Supramolecular Assembly Based on Calix(4)arene and Aggregation-Induced Emission Photosensitizer for Phototherapy of Drug-Resistant Bacteria and Skin Flap Transplantation.

Photodynamic therapy as a burgeoning and non-invasive theranostic technique has drawn great attention in the field of antibacterial treatment but often encounters undesired phototoxicity of photosensitizers during systemic circulation. Herein, a supramolecular substitution strategy is proposed for phototherapy of drug-resistant bacteria and skin flap repair by using macrocyclic p-sulfonatocalix(4)arene (SC4A) as a host, and two cationic aggregation-induced emission luminogens (AIEgens), namely TPE-QAS and TPE-2QAS, bearing quaternary ammonium group(s) as guests. Through host-guest assembly, the obtained complex exhibits obvious blue fluorescence in the solution due to the restriction of free motion of AIEgens and drastically inhibits efficient type I ROS generation. Then, upon the addition of another guest 4,4'-benzidine dihydrochloride, TPE-QAS can be competitively replaced from the cavity of SC4A to restore its pristine ROS efficiency and photoactivity in aqueous solution. The dissociative TPE-QAS shows a high bacterial binding ability with an efficient treatment for methicillin-resistant Staphylococcus aureus (MRSA) in dark and light irradiation. Meanwhile, it also exhibits an improved survival rate for MRSA-infected skin flap transplantation and largely accelerates the healing process. Thus, such cascaded host-guest assembly is an ideal platform for phototheranostics research.

Association Complexes of Calix[6]arenes with Amino Acids Explained by Energy-Partitioning Methods.

Intermolecular complexes with calixarenes are intriguing because of multiple possibilities of noncovalent binding for both polar and nonpolar molecules, including docking in the calixarene cavity. In this contribution calix[6]arenes interacting with amino acids are studied with an additional aim to show that tools such as symmetry-adapted perturbation theory (SAPT), functional-group SAPT (F-SAPT), and systematic molecular fragmentation (SMF) methods may provide explanations for different numbers of noncovalent bonds and of their varying strength for various calixarene conformers and guest molecules. The partitioning of the interaction energy provides an easy way to identify hydrogen bonds, including those with unconventional hydrogen acceptors, as well as other noncovalent bonds, and to find repulsive destabilizing interactions between functional groups. Various other features can be explained by energy partitioning, such as the red shift of an IR stretching frequency for some hydroxy groups, which arises from their attraction to the phenyl ring of calixarene. Pairs of hydrogen bonds and other noncovalent bonds of similar magnitude found by F-SAPT explain an increase in the stability of both inclusion and outer complexes.

Pillar[5]arene based glyco-targeting nitric oxide nanogenerator for hyperthermia-induced triple-mode cancer therapy.

Nitric oxide (NO)-mediated gas therapy (GT) and alkyl radical (R•) therapy (ART) are emerging cancer therapy modes, and multi-mode therapy has been recognized as an attractive strategy for enhancing anti-cancer efficacy. In this work, a thermal-responsive R• initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIBI)-loaded glycol-targeting NO nanogenerator was constructed by first the covalent conjugation of thermal-responsive NO donor of S-nitrosothiols (RSNO) on the surface of mesoporous silica-coated gold nanorods (AuNRs@MSN), then the coating of a supramolecular complex of amino pillar[5]arene (NP5) and galactose derivative (G), and finally the loading of AIBI. The glycol-targeting NO nanogenerator demonstrated specific targeting ability to HepG2 cells owing to the recognition between galactose residues and asialoglycoprotein receptors (ASGPR). Specially, upon 808 nm near-infrared (NIR) irradiation, the AIBI-loaded NO nanogenerator generated hyperthermia to achieve photothermal therapy (PTT), and further GT and ART resulted from the thermal responsiveness of RSNO and AIBI, respectively. In vitro experiments revealed that the AIBI-loaded glyco-targeting NO nanogenerator had good biocompatibility and exhibited effective inhibition to the proliferation of HepG2 cells. This work provides a novel way to supramolecular hybrid drug delivery systems for triple-mode targeting therapy of PTT/GT/ART.

Structurally screening calixarenes as peptide transport activators.

Calixarenes are reportedly excellent activators that can remarkably improve the transport efficiencies of cell penetrating peptides. We employed eight calixarenes to systematically study the influence of structure on activation efficiency, which revealed that the scaffold, head group, and alkyl chain are all significant factors for activation efficiency by affecting affinities with the peptide and membrane.

Cascade catalytic nanoplatform constructed by laterally-functionalized pillar[5]arenes for antibacterial chemodynamic therapy.

Chemodynamic therapy (CDT) is an emerging approach to overcome bacterial infections that can efficiently convert hydrogen peroxide (H2O2) to generate highly toxic hydroxyl radicals (˙OH). How to develop safe and effective CDT-based strategies is in high demand but challenging. Herein, a cascade catalytic nanoplatform (GOx-NCs/Fe3O4) was designed by absorbing glucose oxidase (GOx) onto the surface of covalent-assembled polymer capsules (NCs) encapsulating Fe3O4 nanoparticles. With the presence of glucose, GOx could effectively catalyze it to produce H2O2 and result in a decrease in pH value, both of which would assist the subsequent Fenton reaction. Encapsulated Fe3O4 nanoparticles would subsequently trigger H2O2 to produce ˙OH, which could make antibacterial CDT come true. More importantly, the polymer capsules exhibited little to no cytotoxicity towards mammalian cells, which might provide more opportunities and potential to apply in other fields.

Pillar[5]arene-Based Switched Supramolecular Photosensitizer for Self-Amplified and pH-Activated Photodynamic Therapy.

Photodynamic therapy (PDT) has emerged as a promising and spatiotemporally controllable cancer treatment modality. However, serious skin photosensitization during the PDT process limits the clinical application of PDT. Thus, the construction of "smart" and multifunctional photosensitizers has attracted substantial interest. Herein, we develop a mitochondria-targeting and pH-switched hybrid supramolecular photosensitizer by the host-guest interaction. The PDT efficacy of supramolecular photosensitizers can be quenched by the Förster resonance energy transfer (FRET) effect during long circulation and activated by the dissociation of supramolecular photosensitizers in an acidic tumor microenvironment, benefitting from the dynamic feature of the host-guest interaction and pH responsiveness of the water-soluble pillar[5]arene on gold nanoparticles. The rational integration of mitochondria-targeting and reductive glutathione (GSH) elimination in the hybrid switchable supramolecular photosensitizer prolongs the lifetime of reactive oxygen species generated in the PDT near mitochondria and further amplifies the PDT efficacy. Thus, the facile and versatile construction of switchable supramolecular photosensitizer offers not only the targeted and precise phototherapy but also high therapeutic efficacy, which would provide a new path for the clinic application of PDT.

t-Butyl calixarene/Fe2O3@MWCNTs composite-based potentiometric sensor for determination of ivabradine hydrochloride in pharmaceutical formulations.

Ivabradine hydrochloride (IVB) has shown high medical importance as it is a medication for lowering the heart rate for the symptomatic chronic heart failure and symptomatic management of stable angina pectoralis. The high dose of IVB may cause severe and prolonged bradycardia, uncontrolled blood pressure, headache, and blurred vision. In this study, a highly sensitive carbon-paste electrode (CPEs) was constructed for the potentiometric determination of IVB in pharmaceutical formulations. t-Butyl calixarene (t-BCX) was used as an ionophore due to its ability to mask IVB in the cavity via multiple H-bonding at the lower rim, as estimated quantitatively by the sandwich membrane method (Log ßILn = 8.62). Besides, the use of multi-walled carbon nanotubes decorated with Fe2O3 nanoparticles (Fe2O3@MWCNTs) as an additive for the paste electrode significantly improved the detection limit of the sensor up to 36 nM, with Nernstian response of 58.9 mV decade-1 in the IVB linear dynamic range of 10-3-10-7 M in aqueous solutions. The constructed sensors showed high selectivity against interfering species that may exist in physiological fluids or pharmaceutical formulations (e.g. Na+, K+, NH4+, Ca2+, Mg2+, Ba2+, Fe3+, Co2+, Cr3+, Sr2+, glucose, lactose, maltose, glycine, dopamine, and ascorbic acid). The sensors were successfully employed for IVB determination in the pharmaceutical formulations (Savapran®).

MoS2-Calix[4]arene Catalyzed Synthesis and Molecular Docking Study of 2,4,5-Trisubstituted Imidazoles As Potent Inhibitors of Mycobacterium tuberculosis.

A MoS2-supported-calix[4]arene (MoS2-CA4) nanocatalyst was used for efficient synthesis of 2,4,5-trisubstituted imidazole derivatives from 1-(4-nitrophenyl)-2-(4-(trifluoromethyl)phenyl)ethane-1,2-dione, aldehydes and ammonium acetate under solvent-free conditions. Reusability of the catalyst up to five cycles without any significant loss in the yields of the product is the unique feature of this heterogeneous solid catalysis. Furthermore, the noteworthy highlights of this method are safe reaction profiles, broad substrate scope, excellent yields, economical, solvent-free, and simple workup conditions. All synthesized compounds were evaluated for their in vitro antitubercular (TB) activity against Mycobacterium tuberculosis (Mtb) H37Rv. Among the screened compounds 3c, 3d, 3f, 3m, and 3r had MIC values of 2.15, 2.78, 5.75, 1.36, and 0.75 µM, respectively, and exhibited more potency than the reference drugs pyrazinamide (MIC: 3.12 µM), ciprofloxacin (MIC: 4.73 µM), and ethambutol (7.61 µM). Besides, potent compounds (3c, 3d, 3f, 3m, and 3r) have been tested for inhibition of MabA (ß-ketoacyl-ACP reductase) enzyme and cytotoxic activity against mammalian Vero cell line. A molecular docking study was carried out on the MabA (PDB ID: 1UZN) enzyme to predict the interactions of the synthesized compounds. The results of the in vitro anti-TB activity and docking study showed that synthesized compounds have a strong anti-TB activity and can be adapted and produced more effectively as a lead compound.

Topical Delivery of Curcumin by Choline-Calix[4]arene-Based Nanohydrogel Improves Its Therapeutic Effect on a Psoriasis Mouse Model.

Curcumin (CUR) has shown remarkable efficacy in the treatment of skin diseases, but its effective transdermal delivery is still a major challenge and stimulates interest in the design of novel systems for CUR dispersion, preservation, and delivery facilitation to the deeper layers of the skin. The present work aimed to investigate the potential of a nanohydrogel, formed by a micellar choline-calix[4]arene amphiphile (CALIX) and CUR, in the treatment of skin diseases through an imiquimod (IMQ)-induced psoriasis model. Psoriasis plaques are associated with aberrant keratinization, abnormal distribution of tight junctions (TJs) proteins, and enhanced expression of inflammatory markers. The nanohydrogel restored the normal distribution of TJs proteins ZO1 and occludin and reduced the expression of TNF-α and inducible nitric oxide synthetase (iNOS) compared to the untreated IMQ group. The novelty lies in the calix[4]arene-based nanohydrogel as a potential new soft material for the topical skin delivery of CUR. The nanohydrogel, due to its physicochemical and mechanical properties, enhances the drug water-solubility, preserves CUR from rapid degradation, and eases the local skin administration and penetration.

Assessment of the cytotoxic and genotoxic potential of pillar[5]arene derivatives by Allium cepa roots and Drosophila melanogaster haemocytes.

In this study pillar[5]arene (P5) and a quinoline-functionalized pillar[5]arene (P5-6Q) which is used for detecting radioactive element, gas adsorption and toxic ions were synthesized. These materials were characterized by Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared (FTIR), elemental analysis, melting point, Mass Spectroscopy, Scanning Electron Microscopy (SEM) and Zeta Potential. The cytotoxic and genotoxic potential of P5 and P5-6Q at distinct concentrations of 12.5, 25, 50, and 100 µg/mL were also investigated by Allium ana-telophase and comet assays on Allium cepa roots and Drosophila melanogaster haemocytes. P5 and P5-6Q showed dose dependent cytotoxic effect by decreasing mitotic index (MI) and genotoxic effect by increasing chromosomal aberrations (CAs such as disturbed anaphase-telophase, polyploidy, stickiness, chromosome laggards and bridges) and DNA damage at the exposed concentrations. These changes in P5-6Q were lower than P5. Further research is necessary to clarify the cytotoxic and genotoxic action mechanisms of P5 and P5-6Q at molecular levels.

Studies on the constituents of Helleborus purpurascens: use of derivatives from calix[6]arene, homooxacalix[3]arene and homoazacalix[3]arene as extractant agents for amino acids from the aqueous extract.

The task of this work was to investigate the extraction capacity of various calixarenes for free and esterified amino acids from aqueous acid phases. Furthermore, this method was applied to aqueous extracts of Helleborus purpurascens. Generally, it is known that calixarenes can be used as extractants for ammonium compounds due to π-cation and lone pair cation interactions. As first, tert-Butyl-calix[6]arene and derivatives thereof were used. They had already proven their worth in previous investigations. In addition, tert-Butyl-hexahomooxa-calix[3]arene was used also, which can also enter into lone pair cation interactions. In addition to these well-known calixarenes, new calixarenes were produced and tested. Based on the tert-Butyl-hexahomooxa-calix[3]arene, a phosphor(III)bridged derivative was prepared, combining the three aromatic hydroxyl groups to a phosphite. As a seldom-described class of calixarenes, tert-Butyl-hexahomoaza-calix[3]arene derivatives were used. The nitrogen analogues of tert-Butyl-hexahomooxa-calix[3]arene could be produced as N-benzyl derivatives. The structure of the esterified carboxymethylated derivative of N,N',N″-Tribenzyl-tert-Butyl-hexahomoaza-calix[3]arene could be verified by X-ray structure analysis. It crystallized as a partial cone. The extraction capacity of the described calixarenes was investigated for amino acids from aqueous acidic solutions into an organic phase. For the testing were chosen asparagine, aspartic acid, tyrosine, tryptophane, phenylalanine and pipecolinic acid and their methyl esters. The amino acids and their methyl esters were dissolved in water at different pH values. The calixarenes were dissolved in dichloromethane (DCM) or chloroform. After this preparation, the aqueous acidic amino acid solutions were mixed with the solutions and shaken intensively. In addition, blank values were determined by extracting the aqueous stock solutions of the amino acids and their methyl esters with pure solvents. To determine the extraction rate, the phases were separated and each analysed using GC-FID, partially GC-MS(EI). The evaluation is performed in two ways. On the one hand the depletion in the aqueous phase and on the other hand the content in the organic phase was determined.

Galectin-1 promotes hepatocellular carcinoma and the combined therapeutic effect of OTX008 galectin-1 inhibitor and sorafenib in tumor cells.

BACKGROUND: Galectins are beta-galactose specific binding proteins. In human cancers, including hepatocellular carcinoma (HCC), galectin-1 (Gal-1) is often found to be overexpressed. In order to combat the dismal diagnosis and death rates of HCC, gene silencing and targeted inhibition of Gal-1 was investigated for its improved therapeutic potential. METHODS: Cellular and secretory Gal-1 levels were analyzed using HCC clinical samples. The study of Gal-1 was carried by both knockdown and overexpression approaches. The stable clones were tested by in vitro assays and in vivo experiments. Mass spectrometry was used to identify downstream targets of Gal-1. The upstream regulator of Gal-1, microRNA-22 (miR-22) was characterized by functional assays. The therapeutic effect of inhibiting Gal-1 was also analyzed. RESULTS: Gal-1 overexpression was observed in HCC and correlated with aggressive clinicopathological features and poorer survival. The loss of Gal-1 resulted in hindered cell migration, invasion and anchorage independent growth. This was also observed in the animal models, in that when Gal-1 was knocked down, there were fewer lung metastases. Proteomic profiling of control and Gal-1 knockdown cells identified that the level of retention in endoplasmic reticulum 1 (RER1) was suppressed when Gal-1 level was reduced. The cell motility of Gal-1 knockdown cells was enhanced upon the rescue of RER1 expression. In HCC tissues, Gal-1 and RER1 expressions displayed a significant positive correlation. The upstream regulator of Gal-1, miR-22 was observed to be underexpressed in HCC tissues and negatively correlated with Gal-1. Silencing of miR-22 resulted in the upregulation of Gal-1 and enhanced cell growth, migration and invasion. However, such enhancement was abolished in cells treated with OTX008, an inhibitor of Gal-1. Combinational treatment of OTX008 and sorafenib significantly reduced tumor growth and size. CONCLUSIONS: Gal-1 overexpression was detected in HCC and this played a role in promoting tumorigenic processes and metastasis. The function of Gal-1 was found to be mediated through RER1. The correlations between miR-22, Gal-1 and RER1 expressions demonstrated the importance of miR-22 regulation on Gal-1/RER1 oncogenic activity. Lastly, the combinational treatment of OTX008 and sorafenib proved to be an improved therapeutic option compared to when administering sorafenib alone.

A multifunctional supramolecular vesicle based on complex of cystamine dihydrochloride capped pillar[5]arene and galactose derivative for targeted drug delivery.

Background: Supramolecular vesicles are a novel class of nanocarriers that have great potential in biomedicine.Methods: A multifunctional supramolecular vesicle (CAAP5G) based on the complex of CAAP5 and galactose derivative (G) assembled via host-guest interaction was constructed. Results: Using Human embryonic kidney T (293T) cells as experimental models, the cytotoxic effects of CAAP5G was investigated to 0-50 µmol/L for 24 h. Notably, the CAAP5G vesicles revealed low-toxicity to 293T cells, it was critical to designing drug nano-carriers. Simultaneously, we have evaluated doxorubicin hydrochloride (DOX)-loaded CAAP5G vesicles anticancer efficiency, where DOX-loaded CAAP5G vesicles and free DOX incubated with Human hepatocellular carcinoma cancer cell (HpeG2 cells) and 293T cells for 24 h, 48 h, 72 h. It turned out that CAAP5G vesicles encapsulated anticancer drug (DOX) could decrease DOX side-effect on 293T cells and increase DOX anticancer efficiency. More importantly, the cysteamine as an adjuvant chemotherapy drug was released from CAAP5G vesicles in HepG2 cells where a higher GSH concentration exists. The adjuvant chemotherapy efficiency was evaluated, where free DOX and DOX-loaded CAAP5G vesicles incubated with DOX-resistance HepG2 cells (HepG2-ADR cells) for 24, 48, 72 h, respectively. Conclusion: The results revealed that the DOX encapsulated by CAAP5G vesicles could enhance the cytotoxicity of DOX and provide insights for designing advanced nano-carriers toward adjuvant chemotherapies.

Development of a bioreactor system for cytotoxic evaluation of pharmacological compounds in living cells using NMR spectroscopy.

INTRODUCTION: The evaluation of drug's cytotoxicity is a crucial step in the development of new pharmacological compounds. 31P NMR can be a tool for toxicological screening, as it enables the study of drugs' cytotoxicity and their effect on cell energy metabolism in a real-time, in a non- invasive and non-destructive way. This paper details a step-by-step protocol to implement a bioreactor system able to maintain cell viability during NMR acquisitions, at high cell densities and for several hours, enabling toxicological evaluation of pharmacological compounds in living cells. METHOD: HeLa cells were immobilized in agarose gel threads and continuously perfused with oxygenated medium inside a 5 mm NMR tube. Signals corresponding to intracellular high-energy phosphorous compounds were continuously monitored by 31P NMR to assess cell energy levels, intracellular pH and intracellular free Mg2+ concentrations ([Mg2+]f) under control and in the presence of two different cytotoxic drugs, calix-NH2 or 5-fluorouracil (5-FU). RESULTS: The bioreactor system was effective in maintaining cell energy levels as well as intracellular pH and [Mg2+]f along time, with a good 31P NMR signal to noise ratio. Calix-NH2 and 5-FU decreased cell energy levels by 35% and 39%, respectively, with a negligible increase in intracellular [Mg2+]f, and without affecting intracellular pH. DISCUSSION: The immobilization and perfusion system here detailed, along with 31P NMR, is useful in toxicological evaluation of new pharmacological compounds, enabling the continuous assessment of drugs' effect on energy levels, intracellular pH and [Mg2+]f in intact cells, for several hours without compromising cell viability.

Determination of benzo[α]pyrene in edible oil using tetraoxocalix[2]arene[2]triazine bonded silica SPE sorbent.

Benzo[α]pyrene (BaP) is a well-known carcinogen in edible oil. In this study, a method combined solid-phase extraction (SPE) with fluorescent detection was developed using tetraoxocalix[2]arene[2]triazine sorbent (SiO2-OCA) for the clean-up and enrichment of BaP. The interaction between SiO2-OCA and BaP involves a donor-acceptor complex mechanism. The experimental procedure was as follows: BaP was extracted from edible oil with DMF/H2O (9:1, v/v). Then, the ratio of DMF/H2O was adjusted to 1:2 prior to SPE. The final concentrate was analysed using a fluorescence detector at excitation and emission wavelengths of 255 and 420 nm. The method was fully validated. The linearity was in the range of 0.1-100 µg kg-1 with a coefficient of 0.999. The limits of detection and quantification were 0.03 and 0.1 µg kg-1, respectively. The average recoveries were in the range of 88.0 - 122.3%. The intraday and interday precisions were 6.8% and 9.2%, respectively. Compared with other methods, the method reported in this article shows a good detection limit, high reproducibility and recovery and linearity over a broad concentration range. This established method was also applied to evaluate real samples. The concentration of six tested samples was below 5 µg kg-1.

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for ß-galactosides. The galectin-glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins' action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer.

Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)- and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling.

We recently reported on the activity of cationic amphiphiles in inhibiting TLR4 activation and subsequent production of inflammatory cytokines in cells and in animal models. Starting from the assumption that opportunely designed cationic amphiphiles can behave as CD14/MD-2 ligands and therefore modulate the TLR4 signaling, we present here a panel of amphiphilic guanidinocalixarenes whose structure was computationally optimized to dock into MD-2 and CD14 binding sites. Some of these calixarenes were active in inhibiting, in a dose-dependent way, the LPS-stimulated TLR4 activation and TLR4-dependent cytokine production in human and mouse cells. Moreover, guanidinocalixarenes also inhibited TLR4 signaling when TLR4 was activated by a non-LPS stimulus, the plant lectin PHA. While the activity of guanidinocalixarenes in inhibiting LPS toxic action has previously been related to their capacity to bind LPS, we suggest a direct antagonist effect of calixarenes on TLR4/MD-2 dimerization, pointing at the calixarene moiety as a potential scaffold for the development of new TLR4-directed therapeutics.

Calixarene-mediated liquid membrane transport of choline conjugates 3: The effect of handle variation on neurotransmitter transport.

Upper rim phosphonic acid functionalized calix[4]arene affects selective transport of multiple molecular payloads through a liquid membrane. The secret is in the attachment of a receptor-complementary handle to the payload. We find that the trimethylammonium ethylene group present in choline is one of several general handles for the transport of drug and drug-like species. Herein we compare the effect of handle variation against the transport of serotonin and dopamine. We find that several ionizable amine termini handles are sufficient for transport and identify two ideal candidates. Their performance is significantly enhanced in HEPES buffered solutions. This inquiry completes a series of 3 studies aimed at optimization of this strategy. In completion a new approach towards synthetic receptor mediated selective small molecule transport has emerged; future work in vesicular and cellular systems will follow.

Synthetic mimics of biotin/(strept)avidin.

Biotin/(strept)avidin self-assembly is a powerful platform for nanoscale fabrication and capture with many different applications in science, medicine, and nanotechnology. However, biotin/(strept)avidin self-assembly has several well-recognized drawbacks that limit performance in certain technical areas and there is a need for synthetic mimics that can either become superior replacements or operational partners with bio-orthogonal recognition properties. The goal of this tutorial review is to describe the recent progress in making high affinity synthetic association partners that operate in water or biological media. The review starts with a background summary of biotin/(strept)avidin self-assembly and the current design rules for creating synthetic mimics. A series of case studies are presented that describe recent success using synthetic derivatives of cyclodextrins, cucurbiturils, and various organic cyclophanes such as calixarenes, deep cavitands, pillararenes, and tetralactams. In some cases, two complementary partners associate to produce a nanoscale complex and in other cases a ditopic host molecule is used to link two partners. The article concludes with a short discussion of future directions and likely challenges.

A comparison study of macrocyclic hosts functionalized reduced graphene oxide for electrochemical recognition of tadalafil.

The present work described the comparison of ß-cyclodextrin (ß-CD) and p-sulfonated calix[6]arene (SCX6) functionalized reduced graphene oxide (RGO) for recognition of tadalafil. In this study, tadalafil and two macrocycles (ß-CD and SCX6) were selected as the guest and host molecules, respectively. The inclusion complexes of ß-CD/tadalafil and SCX6/tadalafil were studied by UV spectroscopy and molecular simulation calculations, proving the higher supermolecular recognition capability of SCX6 than ß-CD towards tadalafil. The ß-CD@RGO and SCX6@RGO composites were prepared by a wet-chemical route. The obtained composites were characterized by Fourier transform infrared spectrometry, thermogravimetric analysis, atomic force microscopy, and zeta potential. The SCX6@RGO showed a higher electrochemical response than ß-CD@RGO, which was caused by the higher recognition capability of SCX6 than ß-CD. By combining the merits of SCX6 and the RGO, a sensitive electrochemical sensing platform was developed based on the SCX6@RGO nanohybrids. A linear response range of 0.1-50 µM and 50-1000 µM for tadalafil with a low detection limit of 0.045 µM (S/N=3) was obtained by using this method. The constructed sensing platform was successfully used to determine tadalafil in herbal sexual health products and spiked human serum samples, suggesting its promising analytical applications for the trace level determination of tadalafil.