A Delivery Service for Insulin

10 July 2024

Up to three percent of people with diabetes have an allergic reaction to insulin. A team at Forschungszentrum Jülich has now studied a method that could be used to deliver the active substance into the body in a masked form - in the form of tiny nanoparticles. The insulin is only released in the target organ when the pH value deviates from the slightly alkaline environment in the blood. The molecular transport system could also serve as a platform for releasing other drugs in the body precisely at the target site.

It's an old dream in pharmacy: to deliver an active ingredient to the exact place in the body where it is most needed - a cancer drug, for example, directly to the tumor tissue. This minimizes its side effects on other organs and ensures that it has its maximum effect at its target. "Targeted drug delivery" is the name of this concept. The actual active ingredient is packaged in a transport substance and thus introduced into the body. Once it reaches its destination, a certain stimulus (e.g. the oxygen content or pH value) ensures that the encapsulated cargo is released again.

A team at Forschungszentrum Jülich has just presented the concept for such a drug cab, which could benefit people with diabetes in particular. "Some of those affected are allergic to insulin - the drug that they have to use every day to adjust their blood sugar levels," explains Anastasiia Murmiliuk, a researcher at the Jülich Centre for Neutron Science (JCNS) who played a key role in the development and characterization of the molecular transport system.

Anastasiia Murmiliuk at the small-angle scattering diffractometer KWS-2 of the Heinz Maier-Leibnitz Zentrum (MLZ) in Garching at the rheometer. The MLZ is home to the largest branch of the Jülich Centre for Neutron Science.
Anastasiia Murmiliuk at the small-angle scattering diffractometer KWS-2 of the Heinz Maier-Leibnitz Zentrum (MLZ) in Garching at the rheometer. The MLZ is home to the largest branch of the Jülich Centre for Neutron Science.
Bernhard Ludewig, FRM II / TUM

An allergy to insulin is rare. But for people with type 1 diabetes in particular, there is no alternative to administering the messenger substance. Each time the insulin preparation is injected, the skin around the injection site reddens. The area swells, itches and hurts. It can even result in an anaphylactic reaction with shortness of breath and circulatory problems. "Our idea was to mask the insulin for the immune system. To do this, we selected a synthetic polymer that binds the insulin to itself," says the chemist.

The complexes of insulin and polymer molecules combine to form nanoparticles and can then be transported in the blood vessels to the organs. In the slightly alkaline environment of the blood, the two components initially remain firmly bound together. In the tissue, however, the pH value changes - and insulin and polymer separate from each other.

"Polymers, i.e. long chain molecules, are fascinating compounds. Their properties can be tailored to specific applications," says Anastasiia Murmiliuk. The polymer that the researcher selected for insulin transport is biodegradable and consists of two units: a water-loving part that ensures solubility and stability in the blood, and a charged part that binds the insulin.

Customized polymer

The polymer for insulin transport consists of two units: Longer chain segments made of polyethylene glycol ensure that the complexes are well compatible with water (and therefore also with blood). Connected to them are shorter chain segments that carry positive charges. These are crucial for the polymer to attach to insulin, which itself is negatively charged under the pH value of the blood. The electrostatic interaction between the positive and negative charges ensures that tiny particles just forty nanometers in size are formed from the two components. The pH value at which the two components separate again can be controlled to a certain extent by chemically modifying the polymer.

Using various scattering methods, the team from Jülich was able to determine not only the size of the particles, but also their internal structure: The water-loving sections of the polymer form the outer shell of the particles, while the charged chain parts nestle against the insulin on the inside. "We were able to show that three insulin molecules are closely packed together," explains Anastasiia Murmiliuk. In many conventional preparations, insulin is present in dissolved form in a six-pack, which then has to gradually break down into the active individual molecules. The three-pack in the nanocarriers could therefore act more quickly.

The small-angle neutron scattering method has proven to be particularly useful for studying the polymer insulin particles, says Aurel Radulescu, neutron scattering expert at JCNS: "Unlike X-rays, neutrons can 'see' the hydrogen in a sample and distinguish between hydrogen and deuterium (heavy hydrogen). If we replace the hydrogen in all but one component of the nanoparticles with deuterium, we can specifically visualize only this one component, i.e. only the polymer or only the insulin. In this way, we can selectively create the contrast between the two components and the solvent and see in detail how our drug-taxi is constructed.

"It was particularly important to analyze a broad size range from a few angstroms to micrometers with the same neutron instrument to ensure a thorough structural analysis of the polymer-protein complexes and their larger assemblies. There are very few small-angle neutron diffractometers in the world that offer this capability, and we included some in our study," says Radulescu.

Aurel Radulescu and Anastasiia Murmiliuk in front of the SANS-J small-angle neutron diffractometer at the Japan Research Reactor JRR-3 in Tokai, Japan
Aurel Radulescu and Anastasiia Murmiliuk in front of the SANS-J small-angle neutron diffractometer at the Japan Research Reactor JRR-3 in Tokai, Japan
Japan Atomic Energy Research Institute

So far, the team has only been able to show in the laboratory that the molecular transporter works. Studies in blood and tissue samples are still pending. Nevertheless, the researchers believe that complexes of a synthetic polymer and a natural protein such as insulin can be developed into a pharmaceutical platform. And this would allow not only insulin, but also a variety of active substances to be efficiently introduced into the body: "We tried this out with a dye that occurs in a similar form in blood or in leaf green and is used to diagnose and treat cancer. It was trapped in the nanoparticles and was released after the pH value had changed significantly as the particles fell apart."

In future, this could also be used to encapsulate active ingredients that are poorly soluble in water. Radulescu and Murmiliuk are thinking primarily of anticancer drugs. Since tumors have a different pH value than other cells, this approach can be used to deliver anticancer drugs directly to cancer cells without harming "healthy" cells.

Original publication: Anastasiia Murmiliuk, Aurel Radulescu et al.: Polyelectrolyte-protein synergism: pH-responsive polyelectrolyte/insulin complexes as versatile carriers for targeted protein and drug delivery, Journal of Colloid And Interface Science 665 (2024) 801-813
DOI: 10.1016/j.jcis.2024.03.156


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    Last Modified: 10.07.2024