Cationic Β-cyclodextrin Research Articles

Development of curcumin-cyclodextrin/cellulose nanocrystals complexes: New anticancer drug delivery systems.

The synthesis of curcumin-cyclodextrin/cellulose nanocrystals (CNCx) nano complexes was performed. CNCx were functionalized by ionic association with cationic β-cyclodextrin (CD) and CD/CNCx complexes were used to encapsulate curcumin. Preliminary in vitro results showed that the resulting curcumin-CD/CNCx complexes exerted antiproliferative effect on colorectal and prostatic cancer cell lines, with IC50s lower than that of curcumin alone.

Bio-inspired polymer envelopes around adenoviral vectors to reduce immunogenicity and improve in vivo kinetics

Adenoviral vectors have attracted substantial interest for systemic tumor gene therapy, but further work is needed to reduce their immunogenicity and alter their biodistribution before they can be used in the clinic. Here we describe a bio-inspired, cleavable PEGylated β-cyclodextrin-polyethyleneimine conjugate (CDPCP) that spontaneously coats adenovirus in solution. This cleavable PEG coating reduces the innate and adaptive immunogenicity of adenovirus particles, as well as improves their biodistribution away from the liver and into the tumor. Insertion of a matrix metalloproteinase substrate sequence into the conjugate allows PEG cleavage at the tumor site, simultaneously reducing liver biodistribution and increasing transgene expression in tumors, thereby avoiding the “PEG dilemma”. Cationic β-cyclodextrin–PEI not only provides electrostatic attraction to promote envelope attachment to the viral capsid, but it also improves vector internalization and transduction after PEG cleavage. These results suggest that CDPCP may help expand the use of adenoviral vectors in cancer gene therapy. Statement of significanceThe synthesized β-cyclodextrin–PEI-MMP-cleavable-PEG polymer (CDPCP), held great potential for gene therapy when applied for adenovirus coating. The β-cyclodextrin–PEI provided a powerful electrostatic attraction to attach the whole polymer onto the viral capsid, while the MMPs-cleavable PEG reduced innate and adaptive immunogenicity and improved the biodistribution of adenovirus vectors due to the tumor-specific enzyme triggered PEG cleavage. More importantly, an ingenious cooperation between the two components could solve the PEG dilemma. The CDPCP/Ad complexes exhibited a comprehensive and valued profile to be a candidate vector for future tumor gene therapy, we believe the current investigation on this kind of biomaterial may be of particular interest to the readership of Acta biomaterialia.

Preparation and clay stabilization properties of cationic acrylamide polymer containing β-cyclodextrin

In this study, a new family of short-chain cationic polymer, P(A-β-CD/AM/ATMAC), was synthesized via free radical-initiated aqueous system co-polymerization of acrylamide (AM), allyl trimethyl ammonium chloride (ATMAC), and allyl-β-cyclodextrin (A-β-CD). The optimum conditions of the co-polymerization process are obtained by single-factor experiment: the reaction temperature was 40 °C, the reaction time was 3 h, the initiator dosage was 0.15 wt%, the chain transfer dosage was 0.20 wt%, the total monomer concentration was 25.0 wt%, the monomer molar ratio (AM:A-β-CD:ATMAC) was 65:5:30, and the anti-swelling rate of the polymer can reach 95.2 %. The cationic β-cyclodextrin polymer was structurally characterized using FT-IR and 1H NMR. The weight-average molecular weight of P(A-β-CD/AM/ATMAC) is (1.96 ± 0.05) × 104 g/mol, which was measured by using static laser light scattering. The P(A-β-CD/AM/ATMAC) can not only effectively avoid plugging and reservoir damage in the reservoir with ultra-low permeability (1 md < K 0 < 10 md) but also enhance the flushing resistance, temperature tolerance, and the capability of inhibiting particle dispersion. On the bases of XRD, SEM analyses, the clay stabilization mechanism of P(A-β-CD/AM/ATMAC) is preliminary discussed.

Cationic β-cyclodextrin polymer applied to a dual cyclodextrin polyelectrolyte multilayer system

A polyelectrolyte multilayer film (PEM) based on cationic and anionic β-cyclodextrin polyelectrolytes was coated onto a textile substrate for future drug delivery purposes. We firstly synthesized a novel cationic β-cyclodextrin polymer (polyEPG-CD) by crosslinking β-cyclodextrin (βCD) with epichlorohydrin (EP) under basic conditions, in the presence of glycidyltrimetrylammonium chloride (GTMAC) as cationizing group. The influence of preparation conditions has been investigated in order to preferably obtain a water soluble fraction whose charge density and molecular weights were optimal for the layer-by-layer (LbL) deposition process. The different cationic cyclodextrin polymers obtained were characterized by FTIR, NMR, colloidal titration, conductimetry, thermogravimetric analysis and size exclusion chromatography. Besides, the counterpart polyelectrolyte was a β-cyclodextrin polymer crosslinked with citric acid, polyCTR-CD, whose synthesis and characterization have been previously reported. Finally we realized the Layer by Layer (LbL) build-up of the PEM coating onto the textile support, using the dip coating method, by alternatively soaking it in cationic polyEPG-CD and anionic polyCTR-CD solutions. This multilayer self-assembly was monitored by SEM, gravimetry and OWLS in function of both polyelectrolytes concentrations and ratios. Solutions parameters such as pH, ionic strenght were also discussed.

Separation of folinic acid diastereomers in capillary electrophoresis using a new cationic β-cyclodextrin derivative.

A method for the separation of folinic acid diastereomers by capillary electrophoresis in chiral separation media was developed. Aiming to achieve a good separation of the anionic analytes, a newly synthesized cationic β-cyclodextrin derivative, mono-6-deoxy-6-piperdine-β-cyclodextrin, was applied as the chiral selector. The effect of background electrolyte pH, the concentration of the cyclodextrin additive, and organic modifier on the separation was investigated. A good separation of folinic acid diastereomers was obtained with 30 mmol/L phosphate buffer at pH 6.50 containing 6.0 mmol/L of mono-6-deoxy-6-piperdine-β-cyclodextrin in 10% acetonitrile. Based on the capillary electrophoresis data, the binding constants of each diastereomer with mono-6-deoxy-6-piperdine-β-cyclodextrin were determined. Moreover, a computational modeling study, using the semi-empirical PM3 method, was used to discuss the possible mechanism of separation of folinic acid with mono-6-deoxy-6-piperdine-β-cyclodextrin.

Development of acid-resistant alginate/trimethyl chitosan nanoparticles containing cationic β-cyclodextrin polymers for insulin oral delivery.

In this study, the use of trimethylchitosan (TMC), by higher solubility in comparison with chitosan, in alginate/chitosan nanoparticles containing cationic β-cyclodextrin polymers (CPβCDs) has been studied, with the aim of increasing insulin uptake by nanoparticles. Firstly, TMCs were synthesized by iodomethane, and CPβCDs were synthesized within a one-step polycondensation reaction using choline chloride (CC) and epichlorohydrine (EP). Insulin-CβCDPs complex was prepared by mixing 1:1 portion of insulin and CPβCDs solutions. Then, nanoparticles prepared in a three-step procedure based on the iono-tropic pregelation method. Nanoparticles screened using experimental design and Placket Burman methodology to obtain minimum size and polydispercity index (pdI) and the highest entrapment efficiency (EE). CPβCDs and TMC solution concentration and pH and alginate and calcium chloride solution concentrations are found as the significant parameters on size, PdI, and EE. The nanoparticles with proper physicochemical properties were obtained; the size, PdI, and EE% of optimized nanoparticles were reported as 150.82 ± 21nm, 0.362 ± 0.036, and 93.2% ± 4.1, respectively. The cumulative insulin release in intestinal condition achieved was 50.2% during 6h. By SEM imaging, separate, spherical, and nonaggregated nanoparticles were found. In the cytotoxicity studies on Caco-2 cell culture, no significant cytotoxicity was observed in 5h of incubation, but after 24h of incubation, viability was decreased to 50% in 0.5mμ of TMC concentration. Permeability studies across Caco-2 cells had been carried out, and permeability achieved in 240min was 8.41 ± 0.39%, which shows noticeable increase in comparison with chitosan nanoparticles. Thus, according to the results, the optimized nanoparticles can be used as a new insulin oral delivery system.

High performance acid composition based on cationic β-cyclodextrin inclusion complexes for enhancing oil recovery

The inclusion complex of cationic β-cyclodextrin and 2-phosphonobutane-1,2,4-tricarboxylic acid was prepared as a highly efficient acid composition in the process of oil wells acidizing for enhancing oil recovery. In the progress of acid stimulation, the inclusion complex could not only inhibit clay swelling, but also retard the acid–rock reaction rate and self-regulate dissolution rate. These advantages present significant potential applications to clear acid channel and prolong acidizing distance of real-world oil wells, which contributes to enhancing oil recovery. In addition, a possible interaction mechanism of the novel acid system in the progress of acid treatments was provided.

Study on Acidizing Effect of Cationic β-Cyclodextrin Inclusion Complex with Sandstone for Enhancing Oil Recovery

A novel supramolecular inclusion complex was prepared with cationic β-cyclodextrin and organic phosphoric acid. The inclusion action was investigated by UV–vis spectroscopy, and the cationic β-cyclodextrin inclusion complex was structurally evidenced by 1H and 31P NMR and FT-IR. With linear expansion tests, it was found that the novel inclusion complex possessed excellent clay stability. FT-IR, single-factor, and response surface method analyses showed that the inclusion complex acid system could not only retard acid–rock reaction but also intelligently regulate the acid–rock reaction rate to ensure a sufficient amount of acid to react with high-temperature oil-bearing sandstone reservoir in the progress of acid stimulation. On the basis of the core flood tests, an interaction mechanism was suggested that the inclusion complex acid system may open up for a new possibility to exhibit greater acidizing performance in high clay content, high-temperature, and low-permeability oil reservoirs, which contributes to improving core permeability and enhancing oil recovery.

Tailored cyclodextrin pore blocker protects mammalian cells from clostridium difficile binary toxin CDT.

Some Clostridium difficile strains produce, in addition to toxins A and B, the binary toxin Clostridium difficile transferase (CDT), which ADP-ribosylates actin and may contribute to the hypervirulence of these strains. The separate binding and translocation component CDTb mediates transport of the enzyme component CDTa into mammalian target cells. CDTb binds to its receptor on the cell surface, CDTa assembles and CDTb/CDTa complexes are internalised. In acidic endosomes, CDTb mediates the delivery of CDTa into the cytosol, most likely by forming a translocation pore in endosomal membranes. We demonstrate that a seven-fold symmetrical positively charged β-cyclodextrin derivative, per-6-S-(3-aminomethyl)benzylthio-β-cyclodextrin, which was developed earlier as a potent inhibitor of the translocation pores of related binary toxins of Bacillus anthracis, Clostridium botulinum and Clostridium perfringens, protects cells from intoxication with CDT. The pore blocker did not interfere with the CDTa-catalyzed ADP-ribosylation of actin or toxin binding to Vero cells but inhibited the pH-dependent membrane translocation of CDTa into the cytosol. In conclusion, the cationic β-cyclodextrin could serve as the lead compound in a development of novel pharmacological strategies against the CDT-producing strains of C. difficile.

Interactions of High-Affinity Cationic Blockers with the Translocation Pores of B. Anthracis, C. Botulinum, and C. Perfringens Binary Toxins

Cationic β-cyclodextrin derivatives were recently introduced as highly effective, potentially universal blockers of binary bacterial toxins: anthrax toxin of Bacillus anthracis, C2 toxin of Clostridium botulinum, and iota toxin of Clostridium perfringens. The binary toxins are made of two separate components: the enzymatic A component and the binding/translocation B component, which forms oligomeric channels in the target cell membrane. Here we studied the voltage and salt dependence of the rate constants of binding and dissociation reactions of two structurally different β-cyclodextrins (AmPrβCD and AMBnTβCD) in the PA63, C2IIa, and Ib channels. With all three channels, the blocker carrying extra hydrophobic aromatic groups, AMBnTβCD, demonstrated stronger binding compared with AmPrβCD. This effect is seen as an increased residence time of the blocker in the channels, whereas the time between blockages stays practically unchanged. Surprisingly, the voltage sensitivity, expressed as a slope of the logarithm of the blocker residence time as a function of voltage, was practically the same for all six cases studied, suggesting structural similarities among the three channels. Also, the more-effective AMBnTβCD blocker shows weaker salt dependence of the binding and dissociation rate constants compared with AmPrβCD. By estimating the relative contributions of the applied transmembrane field, long-range Coulomb, and salt-concentration-independent, short-range forces, we found that the latter represent the leading interaction, which accounts for the high efficiency of blockage. In a search for the putative groups in the channel lumen that are responsible for the short-range forces, we performed measurements with the F427A mutant of PA63. We found that the on-rates of the blockage were virtually conserved, but the residence times dropped by more than an order of magnitude, reducing the difference between the efficiencies of the two blockers.

Multifunctional Hybrid Nanocarriers Consisting of Supramolecular Polymers and Quantum Dots for Simultaneous Dual Therapeutics Delivery and Cellular Imaging

A novel multifunctional hybrid nanocarrier consisting of a red fluorescence quantum dot core and a star-shaped cationic β-cyclodextrin polymer shell is demonstrated. Chemotherapeutic drug paclitaxel is supramolecularly preloaded into the nanocarrier, which co-delivers the drug and DNA with an enhanced gene expression, while the quantum dot core allows simultaneous cellular imaging using laser scanning confocal microscopy.

Interactions of High-Affinity Cationic Blockers with the Translocation Pores of B. anthracis, C. botulinum, and C. perfringens Binary Toxins

Cationic β-cyclodextrin derivatives were recently introduced as highly effective, potentially universal blockers of three binary bacterial toxins: anthrax toxin of Bacillus anthracis, C2 toxin of Clostridium botulinum, and iota toxin of Clostridium perfringens. The binary toxins are made of two separate components: the enzymatic A component, which acts on certain intracellular targets, and the binding/translocation B component, which forms oligomeric channels in the target cell membrane. Here we studied the voltage and salt dependence of the rate constants of binding and dissociation reactions of two structurally different β-cyclodextrins (AmPrβCD and AMBnTβCD) in the PA63, C2IIa, and Ib channels (B components of anthrax, C2, and iota toxins, respectively). With all three channels, the blocker carrying extra hydrophobic aromatic groups on the thio-alkyl linkers of positively charged amino groups, AMBnTβCD, demonstrated significantly stronger binding compared with AmPrβCD. This effect is seen as an increased residence time of the blocker in the channels, whereas the time between blockages characterizing the binding reaction on-rate stays practically unchanged. Surprisingly, the voltage sensitivity, expressed as a slope of the logarithm of the blocker residence time as a function of voltage, turned out to be practically the same for all six cases studied, suggesting structural similarities among the three channels. Also, the more-effective AMBnTβCD blocker shows weaker salt dependence of the binding and dissociation rate constants compared with AmPrβCD. By estimating the relative contributions of the applied transmembrane field, long-range Coulomb, and salt-concentration-independent, short-range forces, we found that the latter represent the leading interaction, which accounts for the high efficiency of blockage. In a search for the putative groups in the channel lumen that are responsible for the short-range forces, we performed measurements with the F427A mutant of PA63, which lacks the functionally important phenylalanine clamp. We found that the on-rates of the blockage were virtually conserved, but the residence times and, correspondingly, the binding constants dropped by more than an order of magnitude, which also reduced the difference between the efficiencies of the two blockers.

Chemically bonded cationic β-cyclodextrin derivatives as chiral stationary phases for enantioseparation applications

Vinylene-functionalized cationic β-cyclodextrins are co-polymerized with vinylized silica in the presence of AIBN and conjugated monomers. The chemically immobilized cationic β-cyclodextrins were thereafter applied as chiral stationary phases in packed column supercritical fluid chromatography and demonstrated good and reproducible enantioseparations of racemic pharmaceutical compounds.

A click chemistry route to 2-functionalised PEGylated and cationic β-cyclodextrins: co-formulation opportunities for siRNA delivery

A new approach to the synthesis of amphiphilic β-cyclodextrins has used 'click' chemistry to selectively modify the secondary 2-hydroxyl group. The resulting extended polar groups can be either polycationic or neutral PEGylated groups and these two amphiphile classes are compatible in dual cyclodextrin formulations for delivery of siRNA. When used alone with an siRNA, a cationic cyclodextrin was shown to have good transfection properties in cell culture. Co-formulation with a PEGylated cyclodextrin altered the physicochemical properties of nanoparticles formed with siRNA. Improved particle properties included lower surface charges and reduced tendency to aggregate. However, as expected, the transfection efficiency of the cationic vector was lowered by co-formulation with the PEGylated cyclodextrin, requiring future surface modification of particles with targeting ligands for effective siRNA delivery.

Chemically bonded cationic β-cyclodextrin derivatives and their applications in supercritical fluid chromatography

Cationic β-cyclodextrin (CD) perphenylcarbamoylated derivatives were chemically bonded onto vinylized silica using a radical co-polymerization reaction. The derived materials were used as chiral stationary phases (CSP) in supercritical fluid chromatography (SFC). Enantioseparations were successfully demonstrated on 14 racemates encompassing flavanones, thiazides and amino acid derivatives. The electrostatic force between the analytes and the cationic moiety on β-CD derivative was found to be important for retention and enantioseparation of the racemates. Aromatic cationic moiety on β-CD enabled better enantioseparations than aliphatic cationic moiety. It was also found that the presence of acid additives would result in lower retention of the analytes but often assist the chiral resolutions.

Removal of Nitrophenols by Adsorption Using β-Cyclodextrin Modified Zeolites

Removal of nitrophenols (NPs) from aqueous solutions through the adsorption process by using cationic β-cyclodextrin (CCD) modified zeolite (CCDMZ) was investigated. The effects of particle size, contact time, solution pH values and sodium chloride content in the aqueous on adsorption capacity were evaluated through a series of batch experiments. The results showed that CCDMZ had a higher adsorption capacity for removing NPs at a size fraction of 0.45–0.9 mm while adsorption of NPs on CCDMZ reached equilibrium within 60 min. The adsorption process was apparently influenced by pH values and sodium chloride content in aqueous solution. To ascertain the mechanisms of sorption, the experimental data were modeled by using the pseudo-first and pseudo-second order kinetic equations, and the results indicated that the adsorption kinetics of NPs on CCDMZ well-matched with the pseudo-second order rate expression.

Enantioseparation of dansyl amino acids by ultra-high pressure liquid chromatography using cationic β-cyclodextrins as chiral additives

This work reports the application of ultra-high pressure liquid chromatography (UHPLC) for reasonably fast enantiorecognition of some dansyl amino acids by employing three cationic β-cyclodextrins (β-CDs) as chiral additives. Good resolutions were obtained on an Agilent C18 column (2.1 mm i.d.; 1.8 μm; 50 mm length) with 1% (v/v) triethylammonium acetate buffered at pH 4.7 and acetonitrile as the mobile phase. Most of the analytes could be baseline resolved within 10 min. Increased cationic CD concentration or acetonitrile proportion in the mobile phase results in a decreased retention factor but accentuated selectivity. Furthermore, molecular mechanics calculation was performed and found to be consistent with the experimental results.

Chiral capillary electrophoresis with cationic pyrrolidinium‐β‐cyclodextrin derivatives as chiral selectors

New single-isomer, cationic beta-cyclodextrins, including mono-6-deoxy-6-pyrrolidine-beta-cyclodextrin chloride (pyCDCl), mono-6-deoxy-6-(N-methyl-pyrrolidine)-beta-cyclodextrin chloride (N-CH(3)-pyCDCl), mono-6-deoxy-6-(N-(2-hydroxyethyl)-pyrrolidine)-beta-cyclodextrin chloride (N-EtOH-pyCDCl), mono-6-deoxy-6-(2-hydroxymethyl-pyrrolidine)-beta-cyclodextrin chloride (2-MeOH-pyCDCl) were synthesized and used as chiral selectors in capillary electrophoresis for the enantioseparation of carboxylic and hydroxycarboxylic acids and dansyl amino acids. The unsubstituted pyCDCl exhibited the greatest resolving ability. Most analytes were resolved over a wide range of pH from 6.0 to 9.0 with this chiral selector. In general, increasing pH led to a decrease in resolution. The effective mobilities of all the analytes were found to decrease with increasing CD concentration. The optimal concentration for most carboxylic acids and dansyl amino acid was in the range 5-7.5 mM and >15 mM for hydroxycarboxylic acids. (1)H NMR experiments provided direct evidence of inclusion in the CD cavity.

Effective protection and controlled release of insulin by cationic β-cyclodextrin polymers from alginate/chitosan nanoparticles

In an alginate/chitosan nanoparticle system, insulin was protected by forming complexes with cationic β-cyclodextrin polymers (CPβCDs), which were synthesized from β-cyclodextrin (β-CD), epichlorohydrin (EP) and choline chloride (CC) through a one-step polycondensation. Due to the electrostatic attraction between insulin and CPβCDs, as well as the assistance of its polymeric chains, CPβCDs could effectively protect insulin under simulated gastrointestinal conditions. The nanoparticles have their mean size lower than 350 nm and can load insulin with the association efficiency (AE) up to 87%. It is notable that the cumulative insulin release in simulated intestinal fluid was significantly higher (40%) than that without CPβCDs (18%) because insulin was mainly retained in the core of the nanoparticles and well protected against degradation in simulated gastric fluid. Far-UV circular dichroism analysis also corroborated the preservation of insulin structure during the nanoparticle preparation and release process.

Study of branched cationic β-cyclodextrin polymer/indomethacin complex and its release profile from alginate hydrogel

A series of branched cationic β-cyclodextrin polymers (CPβCDs) with designed chemical structures were synthesized from β-cyclodextrin (β-CD), epichlorohydrin (EP) and choline chloride (CC). Indomethacin (IDM), an anionic drug, was chosen as a model drug to evaluate the drug loading capacities of CPβCDs. The formation of IDM-CPβCD complex was confirmed by 1H NMR and DSC. Phase solubility studies and Job plots indicated that CPβCDs can solubilize IDM up to 100 times of its intrinsic solubility in a 1:1 complexation form. Mechanism studies with the help of adamantane revealed that the effective complexation is a combination of inclusion complexation, charge interaction and hydrophobic interaction. In addition, IDM-CPβCDs loaded alginate hydrogels were prepared and obtained controllable release profile in dissolution tests. The tunable structures of CPβCDs make them promising drug carriers with superior drug loading capacities and controllable drug release abilities.