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Researchers test the efficacy of a new polymer that is an alternative to PEG for drugs used to treat type 2 diabetes.
Biomedical engineers at Duke University have reconfigured a popular drug-delivery technology to evade immune responses that have halted some clinical trials. Polyethylene glycol (PEG) is used as a thickener, solvent, softener, and moisture-carrier, but it can also be attached to active drugs in the bloodstream to slow the body’s clearing of them, greatly lengthening the duration of their effects. The pervasiveness of PEG in daily human life is causing many people to develop antibodies to the polymer. This has led some PEG-modified or PEGylated drugs to lose their longevity and has caused allergic reactions, some of which have been life-threatening.
In a new paper published on Nov. 28, 2016 in Nature Biomedical Engineering, Duke researchers reveal an altered version of PEG that seems to avoid recognition by PEG antibodies already present in individuals. The new technology also displays efficacy, controlling glucose levels in diabetic mice for up to four days when used with a drug that, without PEG, treats type 2 diabetes for just six hours.
The new PEG delivery system was initially developed by Ashutosh Chilkoti, the Alan L. Kaganov professor of Biomedical Engineering and chair of the Biomedical Engineering department at Duke, and graduate student Yizhi (Stacey) Qi to boost production efficiency. Conventional PEG drug-delivery polymers require labor-intensive synthesis and purification, but the new polymers are grown directly from a defined site on a drug molecule. The new polymer looks like a bottle cleaning brush, Duke said in a press release, with many short segments of ethylene glycol sticking out from a primary backbone.
“Growing the polymer directly on the drug is simpler and more efficient in terms of yield than the conventional process,” said Qi in a press release. “The boost in efficiency varies from protein to protein, but our yield is significantly higher and produces more uniform results.”
During a late-stage clinical trial for an anticoagulant that used PEG to extend its effectiveness, Bruce Sullenger, the Joseph W. and Dorothy W. Beard professor of Experimental Surgery and director of the Duke Translational Research Institute, noticed that 10 patients had an immediate, anaphylactic immune reaction because of pre-existing PEG antibodies.
“These allergic reactions stopped the development of an otherwise very promising approach to control blood clotting while limiting bleeding,” said Sullenger. “Because people with pre-existing PEG antibodies are now present in the population and such antibodies can elicit life-threatening allergic reactions, it has become critical for drug development to create alternative formulations of PEG.”
Chilkoti heard about this problem and thought that his lab’s PEG polymer might be a solution. Because each of the molecular chain bristles are so short, existing PEG antibodies might not be able to recognize them. Chilkoti and Qi turned to Michael Hershfield, professor of medicine and biochemistry at the Duke University School of Medicine.
“Nancy Ganson, a scientist in my lab, and I got involved with Professor Chilkoti’s project because we had discovered that anti-PEG antibodies were induced by our PEGylated gout drug during clinical trials” said Hershfield. “We later identified high levels of pre-existing anti-PEG antibodies in the first three patients who had allergic reactions to Dr. Sullenger’s PEGylated anticoagulant. Professor Chilkoti’s initial substitute for PEG still had a little bit of PEG on it, so we needed to see if anti-PEG antibodies could recognize it.”
On their second try at designing a suitable PEG substitute, the antibodies left the new compound alone. Qi then attached her new polymer to a drug used to treat type 2 diabetes and injected it into diabetic mice to see if the system still worked as well. There was almost no loss of efficacy, extending the effects of one drug 16-fold. The team now plans to test for immunological responses in living animals with preexisting PEG antibodies. They also need to determine whether antibodies will be created against the new polymers.
Source: Duke University