Stable Inclusion Complexes Research Articles

Host–guest interactions of Crizotinib with natural and modified cyclodextrins: a combined molecular docking and molecular dynamics simulation approaches

ABSTRACT In this work, molecular docking and molecular dynamics (MD) simulation were applied to investigate the ability of natural cyclodextrins (CDs; Alpha, Beta and Gamma Cyclodextrins) and modified CDs (hydroxypropyl, random methyl and amino Beta Cyclodextrins) to form the stable inclusion complexes (ICs) with Crizotinib, the oral small molecule kinase inhibitor as a chemotropic drug. Results of molecular docking and MD simulation studies demonstrated that Crizotinib forms stable ICs with all natural and modified CDs and in the presence of this drug, all six CDs become more rigid. The presence of Crizotinib and the release of water molecules result in a decrease in the number of hydrogen bonds between cyclodextrins (CDs) and solvent molecules within the encapsulated CDs, compared to the hydrogen bonds observed in free CDs. Additionally, HPBCD exhibited the strongest affinity for binding and established the highest quantity of hydrogen bonds with Crizotinib. Finally, all results of this paper demonstrated the potential of using this formulation to improve the bioavailability of the selected drug.

Physico-chemical studies of inclusion complex between hydrocortisone and cyclodextrins

Hydrocortisone (HC) is widely utilized in the pharmaceutical field for various administration routes, including oral, parenteral, and topical routes. However, its application in ocular disease treatment as a solution is limited due to its poor aqueous solubility. To address this limitation, in this study we aimed to investigate different types of cyclodextrins (CDs) to identify the most effective CD for improving the inherent solubility of HC. Results from scanning electron microscopy, rheology and differential scanning calorimetry (DSC) demonstrated the formation of inclusion complexes, while isothermal titration calorimetry (ITC) investigations accurately determined the thermodynamic parameters associated with the formation of complexes between HC and HPβCD or βCD, at 25 and 37 °C. Additionally, phase solubility studies in PBS buffer at 37 °C confirmed the formation of stable inclusion complexes. Collectively, results indicated that HPβCD was the most effective CD in enhancing the intrinsic solubility of HCs in PBS highlighting its potential for improving the solubility and formulation of HC-based pharmaceutical products.

Host-guest complexation of (pyridinyltriazolylthio) acetic acid with cucurbit[n]urils (n=6,7,8): Molecular calculations and thermogravimetric analysis

Cucurbiturils are cage-like macrocyclic molecules that can form strong host–guest inclusion complexes, offering remarkably higher selectivity over conventional macrocycles towards guests with particular sizes and shapes. Here we use a combination of molecular docking, semiempirical quantum-chemical (PM6, PM7) and high-level DFT calculations along with all-atom molecular dynamics (MD) simulations to characterize 1:1 host-guest complexation between the cucurbit[n]urils (CB[n], where n = 6–8) and biologically active 2-[[5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]thio]acetic acid (PTTA). While the molecular docking and the semiempirical calculations suggest that PTTA favors inserting into larger size cavities of CB[7] and CB[8], the classical OPLS-AA MD simulations of the potential of the mean force (PMF) in an aqueous solution demonstrate the favorable free binding energy of PTTA with all three studied CB[n]s (n = 6–8). These findings were further examined by refining the binding energy of the MD-derived PTTA-CB[n] structures by the high-level dispersion-corrected DFT calculations. Our combined MD/DFT approach provides the detailed host-guest complexation mechanism and suggests that the stability of the host-guest inclusion complex of PTTA with CB[n]s decreases in the order CB[6]>CB[7]>CB[8]. Finally, the formation of the stable inclusion complex of PTTA with CB[6] was validated by thermogravimetric analysis and differential scanning calorimetry measurements, pointing out that low-level quantum-chemical methods might be unable to capture the correct thermodynamics of host-guest supramolecular structures based on cucurbituril macrocycles.

A bipolar Electrode-Electrochemiluminescence sensor for Salmonella typhimurium detection based on β-cyclodextrin Host-Guest recognition

A bipolar electrode electrochemiluminescence (BPE-ECL) with β-cyclodextrin (β-CD) host–guest recognition was constructed for the rapid detection of Salmonella typhimurium (S. typhimurium). Firstly, the sulfhydryl β-CD (SH-β-CD, with inner diameter size: 6.0–6.5 Å) was assembled on the gold-plated cathode of BPE. Ferrocene (Fc, length: 3.5 Å; width: 4.4 Å) labelled signal probe and parts Fc-aptamer complement each other to form a double-stranded DNA (dsDNA). Due to its large size, the dsDNA with a double Fc (width > 8.8 Å) could not be embedded into the cavities of β-CD. In the presence of S. typhimurium, Fc-aptamer bond specifically to S. typhimurium, and the signal probe was shed from the dsDNA. Then, the signal probe (guest) was captured by the SH-β-CD (host) on the surface of the BPE. Due to the principle of spatial matching between Fc and SH-β-CD, a stable inclusion complex could be formed, which made Fc close to the cathode surface of the BPE. When a certain driving voltage was applied, Fc was oxidized to Fc+. The cathode surface of Fc+ would promote electron transfer, causing the [Ru(bpy)3]2+ at the anode emit light, and effectively convert the electrochemical signal into an ECL signal. 101-105 CFU mL−1S. typhimurium was positively correlated with Fc+ and ECL intensity, with a detection limit of 101 CFU mL−1. Therefore, S. typhimurium can be quantitatively detected by the electron transfer rate of the BPE.

Complexation of AAPH (2,2′-azobis(2-methylpropionamidine) dihydrochloride) with cucurbit[7]uril enhances the yield of AAPH-derived radicals

AAPH (2,2′-azobis(2-methylpropionamidine) dihydrochloride), a water-soluble azo compound is widely employed to produce peroxyl radicals for chemical and biological studies. This compound is shown herein to form a stable inclusion complex with cucurbit[7]uril (CB7), a well-established supramolecular host. Competitive binding assays using berberine dye, isothermal titration calorimetry (ITC), and nuclear magnetic resonance (1H NMR) experiments, provided evidence for the inclusion of AAPH inside the CB7 cavity with a binding constant of 2.51 ± 0.76 × 105 M−1 (determined by ITC). Computational analysis at B3LYP-D3BJ/6-311G(d,p) of the complex (AAPH@CB7) showed interactions of the positively-charged amino groups of AAPH with carbonyl functions at the CB7 entrances. Photolysis of AAPH@CB7 by illumination at 365 nm, gave a higher yield of carbon-centered radicals when compared to the absence of CB7, as evidenced by electron paramagnetic resonance spin trapping using α-phenyl-N-t-butylnitrone. Enhanced radical formation was corroborated by increased consumption of pyrogallol red, free Trp and Trp-containing peptides when these were exposed to AAPH@CB7 in the presence of light. The increased yield of radicals generated by AAPH@CB7 is believed to arise from a pull effect of CB7 portals on initial AAPH-derived carbon-centered radicals generated by photolysis. It is proposed that these radicals are exposed and released to the bulk solution and react with O2 to give peroxyl radicals. These results suggest that the AAPH@CB7 complex can be used to generate high yields of peroxyl radicals for their use in studying these species in material, environmental and biomedical sciences amongst others.

Insights on cyclodextrin inclusion complexes in deep eutectic solvents:Water mixtures

The use of cyclodextrins (CDs) in combination with deep eutectic solvents (DESs) is nowadays an emerging and promising strategy for the solvation of hydrophobic compounds, such as aromas. This approach combines the solvation efficiency of the solvent bulk and the complexation ability of CDs. However, literature lacks information about the complexation mechanism in CDs in these non-conventional solvents. Hence, this study aims to elucidate such mechanism by investigating the complexation behavior and the binding ability of β-CD and α-CD towards verbenone and camphor, respectively, in choline chloride:urea DES:water (70:30 wt%) mixture. First, the formation constants (Kf) of the chosen model inclusion complexes were determined by static headspace-gas chromatography (SH-GC). Then, the formation of inclusion complexes was demonstrated by 1H 2D DOSY and 2D ROESY NMR studies. Finally, isothermal titration calorimetry (ITC) experiments were carried out, for the first time in a DES:water mixture, in order to evaluate the thermodynamic parameters of the inclusion phenomenon. Altogether, results proved the formation of stable inclusion complexes in the new non-conventional medium constituted of choline chloride:urea DES:water (70:30 wt%). Interestingly, the thermodynamic signatures and the stoichiometries of interactions were similar between water and choline chloride:urea DES:water (70:30 wt%). In particular, the present study of the α-CD/camphor system constitutes the first report of a 2:1 complex in a DES:water mixture.

Turn-on circularly polarized luminescence for dynamical-racemic and large-hollow AIE macrocycle based on selective recognition for ursolic acid

The macrocycles with the features of large cavity, optical property and CPL response to guest simultaneously are rarely reported but very attractive based on their potential application. Herein, a macrocycle (BiCDB-MC) with dynamically racemic feature, inwardly directed functional groups, a large hollow with size of 1.3 nm and fluorescent property was designed and synthesized. BiCDB-MC was found to have two equally chiral conformations and was dynamically racemic in solution based on their rapidly interconvertion via macrocycle flipping. It was interesting that BiCDB-MC exhibited a selective turn-on CPL response with glum = 0.00248 toward ursolic acid since one of the stable chiral conformations could form a more stable inclusion complex. This kind of turn-on CPL emission for dynamical-racemic macrocycle with CPL recognition for complicated natural chiral compound was described for the first time.

Spectroscopic studies on the supramolecular interactions of methyl benzoate derivatives with p-sulfocalix[6]arene macrocycles

This paper is a continuation of our previous research and aims to further investigate and elucidate the nature and mechanisms of noncovalent supramolecular interactions between four methyl benzoate derivatives (I-IV), which are capable of exhibiting Twisted Intramolecular Charge Transfer (TICT) and/or Excited State Intramolecular Proton Transfer (ESIPT)‐type behavior, and chemical and biological nanocavities. Photophysical and photochemical properties of molecules I-IV in aqueous solution in the presence of well-recognized macrocyclic host p-sulfocalix[6]arenes (SCA[6]) have been studied using steady-state, time-resolved and 1H NMR spectroscopic techniques. The changes in the ground- and excited-state spectroscopic characteristics (absorption and fluorescence spectra, time-resolved fluorescence spectra, fluorescence decay times and 1H NMR spectra) undergo significant modifications upon encapsulation of the investigated methyl benzoate derivative in the macromolecular cavity. For the two compounds (I and II), the interactions with the macrocycles with a hydrophobic SCA[6] cavity lead to the formation of stable inclusion complexes with 1:1 stoichiometry, both in the ground and excited state, while the stoichiometry of the III-SCA[6] and IV-SCA[6] complexes in the ground and excited states is 1:2. The values of the equilibrium constants have been determined from the spectroscopic data using Benesi-Hildebrand and nonlinear regression procedures. The location of the organic molecule inside the SCA[6] has been investigated by 1H NMR experiments. The changes in macrocyclic compound-induced NMR chemical shifts clearly indicate that the chemical structure of inclusion complexes is very different for methyl benzoate derivative-SCA[6] and methyl benzoate derivative-CB[7] systems. Finally, we have shown, using time-dependent fluorescence Stokes shift, that very fast solvation dynamics of pure water is markedly different from that of the confined water molecule in SCA[6] system.

Inclusion complexation of surfactant with β-cyclodextrin and its effect on the mixed micellization of cationic/anionic surfactants

Inclusion complexation of surfactant with β-cyclodextrin (β-CD) is an active research topic in supramolecular chemistry. For the mixed system of β-CD and cationic/anionic surfactants, the thermodynamic and molecular dynamics (MD) simulation studies can provide valuable information about synergism between cationic and anionic surfactants and competition between inclusion complexation and mixed micellization. Experimental results indicated a synergistic effect between CTAB and SL in surface tension reduction efficiency and effectiveness, and in mixed micelle formation. The surface tension experiments indicated that for single surfactant CTAB or SL, the binding stoichiometry was β-CD:surfactant = 1:1. For the 1:1 β-CD/surfactant inclusion complexes, umbrella sampling simulation results indicated that SL bound preferentially to the wide rim of β-CD, while, CTAB had a similar probability of binding to either rim of β-CD. Both experimental and simulation results indicated that the inclusion affinity of β-CD with CTAB was significantly stronger than that of β-CD with SL. Due to the electrostatic attraction between the oppositely charged headgroups, the distance between adjacent CTA+ and L− ions was significantly shorter than that between two adjacent CTA+ (or L−) ions. It encouraged us to explore whether the 1:1:1 β-CD/CTAB/SL inclusion complex could form. The MD simulation results indicated that all four possible initial 1:1:1 conformations were unstable. The final stable inclusion complexes were in 1:1 β-CD/CTAB and 1:1 β-CD/SL forms consistent with the umbrella sampling simulation results of the single surfactant. The results suggested that the inclusion interaction becomes less competitive with mixed micellization as the composition approaches the equimolar ratio of CTAB and SL.

Preparation, physicochemical characterization and computational studies of Plectranthus ornatus codd essential oil/β-cyclodextrin inclusion complex

This study aims to prepare and chemically characterize inclusion complexes (IC) between β-cyclodextrin (β-CD) and Plectranthus ornatus essential oil (OEPO). Samples were evaluated by gas chromatography coupled with mass spectrometry (GC-MS) and Fourier transform infrared spectroscopy (FTIR). Moreover, a theoretical study concerning inclusion complexes of β-CD with the four main compounds of OEPO through Molecular Dynamics (MD) simulations, Density Functional Theory (DFT) and Parametric Method-6 (PM6) calculations was performed. The GC-MS analysis of OEPO resulted in the identification of 36 volatile compounds, with the four main components of this essential oil being: β-caryophyllene (21.52%), terpinen-4-ol (6.89%), phytol (4.00%) and caryophyllene oxide (3.32%). The GC-MS results indicated the presence of OEPO volatile compounds in the ICs prepared by the water/ethanol kneading (KWE) and water kneading (KW) method. More specific, β-CD inclusion complexes with β-butoxyethanol (1.15%), 1,3,8-ρ-menthatriene (0.45%), β-caryophyllene (0.20%), phytol (0.41%) and δ-cadinol (0.20%) prepared by the KWE method were detected, while the KW inclusion method resulted in the encapsulation of β-butoxyethanol (3.98%) only. The higher inclusion content of OEPO molecules in KWE was also confirmed by FTIR, with the KWE complex showing more OEPO absorption bands than KW. The PM6 study showed that hydrogen bonds are important, but hydrophobic interactions are the main driving force for triggering the complex formation of the main OEPO volatile compounds with β-CD. The intermolecular host-guest interactions and the investigation for the most suitable inclusion mode were examined by conducting several Molecular dynamics simulations. Moreover, PM6 and DFT approaches revealed the most stable cyclodextrin inclusion complex structures. These findings are in accordance with the experimental data from GC-MS analysis. The effect of solvent on the interaction energy was also studied through simulations and the results showed that the most stable structures are characterized by the formation of hydrogen bonds between guests and cyclodextrin hosts. The developing of such preparation methods that results in ICs like OEPO/β-CD may be useful in the optimization of existing formulations and therefore, be adopted by the pharmaceutical industry

Evaluation of 6-OxP-CD, an Oxime-based cyclodextrin as a viable medical countermeasure against nerve agent poisoning: Experimental and molecular dynamic simulation studies on its inclusion complexes with cyclosarin, soman and VX.

The ability of the cyclodextrin-oxime construct 6-OxP-CD to bind and degrade the nerve agents Cyclosarin (GF), Soman (GD) and S-[2-[Di(propan-2-yl)amino]ethyl] O-ethyl methylphosphonothioate (VX) has been studied using 31P-nuclear magnetic resonance (NMR) under physiological conditions. While 6-OxP-CD was found to degrade GF instantaneously under these conditions, it was found to form an inclusion complex with GD and significantly improve its degradation (t1/2 ~ 2 hrs) relative over background (t1/2 ~ 22 hrs). Consequently, effective formation of the 6-OxP-CD:GD inclusion complex results in the immediate neutralization of GD and thus preventing it from inhibiting its biological target. In contrast, NMR experiments did not find evidence for an inclusion complex between 6-OxP-CD and VX, and the agent's degradation profile was identical to that of background degradation (t1/2 ~ 24 hrs). As a complement to this experimental work, molecular dynamics (MD) simulations coupled with Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations have been applied to the study of inclusion complexes between 6-OxP-CD and the three nerve agents. These studies provide data that informs the understanding of the different degradative interactions exhibited by 6-OxP-CD with each nerve agent as it is introduced in the CD cavity in two different orientations (up and down). For its complex with GF, it was found that the oxime in 6-OxP-CD lies in very close proximity (PGF⋯OOxime ~ 4-5 Å) to the phosphorus center of GF in the 'downGF' orientation for most of the simulation accurately describing the ability of 6-OxP-CD to degrade this nerve agent rapidly and efficiently. Further computational studies involving the center of masses (COMs) for both components (GF and 6-OxP-CD) also provided some insight on the nature of this inclusion complex. Distances between the COMs (ΔCOM) lie closer in space in the 'downGF' orientation than in the 'upGF' orientation; a correlation that seems to hold true not only for GF but also for its congener, GD. In the case of GD, calculations for the 'downGD' orientation showed that the oxime functional group in 6-OxP-CD although lying in close proximity (PGD⋯OOxime ~ 4-5 Å) to the phosphorus center of the nerve agent for most of the simulation, adopts another stable conformation that increase this distance to ~ 12-14 Å, thus explaining the ability of 6-OxP-CD to bind and degrade GD but with less efficiency as observed experimentally (t1/2 ~ 4 hr. vs. immediate). Lastly, studies on the VX:6-OxP-CD system demonstrated that VX does not form a stable inclusion complex with the oxime-bearing cyclodextrin and as such does not interact in a way that is conducive to an accelerated degradation scenario. Collectively, these studies serve as a basic platform from which the development of new cyclodextrin scaffolds based on 6-OxP-CD can be designed in the development of medical countermeasures against these highly toxic chemical warfare agents.

Supramolecular Assembly of Tetramethylcucurbit[6]uril and 2-Picolylamine.

The supramolecular assembly of symmetrical tetramethylcucurbit[6]uril (TMeQ[6]) and 2-picolylamine (AMPy) has been investigated via various techniques, including ultraviolet-visible (UV-vis) and nuclear magnetic resonance spectroscopy, isothermal titration calorimetry (ITC), and X-ray crystallography. The results indicated that TMeQ[6] could encapsulate the AMPy guest molecule to form a stable inclusion complex. The rotational restriction of the guest in the cavity of TMeQ[6] resulted in a large negative value of entropy. The X-ray crystal structure of the 1:1 inclusion complex between TMeQ[6] and AMPy revealed that AMPy exists in the elliptical cavity of TMeQ[6].

Solubility Enhancement and Inhalation Delivery of Cyclodextrin-Based Inclusion Complex of Delamanid for Pulmonary Tuberculosis Treatment.

Tuberculosis (TB) is a contiguous airborne disease caused by Mycobacterium tuberculosis (M.tb), primarily affecting the human lungs. The progression of drug-susceptible TB to drug-resistant strains, MDR-TB and XDR-TB, has become a global challenge toward eradicating TB. Conventional TB treatment involves frequent dosing and prolonged treatment regimens predominantly by an oral or invasive route, leading to treatment-related systemic adverse effects and patient's noncompliance. Pulmonary delivery is an attractive option as we could reduce dose, limit systemic side-effects, and achieve rapid onset of action. Delamanid (DLD), an antituberculosis drug, has poor aqueous solubility, and in this study, we aim to improve its solubility using cyclodextrin complexation. We screened different cyclodextrins and found that HP-β-CD resulted in a 54-fold increase in solubility compared to a 27-fold and 13-fold increase by SBE-β-CD and HP-ɣ-CD, respectively. The stability constant (265 ± 15M-1) and complexation efficiency (8.5 × 10-4) suggest the formation of a stable inclusion complex of DLD and HP-β-CD in a 2:1 ratio. Solid-state characterization studies (DSC, PXRD, and NMR) further confirmed successful complexation of DLD in HP-β-CD. The nebulized DLD-CD complex solution showed a mass median aerodynamic diameter of 4.42 ± 0.62μm and fine particle fraction of 82.28 ± 2.79%, suggesting deposition in the respiratory airways. In bacterial studies, minimum inhibitory concentration of DLD-CD complex was significantly reduced (four-fold) compared to free DLD in M.tb (H37Ra strain). Furthermore, accelerated stability studies confirmed that the inclusion complex was stable for 4weeks with 90%w/w drug content. In conclusion, we increased the aqueous solubility of DLD through cyclodextrin complexation and improved its efficacy in vitro.

Investigation of the Interaction of Benzo(a)Pyrene and Fluoranthene with Cucurbit[n]urils (n = 6-8): Experimental and Molecular Dynamic Study.

The inclusion complexes of cucurbit[n]uril, CB[n] (n = 6-8), with poly aromatic hydrocarbon (PAH) Benzo(a)Pyrene (BaP), and fluoranthene (FLT) were investigated carefully in aqueous media. Fluorescence and 1H NMR spectroscopy were used to characterize and investigate the inclusion complexes that were prepared in the aqueous media. The most predominant complexes of both guests with hosts were the 1:1 guest: host complexes. Stability constants of 2322 ± 547 M-1, 7281 ± 689 M-1, 3566 ± 473 M-1 were obtained for the complexes of BaP with CB[6], CB[7], and CB[8], respectively. On the other hand, stability constants of 5900.270 ± 326 M-1, 726.87 ± 78 M-1, 3327.059 ± 153 M-1 were obtained for the complexes of FLT with CB[6], CB[7], and CB[8], respectively. Molecular dynamic (MD) simulations were used to study the mode and mechanism of the inclusion process and to monitor the stability of these complexes in aqueous media at an atomistic level. Analysis of MD trajectories has shown that both BaP and FLT form stable inclusion complexes with CB[7] and CB[8] in aqueous media throughout the simulation time, subsequently corroborating the experimental results. Nevertheless, the small size of CB[6] prohibited the encapsulation of the two PAHs inside the cavity, but stable exclusion complex was observed between them. The main driving forces for the stability of these complexes are the hydrophobic forces, van der Waals interactions, electrostatic effect, the π····π and C-H···π interaction. These results suggest that BaP and FLT can form stable complexes with CB[n] (n = 6-8) in solution.

Controlled release and antibacterial properties of nanofiber membrane loaded with tea saponin

The controlled release packaging system has been considered as an efficient strategy for drug delivery, but the contradiction of instability and release difficulty after encapsulation of natural active compound is unsolved. In this research, tea saponin was embedded into the cavity of β-cyclodextrin polymer (β-CDP) to form a stable inclusion complex and then successfully constructed the nanofibers by electrospinning. The optimal polymer substrates (polyacrylonitrile, 0.1 g β-CDP, 0.03 g tea saponin, dendritic mesoporous silica nanoparticles (DMSNs) 3.75 wt% of the mass of PAN) were obtained to fabricate the TS/PAN@ β-CDP-DMSNs with a typical nanofiber structure with uniform diameter distribution and high porosity. The nanofiber exhibited a better thermal stability (270 °C), higher moisture resistance (water contact angle 126.4°) and relatively larger specific surface area. Results of the FTIR and XPS characterization indicate chemical interactions of TS/PAN@ β-CDP-DMSNs via van der Waals forces and hydrogen bonds. As a result, the tea saponin release efficiency increased from 69.30% of liposome to 81.16% of nanofiber at 36 h. Simultaneously, the antibacterial rates against Escherichia coli and Staphylococcus aureus were significantly improved compared with tea saponin and PAN@ β-CDP-DMSNs. This research provides a feasible strategy for the application of the drug delivery systems to both solve the stability and release efficiency of natural active compounds. • A novel TS/PAN@ β-CDP-DMSNs nanofiber was prepared via electrospinning. • Tea saponin with 94.23% purity is obtained by AB-8 macroporous resin. • The PAN@ β-CDP-based nanofiber improves drug stability and release efficiency. • The prepared nanofiber exhibits the remarkable synergistic bacteriostatic effects.

Binding behavior and in vitro cytotoxicity of inclusion complexes between aminopterin and cucurbit[7]uril

Aminopterin (AMT) is a kind of universal antineoplastic drugs, but it has severe toxic and side effects, leaving it rarely used in clinic. Herein, we found that cucurbit[7]uril (CB[7]) and AMT can form stable inclusion complexes, and the formation of CB[7]-AMT 2:1 supramolecular inclusion complex was confirmed by UV-visible absorption spectra, fluorescence spectra, 1H NMR, and molecular modeling calculations in aqueous solution. Binding stability constants (Ks) were determined by UV-visible and fluorescence spectra method, with 3.88 × 1010 L2 mol–2 and 5.24 × 1010 L2 mol–2, respectively. The binding energy was calculated to be 102.6 kcal mol–1 for the CB[7]-AMT complex. And then, through a series of cell experiments of CCK8 assay, DAPI staining and hoechst33342/PI double staining, we fully proved that the CB[7]-AMT complex can reduce the toxicity of AMT to normal cells such as hepatocyte line LO2, and improve its anticancer effect on cancer cells overexpressing spermine, typically like human colon cancer cell line HCT116. It confirmed that the CB[7]-AMT complex had the effect of reducing toxicity and increasing efficiency. These results indicated that CB[7]-AMT inclusion complex might be a promising novel formulation of AMT for its clinical development.

New chromatographic insights on drug:cyclodextrin inclusion complexes and their potential use in drug delivery

ABSTRACT Objectives Cyclodextrins (CDs) play a pivotal role in the controlled release of drugs; however, their ability to gradually release drugs is here interrogated: can cyclodextrins, even those that form strong inclusion complexes, sustain a prolonged release of drugs? Methods An original chromatographic approach was developed and accordingly we classified and determined drugs that form the most stable inclusion complexes with cyclodextrins. β-CD and hydroxypropyl-β-CD (HP-β-CD) were coupled to pullulan (Pul) microspheres and packed into a chromatographic column. Then, different drugs or model compounds were eluted, and values of the retention time (RT) were determined. In vitro release studies were performed for drugs that form the most stable inclusion complexes. Results The drugs with the longest RT value form the most stable inclusion complexes with Pul/β-CD and Pul/HP-β-CD microspheres. Pul/β-CD microspheres form more stable inclusion complexes than Pul/HP-β-CD microspheres. However, in spite of their high stability, they were not able to gradually release the included drug (15 min release time). The cross-chromatographic experiments confirmed the hypothesis that in aqueous solution, drug/cyclodextrin complexes are continuously associated and dissociated. Conclusions If the dissociation of the guest molecule is very rapid, why is it expected that these complexes gradually release the drug?

Development of a ternary cyclodextrin–arginine–ciprofloxacin antimicrobial complex with enhanced stability

Designing useful functionalities in clinically validated, old antibiotics holds promise to provide the most economical solution for the global lack of effective antibiotics, as undoubtedly a serious health threat. Here we show that using the surface chemistry of the cyclodextrin (βCD) cycle and arginine (arg) as a linker, provides more stable ternary antibiotic complex (βCD-arg-cpx). In contrast to classical less stable inclusion complexes, which only modify antibiotic solubility, here-presented ternary complex is more stable and controls drug release. The components of the complex intensify interactions with bacterial membranes and increase the drug’s availability inside bacterial cells, thereby improving its antimicrobial efficacy and safety profile. Multifunctional antibiotics, formulated as drug delivery systems per se, that take the drug to the site of action, maximize its efficacy, and provide optical detectability are envisaged as the future in fighting against infections. Their role as a tool against multiresistant strains remains as interesting challenge open for further research.

Development of dispersive inclusion complex microextraction for the analysis of nitrosamines in medicinal products

A new dispersive inclusion complex microextraction (DICM) approach coupled with ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for the determination of n-nitrosamine impurities in different medicinal products is demonstrated for the first time. The proposed DICM procedures consist of a dispersive liquid phase microextraction steps employing cyclodextrin as an inclusion complex agent to extract n-nitrosamines namely N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-ethyl-N-nitrosoisopropylamine (NEIPA) and N-nitroso-di-n-butylamine (NDBA) present in the medicinal products. The sample solutions were prepared by mixing 5% (m/v) NaCl solution with 1.5 mM β-cyclodextrin and 20 mM sodium dodecyl sulphate to form a stable inclusion complex and subsequently extracted into dichloromethane as an extraction solvent. The enriched solution was reconstituted into aqueous solution prior to UPLC-MS/MS analysis. The method showed good linearity in the range of 0.036–1 ng/mL with a correlation coefficient of at least 0.995, acceptable reproducibility (RSD 0.5–5.8%, n=5), low limits of detection (0.011–0.018 ng/mL), and satisfactory relative recoveries (96–105%). The results obtained were found to be at least 10-fold more sensitive comparable to those obtained using validated direct sample dissolutions coupled with UPLC-MS/MS approach.

Fabrication of fucoxanthin/2-hydroxypropyl-β-cyclodextrin inclusion complex assisted by ultrasound procedure to enhance aqueous solubility, stability and antitumor effect of fucoxanthin

Fucoxanthin (Fx) possesses multiple bioactivities such as antitumor, antioxidant and anti-inflammatory activities, but its application is limited due to the poor water solubility, low bioavailability, and instability to some external harsh conditions. In this study, a stable inclusion complex of Fx and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) was prepared with the aid of ultrasound, which was characterized by scanning electron microscope, Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry techniques. The phase solubility analysis and absorption spectroscopy results showed that Fx formed stoichiometry 1:2 inclusion complex with 2-HP-β-CD, and this could be well proved by molecular simulation. Structural analyses and molecular docking study indicated that Fx was successfully encapsulated into the cavity of 2-HP-β-CD, promoting it soluble in water and stable against heat, storage and gastrointestinal environments. In addition, Fx/2-HP-β-CD inclusion complex exhibited excellent antitumor activity against HCT116 and Caco-2 cell lines with IC50 values of 12.0 μΜ and 14.86 μΜ, respectively. Therefore, it could be a potentially promising way to promote the application of Fx in pharmaceuticals and functional foods by HP-β-CD encapsulation strategy.