A supramolecular assembly of sulfobutyl ether-ß-cyclodextrin and viologen calix[4]resorcinol as the master key to sustainable and eco-friendly catalyst for paraoxon hydrolysis.

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)-ß-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.

Green-step assembly of the supramolecular amphiphile constructed by sodium carboxymethyl cellulose and calixarene for facile loading of hydrophobic food bioactive compounds.

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 homogeneous 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 preparation of nanoparticles by supramolecular self-assembly without use of organic solvents, temperature and ultrasound effects can be an effective strategy for creating water-soluble forms of lipophilic bioactive compounds.

Emergence of Nanoscale Drug Carriers through Supramolecular Self-Assembly of RNA with Calixarene.

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.

Cataleptogenic Effect of Haloperidol Formulated in Water-Soluble Calixarene-Based Nanoparticles.

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.

Interaction of mucin with viologen and acetate derivatives of calix[4]resorcinols.

The mucus layer acts as a selective diffusion barrier that has an important effect on the efficiency of drug delivery systems in the human body. In this regard, currently the drug nanocarriers of various sizes and compositions are being widely developed to study their mucoadhesive properties i.e., the ability to interact with mucin. However, the effective interaction of drug composition with mucin does not guarantee the success due to the fact that there is a further barrier in the form of epithelial cells retained by calcium ions under the mucus layer. In this work, the interaction of mucin (porcine gastric mucin) with calixarenes is considered for the first time. The study of interaction between calixarenes, mucin and calcium ions by a complex of physicochemical methods showed that effective interaction with mucin requires cationic fragments, and binding with calcium is realized due to anionic fragments in the calixarene structure. Therefore, the combination of different chemical groups in the structure of drug nanocarrier plays an important role in successful mucosal drug delivery. Taking into account the wide possibilities of synthetic modification of the macrocyclic platform, calixarenes can find the application in the drug delivery across mucous barriers.

Nanocarriers for Biomedicine: From Lipid Formulations to Inorganic and Hybrid Nanoparticles.

Encapsulation of cargoes in nanocontainers is widely used in different fields to solve the problems of their solubility, homogeneity, stability, protection from unwanted chemical and biological destructive effects, and functional activity improvement. This approach is of special importance in biomedicine, since this makes it possible to reduce the limitations of drug delivery related to the toxicity and side effects of therapeutics, their low bioavailability and biocompatibility. This review highlights current progress in the use of lipid systems to deliver active substances to the human body. Various lipid compositions modified with amphiphilic open-chain and macrocyclic compounds, peptide molecules and alternative target ligands are discussed. Liposome modification also evolves by creating new hybrid structures consisting of organic and inorganic parts. Such nanohybrid platforms include cerasomes, which are considered as alternative nanocarriers allowing to reduce inherent limitations of lipid nanoparticles. Compositions based on mesoporous silica are beginning to acquire no less relevance due to their unique features, such as advanced porous properties, well-proven drug delivery efficiency and their versatility for creating highly efficient nanomaterials. The types of silica nanoparticles, their efficacy in biomedical applications and hybrid inorganic-polymer platforms are the subject of discussion in this review, with current challenges emphasized.

Supraamphiphilic Systems Based on Metallosurfactant and Calix[4]resorcinol: Self-Assembly and Drug Delivery Potential.

Metallic amphiphiles are used as building blocks in the construction of nanoscale superstructures, where the hydrophobic effects induce the self-assembly of the nanoparticles of interest. However, the influence of synergizing multiple chemical interactions on an effective design of these structures mostly remains an open question. In this regard, supraamphiphilic systems based on flexible surfactant molecules and rigid macrocycles are being actively developed, but there are few works on the interaction between metallosurfactants and macrocycles. In the present work, the self-assembly and biological properties of a metallosurfactant with calixarene were studied for the first time. The metallosurfactant, a complex between lanthanum nitrate and two 4-aza-1-hexadecylazoniabicyclo[2.2.2]octane bromide units, and calix[4]resorcinol containing sulfonate groups on the upper rim were used to form a novel supraamphiphilic composition. The system formed was studied using a variety of physicochemical methods, including spectrophotometry, NMR, XRF, and dynamic and electrophoretic light scattering. It was found that the most optimal tetraanionic calix[4]resorcinol to dicationic metallosurfactant molar ratio, leading to mixed aggregation upon ion pair complexation, is 2:3. The mixed aggregates formed in the pentamolar concentration range were able to encapsulate hydrophilic substrates, including the anticancer drug cisplatin, the pure form of which is more cytotoxic toward healthy cells than toward diseased cells. Interestingly, the drug loaded into the macrocycle-metallosurfactant particles was less cytotoxic to a healthy Chang liver cell line and more cytotoxic to tumor M-HeLa cells. This selectivity depends on the amount of cisplatin added. The more drug is added to the macrocycle-metallosurfactant composition, the greater the biological activity against cancer cells. Taking into account that the appearance of resistance of cancer cells to drugs, especially to cisplatin, is one of the most important problems in treatment, the results of this work envisage the potential application of a mixed macrocycle-metallosurfactant system for the design of therapeutic cisplatin compositions.