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.

Supramolecular Self-Assembly of Porphyrin and Metallosurfactant as a Drug Nanocontainer Design.

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.

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.

Design of N-Methyl-d-Glucamine-Based Resorcin[4]arene Nanoparticles for Enhanced Apoptosis Effects.

The addition of specific chemical groups in a macrocycle structure influences its functional properties and, consequently, can provide new possibilities, among which are aggregation properties, water solubility, biocompatibility, stimuli response, biological activity, etc. Herein, we report synthesis of new resorcin[4]arene with N-methyl-d-glucamine groups on the upper rim and n-decyl chains on the lower rim, an investigation of its self-assembly behavior in aqueous media, and its use as a building block for the formation of drug nanocontainer. N-methyl-d-glucamine fragments in the resorcin[4]arene structure promote higher stability in solutions, simplification of self-aggregation, and increased biological activity. Antimicrobial and hemolytic activity assessment revealed that this resorcin[4]arene obtained is nontoxic. The study of cell penetration was carried out with both free and encapsulated doxorubicin (DOX). Surprisingly, DOX-loaded macrocycle aggregates are more efficient in causing apoptosis in human cancer cell line. Conceivably, this knowledge will help in the rational design of DOX combination for novel drug-administration strategies in cancer treatment.

Self-assembled systems based on novel hydroxyethylated imidazolium-containing amphiphiles: Interaction with DNA decamer, protein and lipid.

The study on aggregation capacity of novel imidazolium-containing amphiphiles of 1-(2-hydroxyethyl)alkylimidazolium bromide series and their interaction with bio-objects (DNA decamer, bovine serum albumin, phospholipid) was performed. It was revealed that introduction of hydroxyethyl moiety into the surfactant molecule resulted in 1.5-2-fold decrease of critical micelle concentration. These modified amphiphiles quantitatively bind DNA decamer due to intercalation and hydrophobic interactions with lipoplex formation. The evaluation of membranotropic properties of these surfactants exhibited that initiation of disordering and compression of the model cell wall consisting of dipalmitoyl phosphocholine (regulation of permeability for various compounds) could be achieved by variation of the length of hydrophobic tail of imidazolium-containing amphiphiles. Transition from individual surfactants solutions to their mixtures with protein (bovine serum albumin) is accompanied by 8-fold decrease of aggregation thresholds and characterized by the presence of two critical points. The binding of components of surfactant/BSA binary systems took place through tryptophan amino acid residue of peptide macromolecule.

N-Methyl-d-glucamine-Calix[4]resorcinarene Conjugates: Self-Assembly and Biological Properties.

Deep insight of the toxicity of supramolecular systems based on macrocycles is of fundamental interest because of their importance in biomedical applications. What seems to be most interesting in this perspective is the development of the macrocyclic compounds with biocompatible fragments. Here, calix[4]resorcinarene derivatives containing N-methyl- d-glucamine moieties at the upper rim and different chemical groups at the lower rim were synthesized and investigated. These macrocycles showed a tendency to self-aggregate in aqueous solution, and their self-assembly abilities depend on the structure of the lower rim. The in vitro cytotoxic and antimicrobial activity of the calix[4]resorcinarenes revealed the relationship of biological properties with the ability to aggregate. Compared to macrocycles with methyl groups on the lower rim, calix[4]resorcinarenes with sulfonate groups appear to possess very similar antibacterial properties, but over six times less hemolytic activity. In some ways, this is the first example that reveals the dependence of the observed hemolytic and antibacterial activity on the lipophilicity of the calix[4]arene structure.

Self-assembling and biological properties of single-chain dicationic pyridinium-based surfactants.

In this work, the dicationic surfactants containing viologen and vinylbipyridinium moieties and hexadecyl chains were synthesized, and their aggregation behavior in water solutions was investigated by surface tension, conductivity measurements, hydrophobic probe solubilization, dynamic light scattering and electrophoretic measurements. Effect of UV-light on cis-trans isomerism of vinylbipyridinium derivative was determined. Antimicrobial activity and the influence of these surfactants on cell viability depended on the concentration and type of surfactant used. The results obtained established the structure-property (physicochemical properties and biological activity) relationship of the surfactant molecule namely the primary role of pyridinium head group structure.

Controlling the size and morphology of supramolecular assemblies of viologen-resorcin[4]arene cavitands.

A novel class of self-assembling nanoparticles is formed with viologen-resorcin[4]arene cavitands; the association model is strongly controlled by their hydrophobicity. Interestingly, the cavitand assemblies are designed through click chemistry to form self-assembled noncovalently connected aggregates through counterion displacement. The iodide and benzoate ions are utilized as strongly polarizable counterions to induce cavitand self-assembly. The counterion-mediated decrease in hydrophilicity of the viologen-resorcin[4]arenes is the underlying trigger to induce particle formation. These particles can be used as nanocontainers and find their applications in delivery systems.

Design of supramolecular biomimetic catalysts of high substrate specificity by noncovalent self-assembly of calix[4]arenes with amphiphilic and polymeric amines.

Supramolecular biomimetic catalysts of high substrate specificity are developed based on amphiphilic oxyethylated calix[4]arene bearing iso-nonyl fragments at the upper rim and hexadeca(ethylene glycol) fragments at lower rim (9CO16), and amines of amphiphilic or polymeric nature. Two critical concentrations determined by tensiometry and dye solubilization methods are probably reflect the onset of association process and transition from bimodal to monomodal size distribution revealed by the dynamic light scattering method. Amine components used may form aggregates as well, which is mediated by hydrophobic effect due to occurrence of long-chain alkyl tails. The micellar rate effect of the designed systems toward the cleavage of carboxylic acid ester is shown to be contributed by the formation of mixed aggregates with the reactive functional groups, as well as by the pKa shift of the amine and the character of the distribution of reagents in functional micelles. In the case of long-chain primary amines, an inversion of micellar rate effect (catalysis to inhibition) occurs upon transferring from the less hydrophobic substrate, p-nitrophenyl acetate, to the more hydrophobic analogs, p-nitrophenyl laurate and p-nitrophenyl caprinate. The opposite effect (inhibition of the reaction of p-nitrophenyl acetate and the acceleration of the process of hydrophobic analogs) was observed in systems based on polyethyleneimine.

Novel self-assembling system based on resorcinarene and cationic surfactant.

Mixed association of calix[4]resorcinarene with ethyl sulfonate groups on the lower rim and dimethylaminomethyl groups on the upper rim (CR) and cationic surfactant 4-aza-1-hexadecyl-azoniabicyclo[2.2.2]octane bromide (DABCO-16) is studied by methods of tensiometry, conductometry, potentiometry and NMR spectroscopy at fixed CR concentration and varied surfactant concentration. Beyond ca. 0.4 mM of DABCO-16, mixed aggregates enriched by CR are proved to be formed due to electrostatic forces, while beyond ca. 5 mM, aggregates enriched by surfactant occur due to the hydrophobic effect. Spectrophotometry monitoring of the solubilization of a hydrophobic dye, Orange OT, demonstrated that only the second type of mixed aggregate enriched by DABCO-16 is capable of binding the organic probe, while the mixed system where the surfactant is a minor component shows no binding capacity towards Orange OT. This finding can be used for the design of nanocontainers with controllable binding/release properties.