The fight against neurodegenerative diseases, including Parkinson's disease (PD), is a global challenge of this century. The effectiveness of current PD therapy is limited, since it is diagnosed many years after the onset, following the death of most nigrostriatal dopaminergic neurons regulating motor function. PD treatment could be greatly improved if it was started at an early (preclinical) stage. For this purpose, it is necessary to develop an early diagnosis of PD, which is the goal of our study. We have developed an early diagnosis of PD on animal models using a provocative test by intranasal administration of α-methyl-p-tyrosine methyl ester (αMPTME), a reversible inhibitor of dopamine synthesis. First, we produced the provocative agent, αMPTME in gel, and showed its safety and penetration into the brain bypassing the blood-brain barrier. Then, the optimal dose of αMPTME and time after administration were selected, at which the level of dopamine in the striatum of intact animals decreases, but does not reach the 30% threshold for the appearance of motor disorders in PD patients. Finally, we proved on animal models that intranasal administration of αMPTME can serve as a diagnostic test for preclinical PD. Indeed, intranasal administration of αMPTME to mice in a model of PD at the preclinical stage reversibly reduced the dopamine level in the striatum to the 30% threshold causing short-term motor disorders. Thus, using animal models of PD, we have developed a provocative test for the preclinical diagnosis of PD, a fundamentally new technology in neurology.
A method to increase the thromboresistance of the biospecific antiproteinase hemosorbent was suggested based on simultaneous immobilization of duck egg ovomucoid and blood anticoagulant—heparin or hirudin—in the bulk of polyacrylamide hydrogel. It was demonstrated that modification of the hemosorbent with hirudin resulted in a significant increase of its compatibility with blood with simultaneous preservation of high capacity with regards to serine proteinases.
The effect of the structure of a mucoadhesive, insulin-containing, polymeric hydrogel on the rate of hormone release was studied. It has been shown that a decrease in the pore size of the hydrogel leads to an increase in the rate of insulin release, which contributes to a reduction in the time to achieve a positive effect upon oral administration of the drug while maintaining the physiological pathway of hormone penetration of the blood through the liver.
The effect of the chemical structure of crosslinking agents on the activity of proteins in hydrogels obtained by the copolymerization of acrylamide, a crosslinking agent, and an unsaturated protein derivative is studied. It is shown that interaction between units of the hydrophobic crosslinking agent which increases with an increase in the length of the aliphatic region between the double bonds of the crosslinking agent leads to an additional "hydrophobic crosslinking" of macromolecules and causes a decrease in the activity of the immobilized protein.
The copolymers of methacryloylguanidine hydrochloride with methacrylamide and diallyldimethylammonium chloride are synthesized by radical polymerization. The reactivity ratios of these monomers are determined, and the dependence of the biocidal activity of the copolymers on the structure of the macromolecule chain is studied. It is shown that manifestation of the biocidal activity is determined not only by the composition of the copolymer but also by the nature of the distribution of methacryloylguanidine hydrochloride units along the macromolecule chain.
On the example of published and new experimental data, it was shown that insulin-containing hydrogels based on copolymers of N-(2-D-glucose)acrylamide and acrylamide crosslinked by Concanavalin A can simulate one of the functions of the pancreas, i.e., they can secrete insulin upon an increase in the glucose concentration in the surrounding medium, including a two-stage mechanism with the maximum rate in the first stage.
The method of obtaining hydrogels from sodium alginate interpolymer complexes with the copolymer of methyl vinyl ether and maleic anhydride is developed. It is shown that the interpolymer network is formed via hydrogen bonding between the hydroxyl groups of alginate and the carboxyl groups of the copolymer. The structure of the network, namely, the type of bonds and their density, is primarily controlled by the treatment temperature of the polymer mixture. Using lidocaine as a model drug, it is demonstrated that these complexes can be used as a platform for рН-tunable drug delivery systems.
The dependence of the activity of immobilized trypsin on the conformation of the polymer carrier macromolecule was studied. Fluorescence spectroscopy shows that immobilization of the enzyme on a rigid polymer chain prevents the association of enzyme molecules and ensures the availability of its active centers, even for high-molecular-weight molecules.
Polymeric derivatives of proteins are synthesized by the reaction of the amino groups of proteins with N,N-diethylacrylamides containing terminal carboxyl groups, having a molecular weight of (13–62) × 103, and exhibiting a lower critical solution temperature of 34–29°C. It is shown for the first time that the lower critical solution temperature of the obtained derivatives is determined not only by the molecular weight of the polymer and protein but also by the conformation of the protein macromolecule.
The possibility of creating acid-stable polymeric insulin carriers capable of swelling in a weakly alkaline medium and being adsorbed on the intestinal walls with insulin release has been studied. In vitro and in vivo experiments have shown that the optimal carrier is a gastric-insoluble polymer capsule containing a hydrogel based on a copolymer of acrylamide and acrylic acid modified by a compound that inhibits the enzymes of the small intestine and provides an enhanced mucoadhesive hydrogel.
The kinetics of tyrosine and phenylalanine release from mucoadhesive solutions of polyacrylamide and acrylamide–acrylic acid copolymer adhered to the surface of a polymer hydrogel has been studied. It has been shown that the time of solution retention on the surface exceeds the time of the complete release of amino acids by several times. These results demonstrate the fundamental possibility of creation of intranasal preparations providing the delivery to the brain at rapid release of the drug from a polymer composition adhered to the mucosa of the nose.
This survey summarizes the published and new results of research conducted in leading scientific institutions and clinics in our country. It was shown that the oral administration of dilute solutions of insulin does not cause the destruction of the hormone in the stomach and the degree of its hydrolysis caused by intestinal enzymes significantly decreases. In this case, the hormone enters the bloodstream, practically realizing the natural route of insulin in the bloodstream through the liver.