The review describes the involvement of various hyaluronic acid receptors, including CD44, RHAMM, HARE, TLR, LYVE-1, in maintaining normal homeostasis and aging, as well as in the development of age-associated inflammatory processes (inflamaging) and malignant tumors. The association of CD44 receptor activation with immune cells and the development of coronary heart disease has been shown. In addition, a link between the CD44 receptor and osteoarthritis has been shown, via TLR2 and TLR4. The oncogenic potential of RHAMM in relation to breast, prostate, leukemia, pancreas, lung and glioblastoma cancers has been described, with the strongest expression observed in metastatic tumors. In vivo and in vitro experiments, it was found that fragments of hyaluronic acid with a length of 4 to 25 disaccharides can contribute to the proliferation of lymphatic endothelial cells and lymphangiogenesis. Thus, hyaluronic acid receptors play an important role in the aging process through the regulation of inflamaging and in the development of malignant neoplasms.

Determination the activity of the genes of sirtuin-1, hyaluronidase, TGF-β cytokine, calreticulin in the process of replicative aging of human fibroblasts in vitro and the effect of hyaluronan preparations with gold nanoparticles on the activity of replicative cell aging. Compared the expression of proteins of the studied genes using specific markers at 7 and 14 passages of cultivation of fibroblasts isolated from human skin, without drugs and in the presence of drugs in the growth medium. This work shows a decrease in the activity of the sirtuin 1 gene and an increase in the expression of hyaluronidase in the process of replicative aging of human fibroblasts. Found a means of slowing down replicative aging by activating the SIRT-1 gene and reducing the activity of hyaluronidase in action in the growth medium of hyaluronan preparations with gold nanoparticles. The discussed variants of cell transitions to the pathological state, caused by replicative aging and the mechanisms of slowing down the replicative aging of human fibroblasts.

Гетерополисахарид гиалуронан, являясь ключевым компонентом внеклеточного матрикса, играет важную роль в поддержании определенных физико-химических условий в тканях. Кроме того, гиалуронан может модулировать состояние клеток через взаимодействие с рецепторами и эндоцитоз, однако, эти эффекты недостаточно изучены. Благодаря своим уникальным свойствам, гиалуронан нашел широкое применение в разных областях биомедицины, в частности, активно используется в качестве микроимплантатов в дерму для коррекции возрастных изменений кожи. Вместе с тем, нативный гиалуронан нестабилен при инъекции и подвергается быстрой деградации в ткани, что существенно ограничивает продолжительность вызываемых им эффектов. В данной работе исследуется новая композиция на основе гиалуронана - HR-2, которую отличают ковалентные сшивки между цепями, введенные путем разработанной авторами одностадийной технологии твердофазной модификации полисахаридов. Сшивки препятствуют быстрой деградации гиалуронана. Авторами предложена концепция функционирования гиалуронана в ткани в качестве депо протеиногенных аминокислот и витаминов в целях поддержания биосинтетической активности клеток. Ранее было показано, что сшитый по данной технологии гиалуронан более стабилен в дерме, в связи с чем его действие в качестве депо может быть пролонгировано. В данной работе исследуется влияние на эндотелиоцитоподобные клетки и фибробласты препарата HR-2, представляющего собой новую композицию гиалуроната натрия и сополимера гиалуроновой кислоты с аскорбилфосфатом магния с добавлением глицина, пролина, лизина. В работе проводится сравнение с немодифицированным гиалуронатом натрия. Установлено, что композиция HR-2 в сравнительно высоких концентрациях дозозависимо увеличивает активность дегидрогеназ в фибробластах, что может свидетельствовать о метаболическом их стимулировании. Это отличает препарат HR-2 от нативной гиалуроновой кислоты, ингибирующей в этих же концентрациях метаболическую активность фибробластов. Оба препарата - и HR-2, и нативная гиалуроновая кислота - в малых концентрациях вызывают гормезис-подобный, стимулирующий метаболизм эндотелиоцитов эффект. Цитотоксичность композиции HR-2 ниже нативной гиалуроновой кислоты на обоих клеточных типах. Следует также отметить, что не выявлено достоверного пролиферативного действия обоих препаратов. Полученные в работе новые сведения могут быть использованы для оптимизации режимов применения препаратов гиалуроновой кислоты в биомедицине, с целью достижения максимального терапевтического эффекта и снижения нежелательных последствий его применения. Hyaluronan (HA) is a linear heteropolysaccharide, a key component of the extracellular matrix. It plays an important role in maintaining certain physicochemical conditions in tissues. In addition, hyaluronan can modulate the state of cells through interaction with receptors and endocytosis; however, these effects are not well understood. Due to its unique properties, hyaluronan is widely used in various fields of biomedicine, in particular, as microimplant for correction of age-related skin changes. However, native hyaluronan is unstable when injected and undergoes rapid degradation in the tissue, which significantly limits duration of its effects. In this study, we evaluated a new hyaluronan-based composition, HR-2, which is distinguished by covalent cross-links between the chains. Those cross-links were incorporated using a one-stage technology of solid-phase modification of polysaccharides developed by the authors. The cross-links prevent the rapid degradation of hyaluronan. The authors proposed a concept of injecting hyaluronan into tissue as a depot of proteinogenic amino acids and vitamins in order to maintain the biosynthetic activity of cells. Previously it was shown that hyaluronan produced with this technology was more stable in the dermis, and, therefore, its performance as a depot can be prolonged. In this work, we studied the effect on endotheliocyte-like cells and fibroblasts of HR-2, which is a new composition of sodium hyaluronate and a copolymer of hyaluronic acid with magnesium ascorbyl phosphate supplemented with glycine, proline, and lysine. The study compared HR-2 with unmodified sodium hyaluronate. We found that the composition of HR-2 in relatively high concentrations dose-dependently increased dehydrogenase activities in fibroblasts, that might indicate their metabolic stimulation. This differs HR-2 from native hyaluronic acid, which inhibits the metabolic activity of fibroblasts when added in similar concentrations. Low concentrations of both drugs, HR-2 and native hyaluronic acid, exerted a hormesis-like effect on endotheliocyte metabolism. Cytotoxicity of the HR-2 formulation was lower than of native hyaluronic acid in both cell types. It should also be noted that no reliable proliferative effects of both drugs have been identified. The new information obtained in this study can help optimizing the use of hyaluronic acid drugs in biomedicine to achieve the best therapeutic effect and reduce undesirable consequences of its use.

New biocomposites based on hydroxyapatite and hyaluronic acid are obtained, and their structural and morphological characteristics are studied. With the use of a set of physicochemical methods, the effect of hyaluronic acid as an active medium in the synthesis of hydroxyapatite used to produce synthetic biocomposites close in structure to native hydroxyapatite is investigated.

The rheological properties of sodium hyaluronate aqueous solutions are studied, and the effect of borax additives on them is investigated. It is shown that, at low concentrations, sodium hyaluronate behaves as a typical linear polyelectrolyte in the limit of a high concentration of the salt in both a 0.1 M NaCl aqueous solution and a salt-free solvent. The addition of 1 mole of borax per base-mole of the polymer to the solution of sodium hyaluronate significantly decreases the specific viscosity of the solution if no salt is added and has practically no effect on the viscosity of the solution in 0.1 M NaCl. The viscosity of a semidilute solution of sodium hyaluronate without the added salt decreases as the shear rate is increased in the range 1.5–656 s −1 . With an increase in temperature, viscosity decreases and its dependence on shear rate becomes less pronounced. The same effect is exerted by small amounts of borax. The properties of salt-free solutions are explained by the presence of admixtures of low-molecular-mass ions in them that screen the Coulomb repulsion of charges linked to sodium hyaluronate chains, and the effect of borax may be rationalized by the screening effect of ions resulting from the hydrolysis of borax.

Исследованы реологические свойства водных растворов гиалуроната натрия и влияние на них добавки буры. Показано, что при низких концентрациях гиалуронат натрия ведет себя как типичный линейный полиэлектролит в пределе высокой концентрации соли как в 0.1 М водном растворе NaCl, так и в бессолевом растворителе. Введение в раствор гиалуроната натрия одного моля буры на осново-моль полимера заметно понижает удельную вязкость раствора без добавленной соли и практически не изменяет вязкость раствора в 0.1 М NaCl. Вязкость полуразбавленного раствора гиалуроната натрия без добавленной соли уменьшается с ростом скорости сдвига, варьируемой в интервале 1.5 656 с-1. Повышение температуры понижает вязкость и несколько ослабляет ее зависимость от скорости сдвига. Добавление буры приводит к таким же результатам. Свойства бессолевых растворов объяснены наличием в них примесей низкомолекулярных ионов, которые экранируют кулоновское отталкивание зарядов, связанных с цепью гиалуроната натрия, а влияние буры – экранирующим действием ионов, образующихся в результате гидролиза буры.

The therapy of radioresistant tumors remains an urgent problem in medicine. To solve this problem neutron capture therapy (NCT) and photon activation therapy (PAT) are used. The essential feature of this such technique is the uptake of tumor chemical elements, which interact with thermal neutrons (NCT) and X-rays (PAT). The aims of the investigation were to study a biodistribution of the complexes of hyaluronic acid with boron (3 mg B mL −1 ) and gold (20 mg Au mL −1 ) in mice with melanoma B-16 after intratumoral administration. An optimal time for NCT was 30 minutes after administration when boron concentration in the tumor was more than 30 μg g −1 and exceeded boron content in surrounding tissues. The maximal gold content in tumor (180–260 mg g −1 ) was obtained in 30 minutes after the preparation introduction. The highest ratios of gold in tumor and surrounding tissues (a necessary condition for forming of the local absorbed dose in tumor) was obtained in 0.5 and 1 h. On the basis of the data obtained, it is possible to assume the perspectives of the non-toxic boron compounds for use in NCT and the gold compounds for use primarily as contrast agents for diagnostic purposes.

The technology of solid-state modification of hyaluronic acid (HA) with sodium decahydroborate by deformation in Bridgman anvils was developed. The deformation was carried out at a pressure of 1 GPa and a rotation angle of 500°. The structure of the obtained complexes was studied. It was shown using Raman and IR-Fourier spectroscopy that HA and the polyborates could form a network of cyclic polymeric chelate complexes in which HA acted as a multidentate ligand. The biodistribution of the HA-based B-containing compound in organs and tissues of mice with B-16 melanoma was studied after a single intratumoral administration. The maximum B content in the tumor was observed 15 min after administration. However, it was halved after 1 h and decreased by 5 times by 3 h. The most opportune time for performing a boron-neutron-capture therapy session was 30 min after administration when the tumor B concentration was >30 μg/g and exceeded the content in surrounding tissues. The tumor/muscle and tumor/blood ratios reached 3 and 5, respectively. Use of this non-toxic compound for neutron-capture therapy was deemed promising based on preclinical studies.

The technology of solid-state modification of hyaluronic acid with sodium decahydroborate by deformation in Bridgman anvils has been developed. The deformation was carried out at a pressure of 1 GPa and a rotation angle of 500 degrees. The structure of obtained complexes has been studied. According to the Raman and infrared spectroscopy data, hyaluronic acid and polyborates are capable of forming a network of cyclic polychelate complexes with hyaluronic acid as polydentate ligands. The distribution of hyaluronic acid-based boron compound in organs and tissues in mice with melanoma B-16 has been studied after single intratumor administration. The maximum boron content in tumor was observed 15 min after drug administration, but decreased two times already in 1 h and more than 5 times in 3 h upon administration. The optimum time for BNCT session is 30 min after compound administration, when boron concentration in tumor is greater than 30 μg/g and exceeds that in the surrounding tissues. During this time, the tumor/muscle and tumor/blood concentration ratios were 3 and 5, respectively. The first stage of investigation shows that the proposed compound is non-toxic and has good prospects for use in BNCT.