Recently, supramolecular self-assembly has attracted the attention of researchers worldwide because it enables the creation of nanostructures with unique properties without additional costs. Spontaneous organization of molecules allows the design and development of new nanostructures that can interact with drugs and living cells and generate a response. Therefore, supramolecular structures have enormous potential and can be in demand in various fields of healthcare and ecology. One of the widely used building blocks of such supramolecular assemblies is polymers. This review examines the joint aggregation behavior of various macrocycles (cyclodextrins, calixarenes, cucurbiturils, porphyrins, and pillararenes) with polymers, the functional properties of these supramolecular systems and their potential applications.

Most professional athletes and their coaches are interested in identifying physical and climatic factors that influence the successful overcoming of long distances. If the influence of physical activity on the athlete endurance is obvious, then the influence of climatic conditions on endurance is of interest from the point of view of stimulating biochemical processes. In the present paper, the main factors of altitude and the importance of training activity in mountain conditions for athletes performing prolonged physical activity are considered. The primary attention is devoted to the study of influence of climatic and exercise loading factors on endurance of athletes under conditions of hypoxia. The review analyzes the data on influence of hypoxic conditions on hemodynamic indicators and energy supply in the body of athletes-stayers. Analysis of the effectiveness of the use of training of respiratory muscles under hypoxia to improve working capacity in long distance performance is carried out.

In the present work, a simple supramolecular approach was used to spontaneously form nanoparticles from sodium carboxymethylcellulose and viologen calix[4]resorcinol as a result of joint self-assembly in water at room temperature. Supramolecular interactions between them led to the formation of nanoparticles, the morphology and properties of which depend on polymer/macrocycle ratio. When there is excess of macrocycle, the nanoparticles bind lipophilic oleic acid, and when there is excess of polymer, they bind hydrophilic doxorubicin. Interestingly, the solubilization of lipophilic quercetin into these nanoparticles was significantly increased compared to the pure polymer and macrocycle, regardless of their ratio. The nanoparticles of triple composition (polymer/macrocycle/drug) have a more effective penetration ability in tumorcells than those of double composition (polymer/drug). The presented results are the first step towards the creation of new nanotechnologies to improve the bioavailability and delivery of bioactive components.

Properties of paraoxon, such as poor water solubility, low rate of natural decomposition, ability to accumulate in soil and wastewater, lead to the fact that paraoxon is found in various agricultural products and textiles. In this regard, the search for effective ways of paraoxon degradation becomes an extremely urgent problem, which can be solved by creating catalysts by mimicking paraxonase. In this work, a complex of physicochemical methods was used to study the supramolecular interactions of sodium alginate, which has a calcium-binding ability similar to paraxonase, with viologen calix[4]resorcinol and to reveal the nature of the intermolecular interactions between them resulting in the spontaneous formation of nanoparticles. Before proceeding to the investigation of the binding ability of obtained nanoparticles to paraoxon, the encapsulating effect of nanoparticles on a number of model substrates of different solubility (doxorubicin hydrochloride, quercetin and oleic acid) was studied. The kinetics of paraoxon hydrolysis reaction using these nanoparticles was studied at room temperature in an aqueous medium by spectrophotometric method. The rate of this reaction increases with increasing concentration of stable nanoparticles having hydrophobic domains that ensure paraoxon immobilization. The results obtained allow considering the supramolecular polysaccharide/calixarene system as an effective biomimetic catalyst.

The search for effective ways of paraoxon (POX) degradation becomes an extremely urgent problem, which can be solved by creating effective bioscavengers in the form of three-dimensional macrocycles. In this work, supramolecular interactions in an aqueous medium were studied between (4-sulfobutyl)-β-cyclodextrin, the hydrophobic cavity of which is capable of binding POX, and viologen calix[4]resorcinol, the cationic groups of which are able to facilitate the nucleophilic attack on the phosphorus atom of the pesticide. A complex of physicochemical methods revealed the nature of the interactions between these cyclodextrin and calix[4]resorcinol, as a result of which the spontaneous formation of nanoparticles occurs. The kinetics of POX hydrolysis reaction using these nanoparticles was studied at room temperature in aqueous Tris-buffer medium by spectrophotometric method. Pure cyclodextrin does not exhibit catalytic activity in the POX hydrolysis, but its presence in a mixture with calix[4]resorcinol leads to a fivefold increase in the hydrolysis rate constant compared to pure calix[4]resorcinol.

Stimulus-responsive systems allowing for the controlled release of drugs [...]

Supramolecular self-assembly is a powerful tool for the development of polymolecular assemblies that can form the basis of useful nanomaterials. Given the increasing popularity of RNA therapy, the extension of this concept of self-assembly to RNA is limited. Herein, a simple method for the creation of nanosized particles through the supramolecular self-assembly of RNA with a three-dimensional macrocycle from the calixarene family was reported for the first time. This self-assembly into nanoparticles was realized using cooperative supramolecular interactions under mild conditions. The obtained nanoparticles are able to bind various hydrophobic (quercetin, oleic acid) and hydrophilic (doxorubicin) drugs, as a result of which their cytotoxic properties are enhanced. This work demonstrates that intermolecular interactions between flexible RNA and rigid calixarene is a promising route to bottom-up assembly of novel supramolecular soft matter, expanding the design possibilities of nanoscale drug carriers.

In this study, a water-soluble form of haloperidol was obtained by coaggregation with calix[4]resorcinol bearing viologen groups on the upper rim and decyl chains on the lower rim to form vesicular nanoparticles. The formation of nanoparticles is achieved by the spontaneous loading of haloperidol into the hydrophobic domains of aggregates based on this macrocycle. The mucoadhesive and thermosensitive properties of calix[4]resorcinol–haloperidol nanoparticles were established by UV-, fluorescence and CD spectroscopy data. Pharmacological studies have revealed low in vivo toxicity of pure calix[4]resorcinol (LD50 is 540 ± 75 mg/kg for mice and 510 ± 63 mg/kg for rats) and the absence of its effect on the motor activity and psycho-emotional state of mice, which opens up a possibility for its use in the design of effective drug delivery systems. Haloperidol formulated with calix[4]resorcinol exhibits a cataleptogenic effect in rats both when administered intranasally and intraperitoneally. The effect of the intranasal administration of haloperidol with macrocycle in the first 120 min is comparable to the effect of commercial haloperidol, but the duration of catalepsy was shorter by 2.9 and 2.3 times (p < 0.05) at 180 and 240 min, respectively, than that of the control. There was a statistically significant reduction in the cataleptogenic activity at 10 and 30 min after the intraperitoneal injection of haloperidol with calix[4]resorcinol, then there was an increase in the activity by 1.8 times (p < 0.05) at 60 min, and after 120, 180 and 240 min the effect of this haloperidol formulation was at the level of the control sample.

This review covers nanotherapeutic strategies for solving the global problems associated with Alzheimer's disease (AD). The most dramatic factor contributing humanistic, social and economic urgency of the situation is the incurability of the disease, with the drug intervention addressing only AD symptoms and retarding their progress. Key sources behind these challenges are the inability of the early diagnosis of AD, the lack of comprehensive information on the molecular mechanism of the pathogenesis, the blood- brain barrier obstacles, and the insufficient effectiveness of currently available drugs and therapeutic strategies. The application of nanocarriers allows part of these problems to be solved, together with the improvement of drug bioavailability, prolonged circulation, and overcoming/bypassing the biological barriers. To this date, numerous types and subtypes of nanocarriers are developed and reviewed, the majority of which can be adapted for the treatment of various diseases. Therefore, herein, nanotherapy strategies are specifically categorized in term of the administration routes of AD medicines, with the noninvasive, i.e., transdermal, oral, and intranasal routes emphasized. Further, benefits/ limitations of various nanocarriers are discussed, and perspectives of their application are highlighted.

Selective internalization in cancer cells has great potential to reduce the side effects of cancer therapy. One effective approach to increase targeting to cancer cells is modification of nanocarrier with folate groups, providing interaction with folic acid alpha receptors, which are overexpressed in some types of tumors. In this work, the folic acid-modified calix[4]resorcinol was synthesized. The choice of calix[4]resorcinol as a modified molecule is due to the possibility of simultaneous attachment of four folic groups. However, this synthetic modification did not improve the water solubility of the calixarene skeleton; therefore, its water-soluble form was further prepared in the presence of N-methyl-D-glucamine and the ability of the resulting form to bind doxorubicin hydrochloride was studied. When studying a mixed system of folic acid-based calix[4]resorcinol with doxorubicin, the smallest particles were found at their equimolar ratio. The equimolar complex of the synthesized macrocycle with doxorubicin exhibits folic acid-receptor mediated selective uptake by M-HeLa cells and induces selective cancer death.

Casein is widely used in the creation of biocompatible and functional particles, which are of interest as a delivery system based on the use of colloidal protein aggregates for the encapsulation of nutritional supplements and drugs. A very promising method for the functionalization and ordering of casein molecules is supramolecular self-assembly, which makes it possible to create nanosized materials using bottom-up approach. In this work, three-dimensional calixarene, namely the amphiphilic viologen calix[4]resorcinol, was used for the first time for spontaneous co-aggregation with sodium caseinate in an aqueous medium. A wide range of physicochemical methods were used to study the mechanisms of interaction between sodium caseinate and viologen calix[4]resorcinol, which lead to the formation of functional nanoparticles. Such nanoparticles, obtained spontaneously and without the use of organic solvents, are able to solubilize both hydrophobic (quercetin and oleic acid) and hydrophilic molecules (doxorubicin hydrochloride). In addition to encapsulating and stimulus-sensitive properties, the cytotoxic and penetrating properties of the formed nanoparticles were determined, as well as their distribution in cells.

A biocompatible supramolecular system based on sodium alginate and viologen calix[4]resorcinol for encapsulation of doxorubicin hydrochloride (DOX) has been obtained. Using a set of physicochemical methods, the polymer–macrocycle ratio, at which stable nanoparticles are formed, has been found and their morphological characteristics have been determined. It has been shown that the increase in the concentration of calix[4]resorcinol leads to the increase in the size of nanoparticles, their zeta potential being changed from negative to positive values. It has been established that the optimal supramolecular system for DOX binding is a composition with a macrocycle–polymer ratio of 1 : 50, and a change in the components ratio can induce the drug release. The effect of encapsulated DOX on the physicochemical and biological properties of the supramolecular system has been shown.

The use of biologically active compounds is often limited due to their poor aqueous solubility, which generally reduces their bioavailability and useful efficacy. In this regard, a wide search is currently underway for colloidal systems capable of encapsulating these compounds. In the creation of colloidal systems, long-chain molecules of surfactants and polymers are mainly used, which in an individual state do not always aggregate into homoge-neous and stable nanoparticles. In the present work, cavity-bearing calixarene was used for the first time to order polymeric molecules of sodium carboxymethyl cellulose. A set of physicochemical methods demonstrated the spontaneous formation of spherical nanoparticles by non-covalent self-assembly contributed by macrocycle and polymer, and formed nanoparticles were able to encapsulate hydrophobic quercetin and oleic acid. The prepa-ration of nanoparticles by supramolecular self-assembly without use of organic solvents, temperature and ul-trasound effects can be an effective strategy for creating water-soluble forms of lipophilic bioactive compounds.

The supramolecular system based on viologen calix[4]resorcinol and sodium alginate in an aqueous medium was studied by a set of physicochemical methods. It was found that sodium alginate and viologen calix[4]resorcinol in the range of macrocycle : polymer concentration ratios from 1 : 2 to 1 : 10 form stable nanoparticles capable of encapsulating biologically active hydrophobic substances. In the presence of encapsulated substrates, the selectivity of the action of quercetin and oleic acid against M-HeLa tumor cells increases by 2.47 and 1.14 times, respectively.

A series of novel amphiphilic cavitands of calix[4]resorcinols with viologen fragments on the upper rim synthesized through a combination of viologen moieties and amphiphilic macrocyclic skeleton is reported. The influence of their structure on self-assembly, solubilization and biological properties was found. The driving force of the self-assembly of the synthesized macrocycles is the hydrophobic interactions of their hydrocarbon chains through additional π-stacking interaction between the aromatic rings of neighboring macrocycle molecules, which is enhanced with an increase in the length of the alkyl chains on the lower rim. The lower hemotoxicity of long-chain viologen macrocycles, relative to viologen surfactant, the ability to bind therapeutic molecules and the selective cytotoxic activity to tumor cells are explicit references to viologen derivatives of calix[4]resorcinols as promising drug nanocontainers.

The intention of this Special Issue, entitled "The Self-Assembly and Design of Polyfunctional Nanosystems 2 [...].

Complexes of various nitrogen-containing ligands with transition metals are known for their anticancer activity. At the same time, the shape of aggregates of these complexes can have a significant effect on cytotoxicity and selectivity of action in tumor cells, however, this issue has received insufficient attention in the literature. In this work, the selective binding ability of sulfonate calix[4]resorcinol functionalized at the upper rim by N-methyl-D-glucamine fragments towards copper (II) ion (Cu2+) was demonstrated. N-methyl-D-glucamine calix[4]resorcinol weakly interacts with Zn2+, but effectively binds Cu2+ with the formation of a 2:1 complex. The complexation of calix[4]resorcinol with copper leads to a significant change in the shape of aggregates from rounded to rod-like particles, which is confirmed by TEM images. The rod-like aggregates of calix[4]resorcinol–copper(II) showed a pronounced cytotoxic effect against HuTu 80 cell line, while not affecting Chang liver cells.

The chapter focuses on metal-bearing nanocontainers of different types. First, typical metallosurfactants are discussed, with their synthesis, self-assembling behavior, solubilization properties, and morphological characteristics emphasized. In this section, different metals and ligands are considered, and their influence on aggregation thresholds and structural characteristics is analyzed. These micellar nanocontainers are of particular importance from the viewpoint of biomedical application due to their own antimicrobial properties and therapeutic effects. In addition, the complexation of metallosurfactants with biomolecules is mentioned. Second, development of a conceptually new trend for amphiphilic and supra-amphiphilic system based on metallosurfactants and macrocycles is considered. The design of nanoscale superstructure construction from flexible surfactant molecules and solid macrocycles is being actively developed, but the creation of metallosurfactant/macrocycle compositions has only just begun and limited with few studies. Supramolecular aggregates based on metalloamphiphile–macrocycle complexes have several advantages, such as the simplicity of preparing and further modification with stimulus-sensitive and targeting ligands, and their selective biological activity. Third, catalytically active silver- and palladium-loaded nanocomposites based on amphiphilic resorcinarene macrocycles were developed. For these hybrid supramolecular and polymer nanocontainers, the influence of the morphology and the structure of the organic shell on the stability and catalytic activity are shown.

The combined method of treating malignant neoplasms using photodynamic therapy and chemotherapy is undoubtedly a promising and highly effective treatment method. The development and establishment of photodynamic cancer therapy is closely related to the creation of sensitizers based on porphyrins. The present study is devoted to the investigation of the spectroscopic, aggregation, and solubilization properties of the supramolecular system based on 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TSPP) and lanthanum-containing surfactant (LaSurf) in an aqueous medium. The latter is a complex of lanthanum nitrate and two cationic amphiphilic molecules of 4-aza-1-hexadecylazoniabicyclo[2.2.2]octane bromide. The mixed TSPP–LaSurf complexes can spontaneously assemble into various nanostructures capable of binding the anticancer drug cisplatin. Morphological behavior, stability, and ability to drug binding of nanostructures can be tailored by varying the molar ratio and the concentration of components. The guest binding is shown to be additional factor controlling structural rearrangements and properties of the supramolecular TSPP–LaSurf complexes.

Self-assembly of molecular elements through non-covalent interactions plays a central role in supramolecular chemistry. The intermolecular interactions between macrocyclic and open-chain amphiphilic building blocks have been of large interest for last decade, since their mixed assembly is an example of building nanostructures by supramolecular bottom-up synthesis. Here we report that noncovalent interactions of viologen-based resorcin[4]arene cavitand with sodium dodecyl sulphate can enable self-assembly into highly-ordered supramolecular structures. A set of physicochemical methods was used to study the aggregation and binding properties of the supramolecular system based on these components. It was found that in this system the morphological transitions are observed depending on the ratio of the components of the system. The effectiveness of the mixed compositions as carriers for hydrophilic doxorubicin and hydrophobic antioxidants rutin and quercetin was evaluated, and a high loading efficiency of drugs and the ability to sustained release were found for the equimolar system. This study demonstrates features of such supramolecular structures, highlighting their potential applications in drug delivery.