The effective binding of Rhodamine B (RhB), a xanthene dye, in solutions of amphiphilic sulfobetaine tetrapentylcalix[4]resorcinarene (C5-SB) at millimolar concentrations has been found. Using the FT-PGSE NMR technique, it was determined that the binding fraction (Pb) of RhB in the solution with a С(RhB)/С(С5-SB) ratio of 3.75 mM/5 mM was 0.57, whereas in a solution with an order of magnitude lower concentration, the Pb was only 0.12. This significant difference in interaction is also supported by 2D NOESY and 1H NMR spectra. Based on fluorimetry data, it appears that the influence of C5-SB on the spectral properties of RhB increases as the C5-SB/RhB molar ratio increases, but decreases as the concentration of C5-SB and RhB decreases. By comparing the spectral properties of RhB in the presence of C5-SB and tetrapentylcalix[4]resorcinarene with carboxylic (C5-COO−) and trimethylammonium (C5-N+Me3) peripheral groups, an assumption about the driving forces behind RhB, which led to an enhancement of the emission properties of the dye, was made. The study demonstrates the possibility of controlling the emissive properties of a xanthene dye by binding it to a supramolecular associate with amphiphilic calix [4] resorcinarene.

Nanoassociates containing folic acid (FA) were obtained through solubilization by colloid solutions of three betaine calixresorcinarenes (sulfobetaine tetrapentylcalixresorcinarene & Scy;5-SB, hydroxysulfobetaine tetrapentyl & Scy;5-hSB and tetraundecylcalixresorcinarene C11-hSB). FA was solubilized in its anionic form and fraction of bound molecules of FA was of from 89 % to 99 % (FT-PGSE NMR method data). The driving forces of FA encapsulation in the nanoassociates has been considered with the help of 1 & Ncy; NMR, 2D NOESY NMR, and FT-PGSE NMR data. The macrocycle-FA nanoassociates have average hydrodynamic diameters of 3-5 nm (PDI of 0.184-0.238) and a zeta potential close to zero; however, they were stable for 4-8 weeks. The enhancement of the internalization of the macrocycle-FA nanoassociates into M-HeLa cells compared to unloaded macrocycles self-associates was shown by the flow cytometry and fluorescence microscopy methods. Additionally, the growth of cytotoxicity of Rhodamine B by 19 % in the presence of & Scy;5-SB+FA nanoassociates compared to & Scy;5-SB self-associates in the in vitro PDT experiment on M-HeLa cells was found. Overall, the potential of a supramolecular approach to obtaining folate-functionalized nanocontainers has been demonstrated.

1,4-Bis(5-phenyl-2-oxazolyl)benzene (POPOP) is a common scintillation fluorescent laser dye. In this manuscript, the synthesis of 2-Ar-5-(4-(4-Ar'-1H-1,2,3-triazol-1-yl)phenyl)-1,3,4-oxadiazoles (Ar, Ar' = Ph, naphtalenyl-2, pyrenyl-1, triphenilenyl-2), as PAH-based aza-analogues of POPOP, by means of Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-Ar-1,3,4-oxadiazole and terminal ethynyl-substituted PAHs is reported. An investigation of the photophysical properties of the obtained products was carried out, and their sensory response to nitroanalytes was evaluated. In the case of pyrenyl-1-substituted aza-POPOP, dramatic fluorescence quenching by nitroanalytes was observed.

Amphiphilic calix[4]resorcinarenes are a class of macrocyclic compounds with broad potential utility including nanomedicine. Here the synthesis of new carboxybetaine and carboxybetaine ester calix[4]resorcinarene bearing 4-(dodecyloxy)phenyl groups on the lower rim is presented. The compounds were characterized by 1H-NMR, 13C-NMR, 2D NMR, IR, ESI and elemental analysis. The critical association concentration values are 1.00 × 10−5 and 1.18 × 10−5 mol·L−1 for carboxybetain and ester, respectively. The hemolytic activity of the macrocycles and their cytotoxicity against normal (WI-38, Chang liver) and tumor cells (M-HeLa) are also estimated.

Here the amphiphilic calix[4]resorcinarenes, which form self-associates in an aqueous solution but do not exhibit surface activity, are described. Aqueous solutions of calix[4]resorcinarenes with different zwitter-ionic groups on the upper rim: carboxybetaine (C5-CB, C11-CB, C12OPh-CB), sulfobetaine (C5-SB, C11-SB), hydroxysulfobetaine (C5-hSB, C11-hSB), - and different hydrophobic substituents on the lower rim (pentyl, undecyl, dodecyloxyphenyl) were studied by fluorimetry, Fourier transform pulsed-gradient spin-echo (FT-PGSE) NMR spectroscopy, UV-vis spectroscopy, dynamic light scattering (DLS), and tensiometry. It was found that all macrocycles spontaneously form self-associates in an aqueous solution, but only sulfobetaine and hydroxysulfobetaine calixresorcinarenes with pentyl substituents on the lower rim are surface active. The critical association concentration (CAC) values, which were obtained by different methods, as well as values of averaged hydrodynamic diameter, averaged self-association numbers, solubilizing power, and other parameters of self-association are presented and discussed.

The development of mitochondrial-targeting therapeutic nanoparticles is one of the crucial tasks of nanotechnology and nanomedicine. Here the study of supramolecular macrocycles decorated by lipophilic cationic mitochondrial-targeting fragments in the formation of supramolecular nanoparticles with the potential mitochondria-dependent apoptosis ability is described. Four cavitands based on tetrapentyl-and tetraundecylcalix[4]resorcines were functionalized with pyridinium (C-5-Pyr and C-11-Pyr, respectively) and triethylammonium groups (C5-NEt3 and C-11-NEt3, respectively). Cavitands demonstrate amphiphilic character with critical association concentration values of 1.21, 1.20, 0.27 and 0.13 mM for C-5-Pyr, C-5-NEt3, C-11-Pyr, and C-11-NEt3, respectively (DMSO/H2O 5/95 v/v, conductometry), and form small self-associates (D2O, DMSO-d(6)/D2O 5/95 v/v, FT-PGSE NMR method). The supramolecular modification of cavitands self-associates by the formation of polymer complexes with biocompatible polymer alginate sodium (AlgNa) was carried out. It was found that the size and stability of polymer complexes depends on the cavitand choice; the average hydrodynamic diameter of particles is 142 nm for C-5-Pyr + AlgNa, 122 nm for C-5-NEt3 + AlgNa and C-11-NEt3 + AlgNa, and 615 nm for C-11-Pyr + AlgNa complexes (DLS method). The formation of polymer complexes mainly is the result of electrostatic interaction and leads to the binding of cavitands by alginate in the form of self-associates (electrophoretic light scattering method, IR, fluorimetry). It was shown that pentylcavitands C-5-Pyr and C-5-NEt3 show higher hemotoxicity and cytotoxicity against normal (Chang liver cells) and tumor cells (M-HeLa cells) than undecylcavitands C-11-Pyr and C-11-NEt3. It was found that cavitand C-5-NEt3 reduces the mitochondrial membrane potential and leads to the increase of ROS in M-HeLa cells (Flow cytometry analysis). However C-5-NEt3 + AlgNa complex loses the ability to reduce the membrane potential of mitochondria, the possible reason of which is discussed.

As a result of bright complexation properties, easy functionalization and the ability to self-organize in an aqueous solution, amphiphilic supramolecular macrocycles are being actively studied for their application in nanomedicine (drug delivery systems, therapeutic and theranostic agents, and others). In this regard, it is important to study their potential toxic effects. Here, the synthesis of amphiphilic calix[4]resorcinarene carboxybetaines and their esters and the study of a number of their microbiological properties are presented: cytotoxic effect on normal and tumor cells and effect on cellular and non-cellular components of blood (hemotoxicity, anti-platelet effect, and anticoagulant activity). Additionally, the interaction of macrocycles with bovine serum albumin as a model plasma protein is estimated by various methods (fluorescence spectroscopy, synchronous fluorescence spectroscopy, circular dichroic spectroscopy, and dynamic light scattering). The results demonstrate the low toxicity of the macrocycles, their anti-platelet effects at the level of acetylsalicylic acid, and weak anticoagulant activity. The study of BSA–macrocycle interactions demonstrates the dependence on macrocycle hydrophilic/hydrophobic group structure; in the case of carboxybetaines, the formation of complexes prevents self-aggregation of BSA molecules in solution. The present study demonstrates new data on potential drug delivery nanosystems based on amphiphilic calix[4]resorcinarenes for their cytotoxicity and effects on blood components.

The development of new nanomaterials with therapeutic potential is a modern task due to their outstanding properties and promising effectiveness. Here the usage of acylhydrazone bond-based ?alix[4]resorcinarenemPEG conjugate (C11-mPEG) in the formation of both supramolecular and hybrid nanoparticles with in vitro photodynamic therapy (PDT) activity is described. C11-mPEG is hydrolyzed with a decrease in pH of solution; the conjugate and its degradation product have the low hemolytic activity and low cytotoxicity against normal cells. The self-association of the conjugate was studied in the aqueous solutions with pH 7.4 and 5. C11-mPEG forms self-associates that serve as pH-sensitive supramolecular nanocontainers for photosensitizer Methylene Blue (MB). In the in vitro PDT experiment the stronger decrease of tumor cells (M-Hela cells) viability in the presence of encapsulated MB is observed in comparison with free MB. Also C11-mPEG acts as a stabilizing agent for Ag@AgCl nanoparticles, which were obtained with 5/1 and 2/1 Ag+/C11-mPEG molar ratio and different reducing agents (sodium borohydride and hydrazine hydrate). The stronger cytotoxicity of hybrid NPs against tumor cells in comparison with normal was shown. Further it was found that the irradiation of the hybrid nanoparticles at 630 nm leads to the sharp increase in their cytotoxicity against M-Hela cells. The high level of ROS formation in the cells in the presence of both supramolecular and hybrid NPs under in vitro PDT experiment was determined.

A novel low toxic amide calix[4]resorcinarene–mPEG conjugates of amphiphilic and dendrimeric character were synthesized. It was shown that the growth of the temperature or the ionic strength growth of the solution leads to different demonstration of the amplification of hydrophobic interactions in the conjugates self-associates. It was found that in PBS or 0.9 % NaCl solutions the amphiphilic conjugate form micellar solution, and the dendrimeric conjugate – hydrogel, which is capable of the reversible sol-gel transition. It was shown by DSC analysis that the dendrimeric conjugate binds of 15 % of water molecules in an aqueous solution (non-freezing bound water), but in the salt solution the conjugate-water interaction is practically absent. This leads to the additional self-aggregation of conjugate molecules and to the gel formation. The high degree of substrate sorption by the hydrogel (Methylene Blue, encapsulation effectiveness is 78 %) and its reversible binding-release by the regulation of the solution ionic strength have been demonstrated.

The growing resistance of bacteria to traditional antibiotics makes it necessary to develop new antimicrobial agents with the dissimilar mode of action such as Ag and AgCl nanoparticles. Here the synthesis of silver NPs in the colloidal solutions of calix[4] resorcinarene-mPEG conjugate C-11-mPEG was reported. NPs were synthesized under varied conditions: different Ag+/C-11-mPEG molar ratio, presence/absence of reducing agent (NaBH4), in dark or LED light exposure. It was found that in all cases Ag-AgCl NPs, stabilized by C-11-mPEG, were obtained with the difference in the Ag NPs content and sizes. Physicochemical characteristics of the Ag-AgCl@C-11-mPEG NPs were evaluated by UV-vis, FT-IR, XRPD, XRF, DLS, and TEM methods. The antimicrobial activity of NPs against Gram-positive and Gram-negative bacteria and fungi was studied and the preferred antimicrobial activity against Gram-positive bacteria was found. The proposed scheme of Ag-AgCl@C-11-mPEG NPs and the influence of NPs content on the antimicrobial activity were discussed.

The synthesis of new conjugates of calix[4]resorcinarenes and methoxy-PEG via acylhydrazone bonds and their study in the formation of pH-sensitive low-toxic supramolecular drug delivery systems have described. The syntheses have been performed on the base of two calix[4]resorcinarenes in chair and boat conformations to obtain the dendrimer-like and amphiphilic conjugates, respectively. The structures of the conjugates have been confirmed by H-1, C-13 NMR, and FT-IR spectroscopy, Maldi-TOF mass spectroscopy, and SLS method. The self-association of both amphiphilic and dendrimer-like conjugates has been found (NMR FT-PGSE, fluorimetry, DLS and TEM methods). The hydrolysis of the conjugates at pH 5.5 (proved by H-1 NMR and FT-IR spectroscopy, DLS method) lead to the improved release of the conjugate-encapsulated Dox. The low hemolytic activity and low cytotoxicity against Chang liver cells of the conjugates and products of their hydrolysis have been demonstrated. Meanwhile, the improved cytotoxicity and photodynamic activity of conjugates-encapsulated drugs (Dox and Methylene Blue, respectively) has been found in vitro. The results have indicated the potential using of the calix[4]resorcinarene-mPEG conjugates bearing acylhydrazone bonds as supramolecular drug delivery systems.

The synthesis and study of self-association and encapsulation ability of new low toxic conjugate of tetraphenyleneoxypentylcalix[4]resorcinarene and methoxy-poly(ethylene glycole) (C5OPh-mPEG) were described. The conjugate is characterized by 1H, 13C NMR, FT-IR, MS, SLS methods. In an aqueous solution the conjugate form multimicellar nanoparticles with low polydispersity value (0.1, DLS method). The self-association of the conjugate was studied by DLS, fluorescence, fluorescence anisotropy method, TEM, and SAXS methods. The SAXS data were detailed analyzed, and the conjugate associates structure as ellipsoidal core-shell particles was proposed. The encapsulation efficiency is a result of the affinity of the conjugate low rim substituents to substrates and reaches of 39.8, 26.7, and 28.9% toward naproxen, ibuprofen and doxorubicin drugs, respectively.

Here we present the supramolecular surfactant-macrocycle system which properties are independent on system composition in the wide range of components concentrations. The study of the interaction of octacarboxy-tetra(p-phenylene-oxy-pentyl)calixresorcinarene (C5R) and cetylpyridinuim chloride (CPC) in mixed aqueous solutions were performed by dynamic light scattering and electrophoretic methods, 1H and FT-PGSE NMR methods, absorption and fluorescence spectroscopy, and TEM. The variation of CPC/C5R molar ratio from 30/1 to 10/1 leads to the formation of nanoassociates with similar composition, size, surface potential value, and improved (in compare with CPC) solubilizing properties. The preparation of mixed supramolecular systems which properties are independent on system composition in the wide range of components concentrations is an elegant example of the producing of colloidal materials with the required morphology and properties.

In order to obtain a non-toxic amphiphilic calixresorcinarene capable to form nanoconjugates for drug encapsulation, tetraundecylcalixresorcinarene functionalized by methoxy poly(ethylene glycol) chains has been synthesized. The macrocycle obtained is characterized by low hemotoxicity. In aqueous solution it forms nanoassociates that are able to encapsulate organic substrates of different hydrophobicity, including drugs (doxorubicin, naproxen, ibuprofen, quercetin). The micelles of the macrocycle slowed down the release of the hydrophilic substrates in vitro. In physiological sodium chloride solution and phosphate-buffered saline, the micelles of the macrocycle acquire thermoresponsive properties and exhibit a temperature-controlled release of doxorubicin in vitro. The combination of the low toxicity and the encapsulation properties of the obtained calixresorcinarene–mPEG conjugate shows promising potential for the use as a supramolecular drug-delivery system.

Here we present the consecutive study of colloid systems formed by novel isatin derivative as compound with high pharmacological potential and series of carboxyresorcinarenes. The azo-modified isatin derivative bearing ammonium moiety (I-3) was synthesized and its antimicrobial activity was investigated. To increase its solubility the solubilization experiment using amphiphilic carboxyresorcinarenes, characterized by low hemolytic activity, was carried out. The I-3 – macrocycles systems were studied by NMR, UV–vis, DLS and TEM. The FT PGSE and 2D NOESY NMR methods demonstrated, that solubilization of I-3 is caused by the incorporation of its molecules in the hydrophobic part of the macrocycles associates. Herewith the loading efficiency of I-3 into the macrocycles associates was reached of 20–30% due to the change of the volume of hydrophobic part of associates by varying the length and structure of hydrophobic substituents of macrocyclic amphiphiles.

The octacarboxylic derivative of tetrapentylcalix[4]resorcinarene (1) was used as stabilizer for preparation of silver nanoparticles (AgNPs) hydrosol. The calixresorcinarene-capped nanoparticles Ag@1 are stably dispersed in an aqueous colloid solution and have an average diameter of 4-6 nm (TEM). The interaction of the macrocycle 1, possessed the receptor properties, with the cationic surfactant cetyltrimetylarnmonium bromide (CTAB) leads to the hydrophobization of AgNPs hydrosol. It was shown, that macrocycle 1 in its individual solution forms the hydrophobic associate with 8 mol of CTAB (H-1 NMR, 2D NOESY). Various and complicated influence of CTAB/macrocycle molar ratio on the hydrophobization of AgNPs and their transfer into organic phase was demonstrated. The initial Ag@1 and modified Ag@1-CTAB were characterized by UV-vis and FTIR spectroscopy, DLS, and TG/DSC methods It was shown that the efficiency of water/organic phase transfer depends on the macrocycle/surfactant molar ratio. The presented supramolecular approach can be useful to form the ordered nanostructures through supramolecular modification and self-organization of hybrid metal nanoparticles.

The synthesis of small (2–3 nm) silver nanoparticles in the presence of new amidoaminocarboxylic tetrapentylcalix[4]resorcinarene and the binding of the antitumor drug Doxorubicin by a macrocycle in solution and on the surface of nanoparticles are described.

The sorption behaviour of three kinds of macrocyclic sorbents – amidoamine tetradodecyloxyphenylencalix[4]resorcinarene 1 and tetramethyloxyphenylencalix[4]-resorcinarene 2; composition of calix[4]resorcinarene 1+2, and novel P.1 and P.2 polymers with amidoamine calix[4]resorcinarene units towards three water-soluble azo dyes – methyl orange (MO), acid orange (AO5) and Congo red (CR) was studied. All sorbents form supramolecular complexes with the aforesaid dyes. The best sorbent for MO was shown to be polymer P.1, for the AO5 – composition 1+2 and for the CR – macrocycle 2, with high sorption capacities (373, 497 and 625 mg/g, respectively). The main factor in the binding of dyes by all studied sorbents proved to be surface electrostatic interactions. In addition to the Coulomb interactions, the most important factor for the polymers appeared to be the ‘net’ structure of the polymer with a high concentration of binding sites, providing electrostatic, hydrogen, dipole–dipole and hydrophobic interaction. Hydrophobic substituents in the sorbents exert a significant influence on the dye sorption. The increase of the sorbents' hydrophobicity leads to a lower sorption capacity for MO and CR and a higher sorption capacity for AO5. It was shown that sorption efficiency of the sorbent depends on the ‘dye–sorbent’ structure conformity.

Here we report on the examination of 12 guests (G1-12) interactions with the aggregates of tetramethylensulfonated tetrapentylcalix[4]resorcinarene (H) and the azo-pH-indicator methyl orange (MO). At pH 4.2, addition of 40 and 100 equiv. of the guests to 40: 1 H: MO solution resulted in deprotonation of the dye accompanied by UV/Vis spectra changes. Variation of MO deprotonation degree in the presence of G1-12 is discussed in relation to the guest interactions with the aggregated H and competition with the surface-bound MO. (C) 2014 Elsevier B. V. All rights reserved.