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Essential oils (EOs) are highly appreciated plant products in the food industry as sustainable alternative preservatives due to their high antimicrobial activity. For this reason, active packaging with EOs is a strategy with high potential for the preservation of fresh fruit and vegetables. In this work, the evolution of the physicochemical quality of lemons (var. Verna) in boxes with active paper sheets (EOs encapsulated in β-cyclodextrins) was studied for 5 weeks at 8 ºC, with supplementary commercialization simulation periods (5 days at room temperature). Lemons with active packaging showed less weight loss (1.3 %) compared to control samples (2.1 %), and maintained 30 % more firmness after 5 weeks, while color was not affected (p >0.05). In conclusion, the packaging of lemons with active paper sheets can be considered as an excellent conservation alternative, since it releases EO in a controlled manner preserving the lemon quality during both refrigerated and commercialization periods.

The obtainment of new materials with distinct properties by mixing two or more polymers is a potential strategy in sustainable packaging research. In the present work, a blend of cellulose acetate (CA) and zein (60:40 wt/wt CA:zein) was manufactured by adding glycerol or tributyrin as plasticizers (30% wt/wt), and garlic essential oil (GEO), complexed (IC) or not with β-cyclodextrin (βCD), to produce active packaging. Blends plasticized with tributyrin exhibited a more homogeneous surface than those containing glycerol, which showed major defects. The blends underperformed compared with the CA films regarding mechanical properties and water vapor permeability. The presence of IC also impaired the films’ performance. However, the blends were more flexible than zein brittle films. The films added with GEO presented in vitro activity against Listeria innocua and Staphylococcus aureus. The IC addition into films, however, did not ensure antibacterial action, albeit that IC, when tested alone, showed activity against both bacteria. These findings suggest that the mixture of CA and plasticizers could increase the range of application of zein as a sustainable packaging component, while essential oils act as a natural bioactive to produce active packaging.

(1) Background: New clean technologies are needed to reduce the high frying oil waste in the food industry of fried breaded products, together with the obtention of healthier (less fat content) and safer (less microbial growth and acrylamide formation) breaded products; (2) Methods: This study proposes the new technology consisting of incorporation of encapsulated extra virgin olive oil (EVOO) (α-cyclodextrin: EVOO ratio, 1:2.6) in the breadcrumbs (corn breadcrumbs:encapsulated oil ratio, 2:1) for breading chicken nuggets combined with oil-free pre-cooking (baking 150 °C/5 min) and cooking (baking 180 °C/13 min). As controls, a conventional deep-fat frying (180 °C/30 s) and new technology but without encapsulated EVOO were used; (3) Results: Fat content of baked chicken nuggets with the new technology was reduced by 88%, while no sensory differences were scored compared with conventional deep-fat frying. Furthermore, acrylamide formation was reduced by >55% with the new technology. During storage (4 °C) of pre-cooked chicken nuggets of new technology, microbial growth was reduced by 1.4 log units lower compared with deep-fat frying method; (4) Conclusions: the proposed new technology, based on encapsulated EVOO+oil-free pre-cooking/cooking, allows to obtain chicken nuggets that are healthier, safer, and have a longer shelf-life, while frying oil waste is avoided.

Prednisolone is a widely used immunosuppressive and anti-inflammatory drug type that suffers from low aqueous solubility and bioavailability. Due to the inclusion complexation with cyclodextrins (CDs), prednisolone’s drawbacks that hinder its potential during the administration can be eliminated effectively. Here, we have early shown the electrospinning of free-standing nanofibrous webs of CD/prednisolone inclusion complexes (ICs) in the absence of a polymer matrix. In this study, hydroxypropyl-beta-CD (HPβCD) has been used to form ICs with prednisolone and generate nanofibrous webs with a drug loading capacity of ∼10% (w/w). Pullulan/prednisolone nanofibrous webs have been also fabricated as a control sample having the same drug loading (∼10%, w/w). It has been demonstrated that prednisolone has been found in an amorphous state in the HPβCD/prednisolone nanofibrous web due to inclusion complexation, while it has retained its crystal structure in the pullulan/prednisolone nanofibrous web. Therefore, the HPβCD/prednisolone IC nanofibrous web has shown a faster and enhanced release profile and superior disintegration feature in artificial saliva than the pullulan/prednisolone nanofibrous web. The complexation energy calculated using ab initio modeling displayed a more favorable interaction between HPβCD and prednisolone in the case of a molar ratio of 2:1 than 1:1 (CD: drug). Here, the HPβCD/prednisolone IC nanofibrous web has been developed without using a toxic component or solvent to dissolve drug molecules and boost drug loading in amorphous nature. The investigation of IC nanofibrous webs has been conducted to formulate a promising alternative to the orally disintegrating tablet formulation of prednisolone in the market. The nanofibrous structure and the improved physicochemical properties of prednisolone arising with the complexation might ensure a faster disintegration and onset of action against commercially available and orally disintegrating delivery systems during the desired treatment.

The understanding of the relationship between molecular structure and the thermodynamics of host-guest binding is essential for the rational design of the applications of inclusion complexes. To obtain insight into the factors governing the driving force of complex formation in aqueous solutions, the encapsulation of five pharmaceutically important protoberberine alkaloids was studied in sulfobutylether-β-cyclodextrin having on average 6.4 degrees of substitution (SBE6.4βCD). Spectrophotometric, fluorescence spectroscopic, and isothermal calorimetric measurements showed 1:1 complexation in dilute solutions. From 1.92 × 104 M−1, about an eight-fold decrease of the association constant was observed in the series of berberine ≈ coptisine >> palmatine > epiberberine > dehydrocorydaline. The embedment of these alkaloids in the SBE6.4βCD cavity was entropy-controlled with mildly negative enthalpy contributions. These findings suggest that the stabilization of the examined complexes arises primarily from the hydrophobic interaction between the constituents. The more than three orders of magnitude smaller association constants of protoberberine alkaloids with SBE6.4βCD than with cucurbit[7]uril, a host having similar cavity size, originates from the much smaller exothermicity of the confinement in the former macrocycle.

The 3-(Methylthio) propyl isothiocyanate (MTPITC)-loaded inclusion complex prepared by α-cyclodextrin (α-CD) was incorporated into chitosan (CS) film to fabricate a packaging material for fresh chicken meat preservation. Scanning electron microscope images indicated homogenous dispersion of the MTPITC-α-CD in CS polymer. Fourier-transform infrared and X-ray diffraction techniques revealed that MTPITC-α-CD was incorporated into the CS film matrix by the physical interactions. The introduction of MTPITC-α-CD improved the UV-vis light-blocking ability, with a slight loss of transparency. Although the water solubility and water vapor barrier capacity were not significantly influenced by the addition of MTPITC-α-CD, the antioxidant attribute was significantly enhanced. The CS-MTPITC-α-CD film displayed obvious and sustained suppressive effects against Salmonellatyphimurium, with the inhibition zone diameters of 14.7 mm at 12 h and 7.3 mm at 24 h, respectively. Moreover, the quality index analysis indicated that the CS-MTPITC-α-CD film-wrapped fresh chicken, during refrigerated storage, exhibited better preservative efficacy than the control groups, with the total viable counts of 6.5 Log CFU/g, total volatile base nitrogen of 8.4 mg/100 g, pH of 6.6, thiobarbituric acid-reactive substances of 0.2 mg/kg, and the sensory score of 5 at day 16. Collectively, these results suggest that CS-MTPITC-α-CD film is a prospective packaging candidate for delaying the quality deterioration of chicken meat.

Diphenylguanidine (DPG) is a widely used secondary accelerator for the vulcanization of natural rubber (NR) latex. However, its low water solubility and high toxicity limit its use in high-end NR products. In this study, a water-soluble inclusion complex of DPG and a β-cyclodextrin polymer (β-CDP), termed DPG-β-CDP, was prepared through supramolecular interactions and characterized using Fourier-transform infrared spectroscopy, 1H NMR, scanning electron microscopy, and UV-vis spectroscopy techniques. In comparison with that of DPG, the water solubility of DPG-β-CDP was greatly enhanced because of the water-soluble host molecule. The molar ratio of DPG to the CD unit in β-CDP was determined to be 1:1. At 25 °C, the binding constant of DPG-β-CDP was found to be 9.2 × 105 L/mol by UV-vis spectroscopy. The proposed method for forming inclusion complexes with high potential for use as water-soluble vulcanization accelerators is promising.

Curcumin (CUR), a curcuminoid originating from turmeric root, possesses diverse pharmacological applications, including potent anticancer properties. However, the use of this efficacious agent in cancer therapy has been limited due to low water solubility and poor bioavailability. To overcome these problems, a drug delivery system was established as an excipient allowing improved dispersion in aqueous media coupled with enhanced in vitro anticancer effects. Different analyses such as UV–vis spectroscopy, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), solubility and dissolution assays were determined to monitor the successful encapsulation of CUR within the inner cavity of a β-cyclodextrin (β-CD) complex. The results indicated that water solubility was improved by 205.75-fold compared to pure CUR. Based on cytotoxicity data obtained from MTT assays, the inclusion complex exhibited a greater decrease in cancer cell viability compared to pure CUR. Moreover, cancer cell migration rates were decreased by 75.5% and 38.92%, invasion rates were decreased by 37.7% and 35.7%, while apoptosis rates were increased by 26.3% and 14.2%, and both caused caspase 3 activation toward colorectal cancer cells (SW480 and HCT116 cells). This efficacious formulation that enables improved aqueous dispersion is potentially useful and can be extended for various chemotherapeutic applications. Preliminary toxicity evaluation also indicated that its composition can be safely used in humans for cancer therapy.

The poor aqueous solubility and/or permeability and thereby limited bioavailability largely restricts the pharmaco-therapeutic implications of potent anticancer drugs such as methotrexate (MTX). Furthermore, MTX’s inherently unstable nature makes it difficult to develop a viable oral formulation. In this study we developed the spray-dried amorphous inclusion complexes of MTX with native β-cyclodextrin (β-CD) and its derivatives, namely HP-β-CD, M-β-CD, and DM-β-CD to enhance the aqueous solubility, photostability, permeability, and oral bioavailability of MTX in rats. Our findings show that the 1:1 stoichiometry ratio of MTX and CDs improves the aqueous solubility, stability, and pharmacokinetic profiles of the drug, the better results being obtained particularly with DM-β-CD as a host, which has a higher complexation ability with the drug compared to other β-CDs. Specifically, the pharmacokinetic analysis demonstrated 2.20- and 3.29-fold increments in AUC and Cmax, respectively, in comparison to free MTX. Even though the absorptive permeability of MTX and MTX/DM-β-CD inclusion complexes was similar, the efflux of the absorbed MTX from ICs was significantly lower compared to the free MTX (4.6- vs. 8.0-fold). Furthermore, the physicochemical characterization employing SEM, DSC, and PXRD confirmed the transformation of crystalline MTX to its amorphous state. In solution, 1H NMR studies revealed that MTX embedded into the DM-β-CD cavity resulting in both H-3 and H-5 chemical shifts implied the presence of intermolecular interaction between the drug and CD moiety. It was, therefore, evident that an MTX IC could be a successful oral formulation technique, preventing MTX degradation and enhancing its pharmacologically relevant properties.

This study concentrated on developing quercetin/cyclodextrin inclusion complex-loaded polyvinyl alcohol (PVA) hydrogel for enhanced stability and solubility. Quercetin was encapsulated in hydroxypropyl-β-cyclodextrin (HP-β-CD) by the solvent evaporation method. The prepared quercetin/HP-β-CD inclusion complex showed 90.50 ± 1.84% encapsulation efficiency (%EE) and 4.67 ± 0.13% loading capacity (%LC), and its successful encapsulation was confirmed by FT-IR and XRD. The quercetin/HP-β-CD inclusion complex was well dispersed in viscous solutions of PVA in various amounts (0.5, 1.0, 1.5. 2.5, and 5.0% w/v ratio), and the drug-loaded polymer solution was physically crosslinked by multiple freeze–thaw cycles to form the hydrogel. The cumulative amount of quercetin released from the prepared hydrogels increased with increasing concentrations of the inclusion complex. The introduction of the inclusion complex into the PVA hydrogels had no influence on their swelling ratio, but gelation and compressive strength reduced with increasing inclusion complex concentration. The potential cytotoxicity of quercetin/HP-β-CD inclusion complex hydrogels was evaluated by MTT assay and expressed as % cell viability. The results show biocompatibility toward NCTC 929 clone cells. The inhibitory efficacy was evaluated with 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay, and the results show a higher level of antioxidant activity for quercetin/HP-β-CD inclusion complex hydrogels compared with free quercetin. The findings of our study indicate that the developed quercetin/HP-β-CD inclusion complex hydrogels possess the required properties and can be proposed as a quercetin delivery system for wound-healing applications.

This study aimed to evaluate and compare the efficacy of cyclodextrans (CIs) and cyclodextrins (CDs) in improving the water solubility of a poorly water-soluble drug, clofazimine (CFZ). Among the evaluated CIs and CDs, CI-9 exhibited the highest percentage of drug inclusion and the highest solubility. Additionally, CI-9 showed the highest encapsulation efficiency, with a CFZ:CI-9 molar ratio of 0.2:1. SEM analysis indicated successful formation of inclusion complexes CFZ/CI and CFZ/CD, accounting for the rapid dissolution rate of the inclusion complex. Moreover, CFZ in CFZ/CI-9 demonstrated the highest drug release ratio, reaching up to 97%. CFZ/CI complexes were found to be an effective means of protecting the activity of CFZ against various environmental stresses, particularly UV irradiation, compared to free CFZ and CFZ/CD complexes. Overall, the findings provide valuable insights into designing novel drug delivery systems based on the inclusion complexes of CIs and CDs. However, further studies are needed to investigate the effects of these factors on the release properties and pharmacokinetics of encapsulated drugs in vivo, in order to ensure the safety and efficacy of these inclusion complexes. In conclusion, CI-9 is a promising candidate for drug delivery systems, and CFZ/CI complexes could be a potential formulation strategy for the development of stable and effective drug products.

Doxycycline (DX) is a well-established and broad-spectrum antimicrobial drug. However, DX has drawbacks, such as physicochemical instability in aqueous media and bacterial resistance. The inclusion of drugs in cyclodextrin complexes and their loading into nanocarriers can overcome these limitations. Thus, we studied the DX/sulfobutylether-β-CD (SBE-β-CD) inclusion complex for the first time and used it to reticulate chitosan. The resulting particles were evaluated by their physicochemical characteristics and antibacterial activity. DX/SBE-β-CD complexes were characterized by nuclear magnetic resonance, infrared spectroscopy, thermal analysis, X-ray diffraction, and scanning electron microscopy (SEM), whereas DX-loaded nanoparticles were characterized by dynamic light scattering, SEM, and drug content. The partial inclusion of the DX molecule in CD happened in a 1:1 proportion and brought increased stability to solid DX upon thermal degradation. Chitosan-complex nanoparticles measured approximately 200 nm, with a narrow polydispersity and particles with sufficient drug encapsulation for microbiological studies. Both formulations preserved the antimicrobial activity of DX against Staphylococcus aureus, whereas DX/SBE-β-CD inclusion complexes were also active against Klebsiella pneumoniae, indicating the potential use of these formulations as drug delivery systems to treat local infections.

Funding Information: This work was developed within the scope of the CICS-UBI projects UIDB/00709/2020 and UIDP/00709/2020, financed by national funds through the Portuguese Foundation for Science and Technology/MCTES. This work was also supported by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB. Diana Gomes also acknowledges the doctoral fellowship from FCT ref: 2020.06792.BD. Diana Costa acknowledges FCT her Assistant Researcher Contract 2021.03946.CEECIND. The microscopy facility used in the development of this work is part of the PPBI-Portuguese Platform of BioImaging and is partially supported by the Project POCI-01-0145-FEDER-022122. Publisher Copyright: © 2023 by the authors. Quercetin is a natural flavonoid with high anticancer activity, especially for related-HPV cancers such as cervical cancer. However, quercetin exhibits a reduced aqueous solubility and stability, resulting in a low bioavailability that limits its therapeutic use. In this study, chitosan/sulfonyl-ether-β-cyclodextrin (SBE-β-CD)-conjugated delivery systems have been explored in order to increase quercetin loading capacity, carriage, solubility and consequently bioavailability in cervical cancer cells. SBE-β-CD/quercetin inclusion complexes were tested as well as chitosan/SBE-β-CD/quercetin-conjugated delivery systems, using two types of chitosan differing in molecular weight. Regarding characterization studies, HMW chitosan/SBE-β-CD/quercetin formulations have demonstrated the best results, which are obtaining nanoparticle sizes of 272.07 ± 2.87 nm, a polydispersity index (PdI) of 0.287 ± 0.011, a zeta potential of +38.0 ± 1.34 mV and an encapsulation efficiency of approximately 99.9%. In vitro release studies were also performed for 5 kDa chitosan formulations, indicating a quercetin release of 9.6% and 57.53% at pH 7.4 and 5.8, respectively. IC50 values on HeLa cells indicated an increased cytotoxic effect with HMW chitosan/SBE-β-CD/quercetin delivery systems (43.55 μM), suggesting a remarkable improvement of quercetin bioavailability. publishersversion published

Vitamin D plays a significant role in the physiological functions of the human body. However, the application of vitamin D in functional foods is limited due to its sensitivity to light and oxygen. Therefore, in this study, we developed an effective method to protect vitamin D by encapsulating it in amylose. In detail, vitamin D was encapsulated by amylose inclusion complex, followed by structural characterization and evaluation of its stability and release properties. The results of X−ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy showed that vitamin D was successfully encapsulated in the amylose inclusion complex, and the loading capacity was 1.96% ± 0.02%. The photostability and thermal stability of vitamin D after encapsulation was increased by 59% and 28%, respectively. In addition, in vitro simulated digestion showed that vitamin D was protected through the simulated gastric environment and can be released gradually in the simulated intestinal fluid, implying its improved bioaccessibility. Our findings provide a practical strategy for the development of functional foods based on vitamin D.

International journal of molecular sciences 24(4), 3990 (2023). doi:10.3390/ijms24043990 special issue: "Special Issue "Cyclodextrins: Properties and Applications" / Special Issue Editors: Prof. Dr. Miguel A. Esteso, Guest Editor; Prof. Dr. Carmen M. Romero, Guest Editor", Published by Molecular Diversity Preservation International, Basel

The objective of this study was to investigate characterization of inclusion complexes of flavonoids with hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complexes of flavonoids with HP-β-CD was prepared by the freeze-drying method and its characterization was investigated by different analytical techniques including ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry, and X-ray diffractometry. The catechin/HP-β-CD complex exhibited the highest encapsulation efficiency (83.37%), followed by epicatechin/HP-β-CD (81.51%), morin hydrate/HP-β-CD (81.38%), and quercetin/HP-β-CD (81.16%). The inclusion complexes of HP-β-CD showed a decrease in the absorption of flavonoids with a small shift (≈2 nm) of the λmax, while similar to the characteristic absorption peak of flavonoids. However, the FT-IR spectra of the flavonoid/HP-β-CD inclusion complexes did not display any features that were like the pure flavonoids, although the spectra were very similar to that of HP-β-CD. The melting point of flavonoids disappeared, and the thermal properties of HP-β-CD were altered following formation of the inclusion complex between flavonoids and HP-β-CD, resulting in a shift in the melting peak.

The objective of this study was to synthesize and characterize inclusion complexes of phenolic acids with hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complexes were prepared by the freeze-drying method and characterized using a variety of analytical techniques, including ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffractometry. The results of all these approaches indicated that phenolic acids were able to form an inclusion complex with HP-β-CD, and the phenolic acids/HP-β-CD inclusion compounds exhibited different spectroscopic features and properties based on the phenolic acids employed. The use of the HP-β-CD matrix allowed for higher encapsulation efficiency and afforded capsules with distinct shapes.

In this study, guest:host inclusion complexes of silver cyclohexane di carboxylate (Ag-CdC) with β-cyclodextrin wereprepared by kneading and physical mixing techniques, and analyzed via Fourier transformed infrared spectroscopy (FTIR) andthermogravimetric analyser (TGA). The 1:1 and 1:2 stoichiometry of the guest:host were prepared. Obtained FTIR and TGA resultsshowed that formation of silver cyclohexane di carboxylate (Ag-CdC): β-cyclodextrin (β-CD) inclusion complexes occurred at a massratio of both 1:1 and 1:2. Furthermore, these prepared inclusion complexes were doped in poly(vinyl alcohol) nanofibers duringelectrospinning process for obtaining nanowebs. The formation of nanowebs were investigated with scanning electron microscopy(SEM). Besides, FTIR and TGA analysis were also carried out. Results showed that both inclusion complex preparation and inclusioncomplex added PVA nanowebs production were successful., Bu çalışmada, gümüş sikloheksan di karboksilat (Ag-CdC) ile β-siklodekstrin içeren konuk:konak inklüzyon kompleksleriyoğurma ve fiziksel karıştırma teknikleriyle hazırlanmış ve Fourier dönüştürülmüş kızılötesi spektroskopi (FTIR) ve termogravimetrikanalizör (TGA) ile analiz edilmiştir. Konuk:konak, 1:1 ve 1:2 stokiyometri ile hazırlandı. Elde edilen FTIR ve TGA sonuçları, gümüşsikloheksan di karboksilat (Ag-CdC): β-siklodekstrin (β-CD) inklüzyon komplekslerinin oluşumunun hem 1:1 hem de 1:2'lik kütleoranında gerçekleştiğini gösterdi. Ayrıca, hazırlanan bu inklüzyon kompleksleri, nanoweb elde etmek için elektrospinning işlemisırasında poli(vinil alkol) nanofiberlere katılmıştır. Nanoweblerin oluşumu taramalı elektron mikroskobu (SEM) ile araştırıldı. FTIRve TGA analizleri de ayrıca yapıldı. Sonuçlar, hem inklüzyon kompleksi hazırlama hem de inklüzyon kompleksi eklenmiş PVAnanoweb üretiminin başarılı olduğunu gösterdi.

In this study, we investigated the host–guest interactions between oroxin A (OA) and cucurbit[8]uril (Q[8]) using 1H NMR, MS, UV–vis and IR spectroscopy. The results showed that OA and Q[8] formed an inclusion compound (OA@Q[8]) with a molar ratio of 1:1 and a binding constant of 1.299 × 107 L·mol−1. In addition, the effect of Q[8] on the properties of OA was investigated through comparative experiments. The solubility of OA in water increased 22.47-fold when the concentration of Q[8] was 1 × 10−4 mol·L−1. Q[8] hardly affected the antioxidant capacity of OA, while the cumulative release of OA in gastric juice increased 2.3-fold after forming the inclusion compound with Q[8].

Acetylshikonin (AcSh), as a red colored pigment found in roots of the plants from family Boraginaceae, showed excellent cytotoxic activity. Due to its hydrophobic nature, and thus poor bioavailability, the aim of this study was to prepare acetylshikonin/β-cyclodextrin (AcSh/β-CD) inclusion complex by using coprecipitation method, characterize obtained system by using UV/VIS, IR and 1H NMR spectroscopy, and determine cytotoxic activity. Phase solubility test indicated formation of AL-type binary system (substrate/ligand ratio was 1:1 M/M), with stability constant Ks of 306.01 M−1. Formation of noncovalent bonds between inner layer of the hole of β-CD and AcSh was observed using spectroscopic methods. Notable changes in chemical shifts of two protons (−0.020 ppm) from naphthoquinone moiety (C6-H and C7-H), as well as protons from hydroxyl groups (−0.013 and −0.009, respectively) attached to C5 and C8 carbons from naphthoquinone part indicate that the molecule of AcSh enters the β-CD cavity from the aromatic side. Cytotoxic activity against HCT-116 and MDA-MB-231 cell lines was measured by MTT test and clonogenic assay. Mechanisms of action of free AcSh and inclusion complex were assessed by flow cytometry. In comparison to free AcSh, AcSh/β-CD showed stronger short-term effect on HCT-116 cells and superior long-term effect on both cell lines. Inclusion complex induced more pronounced cell cycle arrest and autophagy inhibition, and induced increase in accumulation of intracellular ROS more effectively than free AcSh. In conclusion, AcSh/β-CD binary system showed better performances regarding cytotoxic activity against tested tumor cell lines. Keywords: Acetylshikonin, β-Cyclodextrin, Inclusion complex, Cytotoxicity

(1) Background: When the body is exposed to microwave radiation, the brain is more susceptible to damage than other organs. However, few effective drugs are available for the treatment of microwave-induced brain injury (MIBI) because most drugs are difficult to cross the blood–brain barrier (BBB) to reach the brain. (2) Methods: Nasal cinnarizine inclusion complexes with thermo-and ion-sensitive hydrogels (cinnarizine ISGs) were prepared to treat MIBI and the characteristics of the inclusion complexes and their thermo-and ion-sensitive hydrogels were evaluated. (3) Results: Due to high viscosity, cinnarizine ISGs can achieve long-term retention in the nasal cavity to achieve a sustained release effect. Compared with the model, the intranasal thermo-and ion-sensitive cinnarizine ISGs significantly improved the microwave-induced spatial memory and spontaneous exploration behavior with Morris water maze and open field tests. Cinnarizine ISGs inhibited the expression of calcineurin and calpain 1 in the brain, which may be related to the inhibition of calcium overload by cinnarizine. (4) Conclusion: Intranasal thermo- and ion-sensitive cinnarizine ISGs are a promising brain-targeted pharmaceutical preparation against MIBI.

Active packaging with essential oils (EOs) encapsulated in β-cyclodextrins is a strategy to achieve a controlled EOs release, whose antimicrobial and antioxidant properties are widely known. The microbial loads of lemons (cv. Verna) packaged in a box including an active paper sheet (EOs encapsulated in β-cyclodextrins) was studied during refrigerated storage (8 ºC) with supplementary commercialization periods (5 days at room temperature). Lemons preserved with active sheets showed 0.5 and ≈3 log CFU cm -2 lower mesophilic loads than control samples after 5 weeks of refrigeration and their respective commercialization periods. In addition, the active sheets reduced Enterobacteriaceae and yeasts/molds growth by ≈1, 1.23, and 0.1 log CFU cm -2, respectively. On the other side, the physicochemical quality (soluble solid content, pH and titratable acidity) of lemons was not affected by the active packaging. In conclusion, the active packaging preserved the microbial quality in lemon while physicochemical quality was not affected.

The main purpose of this work was to compare the effects of the four preparation methods on the TFLX/HP-β-CD inclusion complex. The effects of different preparation methods on the inclusion complex were investigated by SEM, DSC, PXRD, FT-IR and 1H NMR. All the characterization information indicated that the four preparation methods could cause interaction between TFLX and HP-β-CD, but the inclusion complex prepared by solvent evaporation has more reaction sites. Phase solubility experiments demonstrated that the inclusion reaction was spontaneous. In vitro dissolution experiments showed that the dissolution of the inclusion complex in water was: solvent evaporation method (64.39%) > grinding method (42.37%) > ultrasonic method (40.00%) > freezing method (36.08%), and all higher than pure TFLX and physical mixture. These results suggest that the solvent evaporation is the most suitable method for preparing TFLX/HP-β-CD inclusion complexes.

Veratridine (VTD) is a plant neurotoxin that acts by blocking the voltage-gated sodium channels (VGSC) of cell membranes. Symptoms of VTD intoxication include intense nausea, hypotension, arrhythmia, and loss of consciousness. The treatment for the intoxication is mainly focused on treating the symptoms, meaning there is no specific antidote against VTD. In this pursuit, we were interested in studying the molecular interactions of VTD with cyclodextrins (CDs). CDs are supramolecular macrocycles with the ability to form host–guest inclusion complexes (ICs) inside their hydrophobic cavity. Since VTD is a lipid-soluble alkaloid, we hypothesized that it could form stable inclusion complexes with different types of CDs, resulting in changes to its physicochemical properties. In this investigation, we studied the interaction of VTD with β-CD, γ-CD and sulfobutyl ether β-CD (SBCD) by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy. Docking and molecular dynamics studies confirmed the most stable configuration for the inclusion complexes. Finally, with an interest in understanding the effects of the VTD/CD molecular interactions, we performed cell-based assays (CBAs) on Neuro-2a cells. Our findings reveal that the use of different amounts of CDs has an antidote-like concentration-dependent effect on the cells, significantly increasing cell viability and thus opening opportunities for novel research on applications of CDs and VTD. info:eu-repo/semantics/publishedVersion

Persistence and degradation are important factors in determining the safe use of such synthetic products, and numerous studies have been addressed to develop pesticide remediation methods aimed at ameliorating these features. In this frame, the use of different cyclodextrins (CDs) molecules has attracted considerable attention due to their well-known non-toxic nature, limited environmental impact, and capability to reduce the environmental and health risks of pesticides. CDs appear to be a valuable tool for the elimination of pesticides from polluted areas as well as for better pesticide formulations that positively influence their hydrolysis or degradation. The present work investigates the interaction between β-cyclodextrins and three commonly used pesticides (i.e., chlorpropham, monuron, and propanil) both in solution and in the solid state by means of UV-Vis, FT-IR, and X-ray powder diffractometry. We show that such interactions result in all three cases in the formation of inclusion complexes with a 1:1 stoichiometry and binding constants (Kb) of 369.9 M−1 for chlorpropham, 292.3 M−1 for monuron, and 298.3 M−1 for propanil. We also report the energy-minimized structures in silico for each complex. Our data expand and complement the available literature data in indicating CDs as a low-cost and very effective tool capable of modulating the properties that determine the environmental fate of pesticides.

Didymin is a dietary flavonoid that first found in citrus fruits, and possesses antioxidant properties. Our preliminary experiments first discovered that didymin was able to sensitize the resistant cancer cells against chemotherapeutics and combat multidrug resistance. However, its poor aqueous solubility and resultant low bioavailability limit its potentials as an adjuvant phytochemical drug for chemotherapy. Thus, this study prepared the inclusion complex of didymin with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin to improve its bioavailability and then evaluate their chemosensitization effects. The didymin inclusion complexes formulation was prepared and their host-guest structure was characterized by FT-IR, PXRD, DSC, and SEM techniques. In vitro/in vivo results demonstrated that didymin inclusion complex enhanced its water solubility and orally bioavailability. Furthermore, didymin inclusion complex exerted considerable chemosensitivity potency, and improve the anti-tumor effects of chemotherapeutics in vivo. Therefore, didymin inclusion complex could provide a safe, effective, economical, and adjuvant drug for future treatment of chemoresistant cancers.

Cannabidiol (CBD) is one specific kind of the cannabinoid in Cannabis sativa L with a wide range of pharmacological activities. However, the poor water solubility and specificity of CBD limits its application in pharmaceutical field. For solving these problems, in this work, we successfully prepared a targeted carrier by grafting biotin (BIO) onto ethylenediamine-β-Cyclodextrin (EN-CD) in a single step to generate a functionalized supramolecule, named BIO-CD. Subsequently, an amantadine-conjugated cannabinoids (AD-CBD) was prepared and self-assembled with the BIO-CD. A series of methods were used to characterize the inclusion behavior and physicochemical properties of AD-CBD and BIO-CD. The results showed that AD-CBD entered the cavity of BIO-CD and formed a 1:1 host-guest inclusion complex. MTT assay and confocal laser scanning microscopy (CLSM) revealed that the targeting effect and anticancer activity of AD-CBD/BIO-CD inclusion complex against three human cancer cell lines were higher than BIO-CD, AD-CBD and free CBD. Moreover, the inclusion complex could release drugs under weakly acidic conditions. These results demonstrated that AD-CBD/BIO-CD inclusion complex possess excellent targeted and anticancer activity, which is hopeful to be applied in clinic as a new therapeutic approach.

Background There is an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing. Therefore, the combination therapy of anti-inflammatory and anti-tumor drugs may show promising to inhibit colon cancer. 5-aminosalicylic acid (5-ASA) with anti-inflammatory function is effective for maintaining remission in patients with ulcerative colitis and may also reduce colorectal cancer risk. Histone deacetylase (HDAC) plays an essential role in the progression of colon cancer. Butyric acid (BA) is a kind of HDAC inhibitor and thus shows tumor suppression to colon cancer. However, the volatile and corrosive nature of BA presents challenges in practical application. In addition, its clinical application is limited due to its non-targeting ability and low bioavailability. We aimed to synthesize a novel dual-prodrug of 5-ASA and BA, referred as BBA, to synergistically inhibit colon cancer. Further, based on the fact that folate receptor (FR) is over-expressed in most solid tumors and it has been identified to be a cancer stem cell surface marker in colon cancer, we took folate as the targeting ligand and used carboxymethyl-β-cyclodextrin (CM-β-CD) to carry BBA and thus prepared a novel inclusion complex of BBA/FA-PEG-CM-β-CD. Results It was found that BBA/FA-PEG-CM-β-CD showed significant inhibition in cell proliferation against colon cancer cells SW620. It showed a pro-longed in vivo circulation and mainly accumulated in tumor tissue. More importantly, BBA/FA-PEG-CM-β-CD gave great tumor suppression effect against nude mice bearing SW620 xenografts. Conclusions Therefore, BBA/FA-PEG-CM-β-CD may have clinical potential in colon cancer therapy. Graphical Abstract

The interactions of two conformers of newly synthesized photoswitchable azobenzene analogue of methotrexate, called Phototrexate, with two cavitand derivatives, have been investigated in dimethyl sulfoxide medium. Photoluminescence methods have been applied to determine the complex stabilities and the related enthalpy and entropy changes associated to the complex formation around room temperature. Results show opposite temperature dependence of complex stabilities. The structure of the upper rims of the host molecules and the reordered solvent structure were identified as the background of the opposite tendencies of temperature dependence at molecular level. These results can support the therapeutic application of the photoswitchable phototrexate, because the formation of inclusion complexes is a promising method to regulate the pharmacokinetics of drug molecules.

The encapsulation of the famous alkaloid, anabasine, with β-CD was studied to obtain a more stable and bioavailable inclusion complex. Various in silico and experimental studies of the obtained β-CD-anabasine complex are presented. Firstly, molecular docking studies were conducted against the α, β, and γ cyclodextrins to explore which subclass is the best for encapsulation. The obtained results that pointed at β-cyclodextrin were further confirmed by five MD simulations and MM-PBSA studies. Experimentally, the spectral properties of the anabasine β-cyclodextrin complex were determined by FT-IR, 1H, and 13C-NMR spectroscopic methods. Additionally, the surface morphology of the anabasine β-cyclodextrin was investigated using a scanning electron microscope. Furthermore, the outputs of the thermographic measurements utilizing a differential scanning calorimeter were displayed. The activation energy of the reaction of thermo-oxidative destruction of the clathrate complex was calculated, and the kinetic parameters of the thermal destruction processes were decided using the Freeman–Carroll, Sharpe–Wentworth, Achar, and Coates–Redfern methods. The kinetic parameters of the thermal decomposition of the anabasine β-cyclodextrin were in agreement and verified the reliability of the obtained results. The obtained computational, spectral, morphological, and thermogravimetric results verified the successful formation of the anabasine β-cyclodextrin complex.

Due to its low solubility, carbamazepine (CBZ) exhibits slow and incomplete release in the gastrointestinal tract and, hence, variable pharmacokinetics and pharmacodynamic effect. Lots of methods have been devised to improve its solubility, the large number of proposed solutions being a sign that the problem is not yet satisfactorily solved. The persistent problem is that predictable release kinetics, an increased rate but within defined limits, are required to avoid high absorption variability. This paper presents a synthesis of a carbamazepine-β-cyclodextrin inclusion complex (CBZ-β-CD), the characterization of the physical mixture, CBZ, β-CD and the CBZ-β-CD inclusion complex using Fourier transform infrared spectroscopy, scanning electron microscopy, simultaneous thermal analysis and X-ray diffraction, formulation of chewable tablets, determination of the dissolution of carbamazepine in medium containing 1% sodium lauryl sulfate (LSS), and in simulated saliva (SS), mathematical modeling of release kinetics. The kinetics of total CBZ release from tablets containing CBZ-β-CD and super-disintegrant F-Melt in both SS and LSS followed two steps: a burst release in the first minutes and a slower release in intervals up to 60 min. The release in the second phase has been well described by the Higuchi and Peppas models, which advocate a controlled release by combined diffusion and with some phenomena of swelling and relaxation of the matrix generated by the crospovidone component of the F-Melt excipient.

A combination of Fourier transform infrared spectroscopy in attenuated total reflectance geometry (FTIR-ATR) and 2D correlation analysis (2D-COS) was applied here for the first time in order to investigate the temperature-dependent dynamical evolution occurring in a particular type of inclusion complex, based on sulfobutylether-β-cyclodextrin (SBE-β-CD) as hosting agent and Coumestrol (7,12-dihydorxcoumestane, Coum), a poorly-soluble active compound known for its anti-viral and anti-oxidant activity. For this purpose, synchronous and asynchronous 2D spectra were calculated in three different wavenumber regions (960–1320 cm−1, 1580–1760 cm−1 and 2780–3750 cm−1) and over a temperature range between 250 K and 340 K. The resolution enhancement provided by the 2D-COS offers the possibility to extract the sequential order of events tracked by specific functional groups of the system, and allows, at the same time, the overcoming of some of the limits associated with conventional 1D FTIR-ATR analysis. Acquired information could be used, in principle, for the definition of an optimized procedure capable to provide high-performance T-sensitive drug carrier systems for different applications.

Glaucocalyxin A (GLA), is a diterpenoid extracted from Hara and has been studied for decades for its diverse bioactivities. However, GLA presents poor solubility in water and low bioavailability through oral administration which has hindered its application in the clinic. So in this study, we prepared the inclusion complex of GLA in SBE-β-CD by ultrasound method and evaluated its antitumor effect and cytotoxic effect on cancer cells. The production of GLA-SBE-β-CD inclusion complex was optimized using Box-Behnken design. The inhibitory effects of GLA and GLA-SBE-β-CD were investigated on the Hela, A549, HepG2, and SiHa cells in vitro by MTT staining assay. Pharmacokinetic studies were conducted on Sprague-Dawley mice via caudal injection to study the distribution, metabolism, and elimination of GLA-SBE-β-CD in vivo. Tumor-bearing nude mice were taken as the model and adopted to evaluate the inhibitory rate of GLA and GLA-SBE-β-CD on the transplanted tumor. A series of physical characterization results confirmed the fact that GLA-SBE-β-CD inclusion complex was successfully prepared. A production of 87.28% was achieved based on the Box-Behnken design. In the cancer cell inhibition studies, GLA and GLA-SBE-β-CD exhibited apparent concentration-dependent inhibitory actions on four kinds of tumor cells and better inhibition was achieved in GLA-SBE-β-CD group. The pharmacokinetic results showed that the duration of GLA in blood was prolonged and enhanced bioavailability was achieved. GLA and GLA-SBE-β-CD both showed an effective inhibition on the transplanted tumor growth, while the anti-tumor effect of GLA-SBE-β-CD (inhibitory rate of 45.80%) was significantly stronger than that of GLA (30.76%) based on the change of tumor weight and tumor volume.

Anthocyanidins, the aglycons of anthocyanins, are known, beyond their function in plants, also as compounds with a wide range of biological and pharmacological activities, including cytostatic effect against various cancer cells. The nature and position of the substituents in the flavylium cation is essential for such biological properties, as well as the equilibrium between the multistate of the different chemical species that are generated by the flavylium cation, including quinoidal base, hemiketal, and cis- and trans-chalcones. In this work, eight new flavylium derivatives were synthesized, characterized for confirmation of the structure by FT-IR and 2D-NMR, and investigated in vitro as possible cytostatic compounds against HCT116 and HepG2 cancer cells. The most active two compounds were explored for their halochromic properties that can influence the biological activity and subjected to molecular encapsulation in β-cyclodextrin derivatives in order to increase their solubility in water and bioavailability. The anticancer effect was influenced by the position (6-, 7-, or 8-) of the methoxy group in the β-ring of the methoxy-4′-hydroxy-3′-methoxyflavylium cation, while the study of the halochromic properties revealed the important role played by the chalcone species of the pH-dependent multistate in both the uncomplexed and inclusion complex forms of these anthocyanidins.

Anthocyanins have great health benefits, especially malvidin. Vitis amurensis Rupr are rich in malvidin, and malvidin-3-O-glucoside (Mv3G) monomer is the most abundant. However, natural anthocyanins are unstable, which limits their wide application in the food field. Soybean insoluble dietary fiber (SIDF) has high stability, and it can be used as an inert substrate to construct a stable system, which may improve the stability of anthocyanins. The optimal condition to construct a stable system of SIDF and Mv3G at pH 3.0 was determined by an orthogonal experiment. The results indicated that SIDF effectively improved the stability of Mv3G under different pH values (1.0~7.0), high temperature (100 °C for 100 min), and sunlight (20 ± 2 °C for 30 d) conditions. The absorption peak intensity of the UV–VIS spectrum of SIDF-Mv3G was enhanced, which indicated that there was interaction between SIDF and Mv3G. Fourier transform infrared spectroscopy analyses revealed that the -OH stretching vibration peak of SIDF-Mv3G was changed, which indicated that the interaction between SIDF and Mv3G was due to hydrogen bonding. X-ray diffraction analysis showed that the crystalline morphology of SIDF was opened, which was combined with Mv3G, and SIDF made Mv3G change to a more stable state. Scanning electron microscope analysis showed that SIDF and Mv3G were closely combined to form an inclusion complex. Overall, this study provides valuable information for enhancing the color stability of anthocyanins, which will further expand the application of anthocyanins in the food field.

Background: Glibenclamide is an oral antidiabetic drug which is practically insoluble in water. Formation of s-cyclodextrin inclusion complex was able to increase glibenclamide solubility. Objective: Aims of this study are to characterize, formulate and evaluate inclusion complex tablets of glibenclamide to meet the requirements in Pharmacopeia. Methods: Inclusion complex was prepared in a 1: 1 and 1: 2 molar ratio by spray drying method. Characterization were performed by using Fourier Transform Infrared (FTIR) spectroscopy and Scanning Electron Microscope (SEM). Further, it was formulated into tablets by direct compression technique using primojel and crospovidone as disintegrants. Uniformity weight, hardness, friability, disintegration, and tablets were evaluated include dissolution. Dissolution studies of inclusion complex were performed by using United States Pharmacopeia (USP) II apparatus. Drug concentration dissolution was determined with high pressure liquid chromatography (HPLC). Results: Result of FTIR and SEM provided evidence of glibenclamide and s-cyclodextrin complex formation after using spray drying methods. The tablet evaluation with primojel and crospovidone as disintegrant showed that increase concentration of disintegrant would increase disintegration time of the tablets. All of the formulas meet the requirements in the Pharmacopoeia. Conclusion: The inclusion complex of glibenclamide–s cyclodextrin successfully used for enhancing the solubility of glibenclamide. The tablets meet the requirements in Pharmacopeia.

In this study, we attempted to prepare an amylose-oligo[(R)-3-hydroxybutyrate] (ORHB) inclusion complex using a vine-twining polymerization approach. Our previous studies indicated that glucan phosphorylase (GP)-catalyzed enzymatic polymerization in the presence of appropriate hydrophobic guest polymers produces the corresponding amylose–polymer inclusion complexes, a process named vine-twining polymerization. When vine-twining polymerization was conducted in the presence of ORHB under general enzymatic polymerization conditions (45 °C), the enzymatically produced amylose did not undergo complexation with ORHB. However, using a maltotriose primer in the same polymerization system at 70 °C for 48 h to obtain water-soluble amylose, called single amylose, followed by cooling the system over 7 h to 45 °C, successfully induced the formation of the inclusion complex. Furthermore, enzymatic polymerization initiated from a longer primer under the same conditions induced the partial formation of the inclusion complex. The structures of the different products were analyzed by X-ray diffraction, 1H-NMR, and IR measurements. The mechanism of formation of the inclusion complexes discussed in the study is proposed based on the additional experimental results.

Cyclodextrins (CDs) and their derivatives have good prospects in soil remediation application due to their ability to enhance the stability and solubility of low water-soluble compounds by inclusion performance. To investigate the effect of different structural properties of cyclodextrin and its derivatives on the inclusion complexation, molecular dynamic (MD) simulations were performed on the inclusion complexes formed by three kinds of CDs with polycyclic aromatic hydrocarbons (PAHs). Based on neutral β-CD, the other two CDs were modified by introducing substitutional groups, including 2-hydroxypropyl and sulfonated butyl (SBE) functional groups in the ring structure, called HP-CD and SBE-CD. MD results show that PAH can merely enter into the cavity of SBE–β-CD from its wide rim. The substitutional groups significantly affect the structure of CDs, which may also cause the flipping of the glucose units. However, the substitutional groups can also enlarge the volume of the hydrophobic cavity, resulting in a tight combination with the guest molecules.

Unprotected exposure of skin to solar ultraviolet radiation (UVR) may damage the DNA of skin cells and can lead to skin cancer. Sunscreens are topical formulations used to protect skin against UVR. The active ingredients of sunscreens are UV filters that absorb, scatter, and/or reflect UVR. Preventing the formation of free radicals and repairing DNA damages, natural antioxidants are also added to sunscreens as a second fold of protection against UVR. Antioxidants can help stabilise these formulations during the manufacturing process and upon application on skin. However, UV filters and antioxidants are both susceptible to degradation upon exposure to sunlight and oxygen. Additionally, due to their poor water solubility, natural antioxidants are challenging to formulate and exhibit limited penetration and bioavailability in the site of action (i.e., deeper skin layers). Cyclodextrins (CDs) are cyclic oligosaccharides that are capable of forming inclusion complexes with poorly soluble drugs, such as antioxidants. In this review, we discuss the use of CDs inclusion complexes to enhance the aqueous solubility of antioxidants and chemical UV filters and provide a protective shield against degradative factors. The role of CDs in providing a controlled drug release profile from sunscreens is also discussed. Finally, incorporating CDs inclusion complexes into sunscreens has the potential to increase their efficiency and hence improve their skin cancer prevention.

The quantitative structure-retention relationship (QSRR) models are not only employed in retention behaviour prediction, but also in an in-depth understanding of complex chromatographic systems. The goal of the present research is to enable the comprehensive understanding of retention underlying the separation in β-cyclodextrin (CD) modified reversed-phase high performance liquid chromatography (RP-HPLC) systems, through the development of mixed QSRR models. Moreover, the amount of β-CD adsorbed on the stationary phase surface (β-CDA) is added as the model's input in order to evaluate its contribution to both model performances and retention. Nuclear magnetic resonance (NMR) experiments were conducted to confirm the predicted inclusion complex structures and support the application of in silico tools. The most significant descriptors revealed that retention is governed by the steric factors 7.5 A distant from the geometrical centre of a molecule, 3D arrangement of atoms determining the molecular size and shape, lipophilicity indicated by topological distances, as well as the unbound system's energy, related to the inclusion complex formation. In addition, a notable effect of the pH of the aqueous phase on the retention of ionizable analytes was shown. In the case of pH of the aqueous phase and β-CDA the change in retention behaviour of the studied analytes was observed only at the highest β-CDA value (5.17 μM/m2), but it was not related to the ionization state of analytes. When the analytes did not change the ionization form across the investigated studied pH range, and the acetonitrile content in the mobile phase was 25% (v/v), the retention factor had low values regardless of the β-CDA; under these circumstances the retention is probably acetonitrile driven.

[Resumen]: La búsqueda de nuevos macrociclos con capacidad para complejar distintas moléculas ha despertado un gran interés en el campo de la Química Supramolecular. Concretamente, la investigación se ha centrado en aquellos capaces de responder a distintos estímulos y compatibles con el medio biológico, por su importancia en biomedicina. Uno de los macrociclos más prometedores es el ciclofano tetracatiónico blue box, ya que puede formar complejos de inclusión con compuestos aromáticos π-excedentes de tamaño adecuado. No obstante, su síntesis es un proceso largo, poco rentable y con bajo rendimiento. Para conseguir una síntesis más eficaz, se está desarrollando actualmente una metodología basada en la química covalente dinámica de iminas para el ensamblaje de análogos de la blue box. Esto ha permitido recientemente la obtención de un análogo acil hidrazona, la white box así como de un derivado de dihidrazona, la red box. En el presente estudio se ha sintetizado el macrociclo red box y un análogo funcionalizado del mismo¸ que puede sufrir numerosas modificaciones, de forma sencilla y eficiente, gracias al ensamblaje de sus componentes mediante la formación de nuevos enlaces imina bajo control cinético. Además, se estudia el posible uso en biomedicina de la red box, mediante la formación de complejos de inclusión con dos sustratos de gran utilidad, como son el naproxeno y el 8-metoxipsoraleno. [Resumo]: A procura de novos macrociclos con capacidade para complexar distintas espertou un gran interese no campo da Química Supramolecular. Concretamente, a investigación centrouse naqueles capaces de responder a distintos estímulos e compatibles co medio biolóxico, pola súa importancia en biomedicina. Un dos macrociclos máis prometedores é o ciclofano tetracatiónico blue box, xa que pode formar complexos de inclusión con compostos aromáticos π-excedentes de tamaño adecuado. Non obstante, a súa síntese é un proceso largo e cun baixo rendemento. Para conseguir unha síntese máis eficaz, estase desenrolando unha nova metodoloxía que fai uso medio da química covalente dinámica de iminas para a ensamblaxe de análogos da blue box. Isto permitiu obter recentemente un análogo con un grupo acil hidrazona, a white box e, así como de un derivado de dihidrazona, a red box. No presente estudio sintetizouse o macrociclo red box e un análogo funcionalizado do mesmo, que pode sufrir numerosas modificacións, de forma sinxela e eficiente, grazas á ensamblaxe dos seus compoñentes mediante a formación de novos enlaces imina baixo control cinético. Ademais, estúdase o posible uso en biomedicina da red box, mediante a formación de complexos de inclusión con dous substratos de grande utilidade, como son o naproxeno e o 8-metoxipsoraleno. [Abstract]: The search for new macrocycles with the ability to form complexes with several molecules of interest is highly relevant in the field of Supramolecular Chemistry. Specifically, research has been focused on those macrocycles capable of reacting to different stimuli on a biological environment, due to their importance in the field of biomedicine. One of the most promising macrocycles is the tetracationic cyclophane blue box, as it can form inclusion complexes with suitably-sized aromatic π-donors. However, its synthesis is a long kinetically-controlled low yielding process. To achieve an efficient synthesis, a new methodology is currently being developed, that makes use of dynamic covalent chemistry of imines for the assembly of blue box analogues. This has made possible the development of an acyl hydrazone analogue, the white box, and, more recently, a dihydrazone derivative, the red box. In the present study, the red box macrocycle and a functionalized analogue have been synthesized¸ which can undergo various modifications, in a simple and efficient way, thanks to the assembly of its components through the formation of new imine bonds under kinetic control. In addition, the possible use in biomedicine of the red box is studied, through the formation of inclusion complexes with two very useful substrates, such as naproxen and 8-methoxypsoralen. Traballo fin de grao (UDC.CIE). Química. Curso 2020/2021

Orientador: Laura de Oliveira Nascimento Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Farmacêuticas Resumo: A doxiciclina (DX) é um medicamento antimicrobiano de uso consolidado e que pode ser utilizado para tratar infecções respiratórias e bucais. No entanto, o uso da DX é limitado devido à sua instabilidade em meio aquoso, resistência bacteriana e baixa penetração celular. Sabe-se que a inclusão de fármacos em complexos de ciclodextrina ou em nanopartículas (NPs) podem superar essas desvantagens. Assim, este trabalho teve como objetivo desenvolver complexos de inclusão DX/sulfobutiléter-?-ciclodextrina (SBE-?-CD) e nanopartículas de quitosana carregadas com DX e em seguida, avaliar suas propriedades físico-químicas e antimicrobianas. A formação dos complexos DX/SBE-?-CD foi confirmada por ressonância magnética nuclear, espectroscopia de infravermelho, análises térmicas, difração de raios X e microscopia eletrônica de varredura (MEV). Não foram observadas melhorias na estabilidade da DX em solução após a formação do complexo, entretanto, o complexo no estado sólido proporcionou maior estabilidade térmica para o fármaco. Nanopartículas carregadas com DX foram caracterizadas por espalhamento dinâmico de luz (DLS) e SEM. A metodologia aplicada resultou em nanopartículas monodispersas satisfatórias (índice de polidispersão: 0,039, tamanho de partícula: 209,7 nm, potencial zeta: +17,5 mV) com taxa de encapsulação (25,2%) suficiente para ser avaliada em estudos microbiológicos. Ambas as formulações (NPs e complexo) mantiveram a atividade antimicrobiana da DX contra Staphylococcus aureus, enquanto apenas os complexos de inclusão DX/SBE-?-CD foram ativos contra Klebsiella pneumoniae. Acreditamos que NPDX não tenha mostrado ação contra K. pneumoniae devido a concentração testada estar próxima ao limite da concentração inibitória mínima para essa cepa, porém, é possível solucionar essa questão através da liofilização das NPs, que permitiria o aumento da concentração da formulação. Assim, as formulações obtidas foram capazes de proteger o fármaco termicamente e têm potencial para serem utilizadas como sistemas de liberação de fármacos para o tratamento de infecções locais Abstract: Doxycycline (DX) is a well-established antimicrobial drug that could be used to treat respiratory and buccal infections. Nonetheless, DX use is limited due to its instability in aqueous media, bacterial resistance, and low cellular penetration. It is known that the inclusion of drugs in cyclodextrin complexes or nanoparticles (NPs) can overcome these drawbacks. Thus, this study aimed to develop DX/sulfobutylether-?-Cyclodextrin (SBE-?-CD) inclusion complexes and DX-loaded chitosan nanoparticles and evaluate their physicochemical and antimicrobial properties. The formation of DX/SBE-?-CD complexes were confirmed by nuclear magnetic resonance, infrared spectroscopy, thermal analysis, X-ray diffraction and scanning electron microscopy (SEM). No improvements in DX stability in solution were observed after complex formation, however, it was identified that the complex in solid state provided increased thermal stability for the drug. DX-loaded nanoparticles were characterized by dynamic light scattering (DLS) and SEM. The applied methodology resulted in appropriate monodisperse nanoparticles (polydispersity index: 0.039, particle size: 209.7 nm, zeta potential: 17.5 mV) with sufficient encapsulation rate (25.2%) to be evaluated in microbiological studies. Both formulations (NPs and complex) maintained the antimicrobial activity of DX against Staphylococcus aureus, while only the DX/SBE-?-CD inclusion complexes were active against Klebsiella pneumoniae. We believe that NPDX has not shown action against K. pneumoniae due to the concentration tested being close to the limit of minimum inhibitory concentration, however, it is possible to solve this issue through lyophilization of NPs, which would allow increased concentration. Thus, the formulations obtained are able to protect the drug thermally and have the potential to be used as drug delivery systems for the treatment of local infections Mestrado Fármacos, Medicamentos e Insumos para Saúde Mestra em Ciências FAPESP 2019/08281-5 CAPES 0

[SPA] El brócoli es una inflorescencia cuya vida útil puede verse altamente reducida durante su conservación postcosecha debido a la alta sensibilidad de esta Brassica al etileno. El efecto visual más evidente debido al etileno es el amarilleamiento de esta hortaliza. La producción de etileno del brócoli podría ser reducida con aceites esenciales (AEs), incluso a bajas concentraciones. En esta Tesis se estudiará el efecto de aceites esenciales (complejos de inclusión formados con β-ciclodextrina) liberados de un envase activo sobre la producción de etileno del brócoli. Los resultados esperados son: un descenso en la producción de etileno (y conocimiento de la expresión génica de las enzimas claves en la ruta de biosíntesis del etileno) y un aumento de la vida útil del brócoli con el envase activo con aceites esenciales. [ENG] Broccoli is an inflorescence whose useful life can be highly reduced during its post-harvest storage due to the high sensitivity of this Brassica to ethylene. The most obvious visual effect due to ethylene is the yellowing of this vegetable. The ethylene production in broccoli could be reduced with essential oils (EOs), even at low concentrations. In this Thesis, the effect of encapsulated essential oils (inclusion complexes formed with β-cyclodextrin) released from an active package will be studied on the ethylene production of broccoli. The expected results are: decrease of the ethylene production (understanding the gene expression of the key enzymes of the ethylene biosynthesis pathway) and extension of the broccoli shelf life with the active packaging with EOs.

In this work, rutin (RUT)&ndash, &beta, cyclodextrin (&beta, CD) inclusion complexes are prepared by Supercritical AntiSolvent (SAS) precipitation. Well-defined composite microparticles are obtained at guest:host ratios equal to 1:2 and 1:1 mol:mol. The dimensions of composite particles range between 1.45 &plusmn, 0.88 &micro, m and 7.94 &plusmn, 2.12 &micro, m. The formation of RUT&ndash, CD inclusion complexes has been proved by different analyses, including Fourier transform infrared spectroscopy, Differential Scanning Calorimetry, X-ray diffraction, and UV-vis spectroscopy. The dissolution tests reveal a significant improvement in the release rate of RUT from inclusion complexes. Indeed, compared to the unprocessed RUT, the dissolution rate is about 3.9 and 2.4 times faster in the case of the complexes RUT&ndash, CD 1:2 and 1:1 mol:mol, respectively. From a pharmaceutical/nutraceutical point of view, CD-based inclusion complexes allow the reduction of the polymer amount in the SAS composite formulations.

Ozone (O3) has been widely used for the elimination of recalcitrant micropollutants in aqueous environments, due to its strong oxidation ability. However, the utilization efficiency of O3 is constrained by its low solubility and short half-life during the treatment process. Herein, an integrated approach, using nanobubble technology and micro-environmental chemistry within cyclodextrin inclusion cavities, was studied in order to enhance the reactivity of ozonisation. Compared with traditional macrobubble aeration with O3 in water, nanobubble aeration achieved 1.7 times higher solubility of O3, and increased the mass transfer coefficient 4.7 times. Moreover, the addition of hydroxypropyl-β-cyclodextrin (HPβCD) further increased the stability of O3 through formation of an inclusion complex in its molecule-specific cavity. At a HPβCD:O3 molar ratio of 10:1, the lifespan of O3 reached 18 times longer than in a HPβCD-free O3 solution. Such approach accelerated the removal efficiency of the model micropollutant, 4-chlorophenol by 6.9 times, compared with conventional macrobubble ozonation. Examination of the HPβCD inclusion complex by UV–visible spectroscopy and Nuclear Magnetic Resonance analyses revealed that both O3 and 4-chlorophenol entered the HPβCD cavity, and Benesi-Hildebrand plots indicated a 1:1 stoichiometry of the host and guest compounds. Additionally, molecular docking simulations were conducted in order to confirm the formation of a ternary complex of HPβCD:4-chlorophenol:O3 and to determine the optimal inclusion mode. With these results, our study highlights the viability of the proposed integrated approach to enhance the ozonation of organic micropollutants.

Risperidone (RSP) is an atypical antipsychotic drug which acts as a potent antagonist of serotonin-2 (5TH2) and dopamine-2 (D2) receptors in the brain, it is used to treat schizophrenia, behavioral and psychological symptoms of dementia and irritability associated with autism. It is a poorly water soluble benzoxazole derivative with high lipophilicity. Supramolecular adducts between drug substance and two methylated &beta, cyclodextrins, namely heptakis(2,6-di-O-methyl)-&beta, cyclodextrin (DM-&beta, CD) and heptakis(2,3,6-tri-O-methyl)-&beta, cyclodextrin (TM-&beta, CD) were obtained in order to enhance RSP solubility and improve its biopharmaceutical profile. The inclusion complexes were evaluated by means of thermoanalytical methods (TG&mdash, thermogravimetry/DTG&mdash, derivative thermogravimetry/HF&mdash, heat flow), powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy and saturation solubility studies. Job&rsquo, s method was employed for the determination of the stoichiometry of the inclusion complexes, which was found to be 2:1 for both guest&ndash, host systems. Molecular modeling studies were carried out for an in-depth characterization of the interaction between drug substance and cyclodextrins (CDs). The physicochemical properties of the supramolecular systems differ from those of RSP, demonstrating the inclusion complex formation between drug and CDs. The RSP solubility was enhanced as a result of drug encapsulation in the CDs cavity, the higher increase being obtained with DM-&beta, CD as host, the guest&ndash, host system RSP/DM-&beta, CD can thus be a starting point for further research in developing new formulations containing RSP, with enhanced bioavailability.

Detailed studies on the stability, interaction, and microstructure of host‐guest complexes in the vacuum of 5‐fluorouracil (5FU) with β‐cyclodextrin (βCD) were performed using B3LYP with the inclusion of Grimme's dispersion correction GD3 term and 6‐31+G(d,p) basis set. Among several studied 1:1 5FU‐βCD complexes, the one placing the keto tautomer of 5FU vertically in the host cavity and forming N‐H···OCD and CO···HOCD hydrogen bonds with hydroxyl groups of the smaller rim of βCD has the highest stability (Eint = −195 kJ/mol). Interestingly, there are no interactions with the inner hydrophobic part of the βCD host cavity. The strength of the intermolecular H‐bonds to the smaller rim of βCD is comparable to those in 5FU‐water and 5FU‐methanol clusters, used as model systems characterizing the noncovalent interactions. Of several studied host‐guest complexes, the inner ones are more stable than the outer systems. Our results reveal that taking dispersion interaction in DFT into account is essential for reliable modeling of the structure, interaction, and stability of 5FU‐βCD complexes. This study is crucial for understanding the interaction of 5FU with βCD in the solid state and additionally suggests the presence of equilibrium between 5FU‐βCD complex and solvated 5FU.

The complexes formed by beta-cyclodextrin and some amino acids (alanine, valine, leucine and isoleucine) in vacuo are studied by molecular mechanics and dynamics simulations. These methods have been improved with respect to our previous studies with amino acids, regarding the determination of molecular structures or initial enantiomer dispositions in the molecular dynamics trajectories. The greatest contribution to the interaction energy is from the van der Waals term, although the discrimination between enantiomers is due mainly to the electrostatic contribution. The lowest energy structures of the complexes obtained from molecular mechanics are inclusion complexes in which the carboxylic end of amino acids is pointing towards the narrow (D-) or wide rim (L-) of beta-cyclodextrin. The position probability density provided by molecular dynamics also confirms inclusion complex formation, because the guests spend most time inside the cavity of beta-cyclodextrin along its axis, with the carboxylic end pointing towards the narrow rim. The L-amino acids are the first eluted enantiomers in all cases and chiral discrimination increases with the size of guests, except leucine, which has the lowest capacity to discriminate. During the simulation, Ala and Val remain in weakly enantioselective regions, while Leu and Ile stay in zones with great chiral selectivity.

The quality loss of fruit and vegetables should be minimized to reduce food waste during retail. In that sense, sustainable and effective post-harvest techniques/technologies are needed, showing active packaging including encapsulated essential oils a high potential. In that sense, we studied the effect of different sized active packages (including β-cyclodextrin-EOs inclusion complex) on the quality of grapes, nectarines, and lettuces (as models of berry fruit, stone fruit, and leafy vegetables) during storage at 2°C (90–95% relative humidity). The active industrial tray showed the best effect on grapes and lettuce quality, as it reduced rachis dehydration and product weight loss (reduced by ≈50% in grapes after 30 days), reduced berry shatter (reduced by ≈40% in grapes after 30 days), highly maintained the physicochemical quality (soluble solid content, titratable acidity and firmness), and also reduced microbial growth (0.5–1.4 lower log units than non-active industrial tray). For nectarines, the package with the biggest active surface (large tray, 200 × 300 × 90) also showed the best-quality retention compared to smaller packages, showing nectarines within active large tray better microbial quality (0.6–1 lower log units than non-active large tray) and firmness. As expected, flow packaging of nectarines (using active trays) better controlled the product weight loss. In conclusion, active cardboard packages with greater active surface better preserved quality of grapes, nectarines and lettuce, which sensory quality was accepted after more than 30, 25, and 14 days at 2°C, respectively, contrary to non-active samples (~1 week less).