliver antibodies for the prevention of infectious diseases like SARS-CoV-2.
Though the recent study on GLP-1s focused on treating type 2 diabetes, the same formulation could also be used to treat obesity, said Appel.
The researchers tested the tech using two GLP-1 receptor agonists — semaglutide and liraglutide. In rats, one shot maintained therapeutic serum concentrations of semaglutide or liraglutide over 42 days. With semaglutide, a significant portion was released quickly, followed by controlled release. Liraglutide, on the other hand, was released gradually as the hydrogel dissolved. This suggests the liraglutide hydrogel may be better tolerated, as a sudden peak in drug serum concentration is associated with adverse effects.
The researchers used pharmacokinetic modeling to predict how liraglutide would behave in humans with a larger injection volume, finding that a single dose could maintain therapeutic levels for about 4 months.
“Moving forward, it will be important to determine whether a burst release from the formulation causes any side effects,” Abramson noted. “Furthermore, it will be important to minimize the injection volumes in humans.”
But first, more studies in larger animals are needed. Next, Appel and his team plan to test the technology in pigs, whose skin and endocrine systems are most like humans’. If those trials go well, Appel said, human clinical trials could start within 2 years.
Sources
Eric Appel, PhD, is an associate professor of materials science and engineering at Stanford University, and Alex Abramson, PhD, is an assistant professor in the chemical and biomolecular engineering department at Georgia Tech.
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