Nanogel against hyperglycemia
Glucose-sensitive nanogel successfully fights hyperglycemia in rats
Arkady Kuramshin, "Elements"
Fig. 1. The behavior of a glucose-sensitive nanogel depending on its concentration in the blood. The action of the nanogel is based on the reversible reaction of glucose with the residues of boronic acid, which is part of the polymer from which the nanogel is made. At high glucose levels, its molecules bind with a polymer, preventing hyperglycemia in experimental animals, and with a decrease in blood glucose, they are partially released from the polymer "sponge", preventing the development of hypoglycemic syndrome. A drawing from the article under discussion in Nanoscale.
Researchers from Canada suggest a non–hormonal – not requiring, in particular, insulin injections - way to cope with high blood glucose. A new approach to combating hyperglycemia is based on the use of a nanogel that can reversibly absorb glucose molecules from the blood. Experiments on rats have shown that a single administration of such a nanogel allows you to maintain normal glucose levels for six hours. It is assumed that nanogel can be used in the treatment of diabetes in patients who, for various reasons, are not helped by insulin.
Whatever carbohydrates we consume with food (nutritionists distinguish between fast carbohydrates, which, for example, include sucrose and fructose, and slow – starch, glycogen), as a result of biochemical reactions, they turn into glucose – the main carbohydrate of the blood and the whole body, the main and universal source of energy for it.
The main role in the regulation of carbohydrate metabolism of the body is played by insulin, the hormone of the pancreas. This protein stimulates the processing of glucose by cells. Almost all tissues and organs (for example, liver, muscles, adipose tissue) are able to process glucose only in its presence. Glucose, which the body does not process into chemical energy immediately after its receipt, is stored in the liver and muscles in the form of glycogen polysaccharide – insulin is also needed for this process.
However, it may happen that the body produces less insulin than it needs, or the mechanism of interaction of insulin with cells is disrupted in it. Because of this, glucose begins to accumulate in the blood (hyperglycemia develops), and most of the organs lose their main source of energy. This pathological condition is characteristic of diabetes mellitus – a chronic disease, the peculiarity of which is a violation of all types of metabolism: carbohydrate, fat, protein, mineral and water-salt.
Type 1 diabetes (juvenile diabetes) is characterized by the development of absolute lifelong insulin deficiency. In type 2 diabetes, insulin is produced in normal or even increased amounts, but the mechanism of interaction of insulin with the body's cells is disrupted. According to WHO estimates, diabetes ranks seventh among the causes of death. As of 2014, 422 million diabetic patients were registered in the world, and according to 2016 data, 1.6 million deaths were directly caused by this disease. Diabetes is one of the main causes of blindness, kidney failure, heart attacks, strokes and other serious health problems: increased blood glucose over time leads to serious damage to many body systems, especially the nervous and circulatory.
About 10% of people diagnosed with diabetes suffer from type 1 diabetes, which requires daily insulin injections. But for some categories of patients, insulin therapy is moderately effective or completely ineffective – first of all, these are HIV patients or those suffering from obesity (E. R. Feeney, P. W. Mallon, 2011. Insulin resistance in treated HIV infection).
Since insulin injections are not always a panacea, new forms of diabetes mellitus treatment are being actively developed, which is primarily required by people with insulin resistance. There are many different approaches here. One of them is connected with "smart" polymer materials that are capable of forming nanoscale particles of gels compatible with the body, the so–called medical nanogels.
Such nanogels were tried to be used as a "sponge", which, getting into the blood of a diabetic patient, slowly releases hormones that ease the patient's condition. This method proved difficult to implement in practice due to the low stability of hormones (J. Li et al., 2017. Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices). Therefore, methods began to develop in which polymer nanogels should work as a "vacuum cleaner", reversibly binding glucose molecules contained in the blood and thus maintaining the desired blood sugar level.
Such nanogels should use substances whose functional groups are capable of binding glucose. And since these nanogels will have to work in human blood, these substances should dissolve well in water and be biologically compatible. Glucose binds to various proteins, but the most effective of them, concanavalin A, unfortunately, exhibits an immunogenic effect (W. Li et al., 2011. Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics).
Another promising substance suitable for the manufacture of "anti-glucose" nanogels are boronic acids and their derivatives, which are also capable of reacting with glucose. Researchers from the University of Toronto, led by Shirley Wu, within the framework of this approach, suggested that a gel containing a polymer with residues of boronic acids (for binding sugars in the blood) and a zwitter-ion polymer (for more effective biological compatibility) would have the necessary properties. A zwitter ion is a molecule that, being generally electroneutral, has parts with negative and positive charges. Firstly, zwitter-ion polymers dissolve well in water, which simplifies their transfer through the circulatory system. Secondly, since most proteins themselves are zwitter ions, nanogels from synthetic zwitter-ion polymers remain stable in biological fluids (A. G. Nejad et al., 2016. In Situ Synthesis of Antimicrobial Silver Nanoparticles within Antifouling Zwitterionic Hydrogels by Catecholic Redox Chemistry for Wound Healing Application).
To test their assumptions, Shirley Wu and colleagues received an injectable nanogel. To do this, one of the polymer precursors was first synthesized – a monomer containing a fragment of boronic acid – 4-acrylamido-3-fluorophenylboronic acid (AFBA). In order for the residue of boronic acid to reversibly bind glucose at a physiological blood pH value (7.35–7.45), a fluorine atom was introduced into the benzene ring, the electronic effects of which "fine-tuned" the strength of boronic acid. From this monomer and the zwitter-ion structure monomer (SBMA), a copolymer was obtained by radical polymerization, which self-organized into a nanogel in an aqueous medium. SEM and PEM studies have shown that the copolymer particles are spheres with an average diameter of 400 nanometers (Fig. 2).
Fig. 2. On the left are the chemical formulas of monomers, which make up polymers that form a glucose–sensitive nanogel. On the right are the particles of this nanogel, the image was obtained using scanning electron microscopy. A drawing from the article under discussion in Nanoscale.
Glucose–sensitive nanogels can both absorb and release glucose - it all depends on the concentration of glucose in the blood. As schematically shown in Fig. 1, at a high concentration of glucose, it forms compounds of the composition 1:1 with the residues of boronic acid located on different polymer strands. This leads to the swelling of the nanogel particle and the storage of glucose molecules in it. A decrease in the glucose content in the blood leads to the fact that the equilibrium shifts and the nature of the binding of glucose with fragments of boronic acid changes: at low concentrations, one fragment of glucose acts as a bridge linking two boron-containing fragments at opposite ends of the polymer chain. At the same time, excess glucose, which was previously associated with the cross–linked residue of boronic acid, is released and cross-linking of polymers occurs and, as a consequence, a decrease in the volume of nanogel particles.
Nanogel was tested on laboratory rats, in which type 1 diabetes was forcibly induced for this purpose. To do this, the rats were given streptozotocin for two weeks, a substance that destroys cells that produce insulin. Rats with a blood glucose content of 17 mmol/l were selected for the test (a person with such a glucose level is on the verge of falling into a diabetic coma). The rats were divided into four groups. The first was given a subcutaneous injection of nanogel (dosage 83 mg/ kg), two were injected with recombined human insulin in different dosages, and one (control) group was left untreated. Another control group was represented by healthy rats injected with nanogel. The glucose content in the blood of the subjects was measured 15 minutes after injection and then every 15 minutes, while the sugar level remained within the euglycemic window (the optimal concentration of glucose in the blood for the body, in Fig. 3 it is shown by an orange rectangle).
Fig. 3. Testing the effectiveness of glucose-sensitive nanogel in rats. The lines of different colors correspond to groups of rats that were given different substances. The orange rectangle is the euglycemic window. A drawing from the article under discussion in Nanoscale.
Tests have shown that when the nanogel is administered, the glucose level drops somewhat slower than after an insulin injection, but at the same time the normal blood sugar content of the rodent is maintained for six hours. For comparison: when insulin was administered at a normal dosage (during this particular study), the blood sugar content began to exceed the norm within three hours after injection, and with an increased dosage, a lack of sugar in the blood was observed within an hour after administration. The polymer nanogel does not affect the glucose content in the blood of healthy rats (but an insulin injection to healthy rodents would lead to a drop in blood sugar and hypoglycemic shock). Simply put, glucose-sensitive polymer nanogels more effectively regulated the glucose content in the blood of diabetic rats than insulin.
But, despite the optimistic results of tests on laboratory animals, before testing on humans, this nanogel must pass quite a few more tests, the purpose of which is to prove the safety of the drug for humans.
Source: Nejad et al., Glucose regulation by modified boronic acid-sulfobetaine zwitterionic nanogels – a non-hormonal strategy for the potential treatment of hyperglycemia // Nanoscale. 2019.
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