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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Macromolecular Chemistry".

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 27262

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Dr. Tivadar Feczkó

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1. Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar tudosok krt. 2., H-1117 Budapest, Hungary
2. Faculty of Engineering, University of Pannonia, Egyetem u. 10., H-8200 Veszprém, Hungary
Interests: polymeric nanoparticles; drug delivery; microencapsulation of phase change materials; energy storage
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. László Biczók

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Research Centre for Natural Sciences, Magyar tudosok krt. 2., H-1117 Budapest, Hungary
Interests: inclusion complexes; self-assembly; supramolecular systems; nanoparticles; fluorescence spectroscopy

Special Issue Information

Dear Colleagues,

Supramolecular chemistry uses the non-covalent-type intermolecular forces. The selective complexation of host and guest molecules results in versatile and especially useful structures. Macrocyclic oligomers, such as cyclodextrins, calixarenes, cucurbiturils, pillararenes, resorcinarenes, spherands, and crown ethers, are the most frequently applied macrocyclic cavitands. The self-assembly processes occur via weak molecular interactions, such as hydrogen bonding, van der Waals forces, hydrophobic interactions, or metal-coordination. Mostly cavity size determines whether a guest molecule can be accommodated by a host. Shape, electrostatic surface of guest, and the inner phase of the host also influence the existence of interactions and whether a chemical manipulation or entrapment of the guest can be generated. In biological applications, natural availability, good water solubility, and biocompatibility are also important considerations. The field of molecular encapsulation provides a challenging platform for enzyme-like molecular recognition, catalytic and photosensitizing applications, molecular recognition and sensing, gas storage, drug delivery, toxic waste removal, water purification, molecular separation, solar cells, energy conversion, and biomedical engineering. The fabricated complexes can be further processed to nanostructures. In drug delivery, probably the most frequently studied cavitands are cyclodextrins, which increase the water solubility of hydrophobic drugs and thus substantially improve their bio-availability. Host–guest supramolecular complexation can provide protection against photoinitiated, hydrolytic, and oxidative degradations of the active agents. In this Special Issue of Molecules entitled "Molecular Encapsulation", original research papers, communications, or review articles on any of these aspects are welcome.

Dr. Tivadar Feczkó
Prof. Dr. László Biczók
Guest Editors

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Keywords

supramolecular chemistry
host–guest interaction
macrocyclic oligomers
nanostructures

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Published Papers (10 papers)

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Research

20 pages, 5432 KiB

Open AccessArticle

Host–Guest Interaction Study of Olmesartan Medoxomil with β-Cyclodextrin Derivatives

by Minodora Andor, Claudia Temereancă, Laura Sbârcea, Adriana Ledeți, Dana Emilia Man, Cristian Mornoș, Amalia Ridichie, Denisa Cîrcioban, Gabriela Vlase, Paul Barvinschi, Angela Caunii, Renata-Maria Văruţ, Cristina Maria Trandafirescu, Valentina Buda, Ionuț Ledeți and Matilda Rădulescu

Molecules 2024, 29(10), 2209; https://doi.org/10.3390/molecules29102209 - 8 May 2024

Viewed by 1030

Abstract

Olmesartan medoxomil (OLM) is a selective angiotensin II receptor antagonist used in the treatment of hypertension. Its therapeutic potential is limited by its poor water solubility, leading to poor bioavailability. Encapsulation of the drug substance by two methylated cyclodextrins, namely randomly methylated β-cyclodextrin (RM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD), was carried out to overcome the limitation related to OLM solubility, which, in turn, is expected to result in an improved biopharmaceutical profile. Supramolecular entities were evaluated by means of thermoanalytical techniques (TG—thermogravimetry; DTG—derivative thermogravimetry), spectroscopic methods including powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier-transform infrared (UATR-FTIR) and UV spectroscopy, saturation solubility studies, and by a theoretical approach using molecular modeling. The phase solubility method reveals an A_L-type diagram for both inclusion complexes, indicating a stoichiometry ratio of 1:1. The values of the apparent stability constant indicate the higher stability of the host–guest system OLM/RM-β-CD. The physicochemical properties of the binary systems are different from those of the parent compounds, emphasizing the formation of inclusion complexes between the drug and CDs when the kneading method was used. The molecular encapsulation of OLM in RM-β-CD led to an increase in drug solubility, thus the supramolecular adduct can be the subject of further research to design a new pharmaceutical formulation containing OLM, with improved bioavailability. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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20 pages, 6269 KiB

Open AccessArticle

Amphiphilic Cyclodextrin Nanoparticles as Delivery System for Idebenone: A Preformulation Study

by Federica De Gaetano, Angela Scala, Consuelo Celesti, Kim Lambertsen Larsen, Fabio Genovese, Corrado Bongiorno, Loredana Leggio, Nunzio Iraci, Nunzio Iraci, Antonino Mazzaglia and Cinzia Anna Ventura

Molecules 2023, 28(7), 3023; https://doi.org/10.3390/molecules28073023 - 28 Mar 2023

Cited by 8 | Viewed by 2179

Abstract

Idebenone (IDE), a synthetic short-chain analogue of coenzyme Q10, is a potent antioxidant able to prevent lipid peroxidation and stimulate nerve growth factor. Due to these properties, IDE could potentially be active towards cerebral disorders, but its poor water solubility limits its clinical application. Octanoyl-β-cyclodextrin is an amphiphilic cyclodextrin (ACyD8) bearing, on average, ten octanoyl substituents able to self-assemble in aqueous solutions, forming various typologies of supramolecular nanoassemblies. Here, we developed nanoparticles based on ACyD8 (ACyD8-NPs) for the potential intranasal administration of IDE to treat neurological disorders, such as Alzheimer’s Disease. Nanoparticles were prepared using the nanoprecipitation method and were characterized for their size, zeta potential and morphology. STEM images showed spherical particles, with smooth surfaces and sizes of about 100 nm, suitable for the proposed therapeutical aim. The ACyD8-NPs effectively loaded IDE, showing a high encapsulation efficiency and drug loading percentage. To evaluate the host/guest interaction, UV-vis titration, mono- and two-dimensional NMR analyses, and molecular modeling studies were performed. IDE showed a high affinity for the ACyD8 cavity, forming a 1:1 inclusion complex with a high association constant. A biphasic and sustained release of IDE was observed from the ACyD8-NPs, and, after a burst effect of about 40%, the release was prolonged over 10 days. In vitro studies confirmed the lack of toxicity of the IDE/ACyD8-NPs on neuronal SH-SY5Y cells, and they demonstrated their antioxidant effect upon H₂O₂ exposure, as a general source of ROS. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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15 pages, 2616 KiB

Open AccessArticle

Effects of Hydroxypropyl-Beta-Cyclodextrin on Cultured Brain Endothelial Cells

by Szilvia Veszelka, Mária Mészáros, Gergő Porkoláb, Ágnes Rusznyák, Katalin Szászné Réti-Nagy, Mária A. Deli, Miklós Vecsernyés, Ildikó Bácskay, Judit Váradi and Ferenc Fenyvesi

Molecules 2022, 27(22), 7738; https://doi.org/10.3390/molecules27227738 - 10 Nov 2022

Cited by 1 | Viewed by 2459

Abstract

The application of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) in the treatment of the rare cholesterol and lipid storage disorder Niemann–Pick disease type C opened new perspectives in the development of an efficient therapy. Even if the systemic administration of HPBCD was found to be effective, its low permeability across the blood–brain barrier (BBB) limited the positive neurological effects. Nevertheless, the cellular interactions of HPBCD with brain capillary endothelial cells have not been investigated in detail. In this study, the cytotoxicity, permeability, and cellular internalization of HPBCD on primary rat and immortalized human (hCMEC/D3) brain capillary endothelial cells were investigated. HPBCD shows no cytotoxicity on endothelial cells up to 100 µM, measured by impedance kinetics. Using a fluorescent derivative of HPBCD (FITC-HPBCD) the permeability measurements reveal that on an in vitro triple co-culture BBB model, FITC-HPBCD has low permeability, 0.50 × 10⁻⁶ cm/s, while on hCMEC/D3 cell layers, the permeability is higher, 1.86 × 10⁻⁵ cm/s. FITC-HPBCD enters brain capillary endothelial cells, is detected in cytoplasmic vesicles and rarely localized in lysosomes. The cellular internalization of HPBCD at the BBB can help to develop new strategies for improved HPBCD effects after systemic administration. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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12 pages, 3362 KiB

Open AccessArticle

Entropy-Driven Inclusion of Natural Protoberberine Alkaloids in Sulfobutylether-β-Cyclodextrin

by Zsombor Miskolczy, Mónika Megyesi and László Biczók

Molecules 2022, 27(21), 7514; https://doi.org/10.3390/molecules27217514 - 3 Nov 2022

Cited by 4 | Viewed by 1745

Abstract

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 (SBE_6.4βCD). 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 SBE_6.4βCD 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 SBE_6.4βCD than with cucurbit[7]uril, a host having similar cavity size, originates from the much smaller exothermicity of the confinement in the former macrocycle. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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15 pages, 3633 KiB

Open AccessArticle

Encapsulation of Metronidazole in Biocompatible Macrocycles and Structural Characterization of Its Nano Spray-Dried Nanostructured Composite

by Mirella Mirankó, Mónika Megyesi, Zsombor Miskolczy, Judit Tóth, Tivadar Feczkó and László Biczók

Molecules 2021, 26(23), 7335; https://doi.org/10.3390/molecules26237335 - 2 Dec 2021

Cited by 3 | Viewed by 2133

Abstract

Due to the great potential of biocompatible cucurbit[7]uril (CB7) and 4-sulfonatocalix[4]arene (SCX4) macrocycles in drug delivery, the confinement of the pharmaceutically important metronidazole as an ionizable model drug has been systematically studied in these cavitands. Absorption and fluorescence spectroscopic measurements gave 1.9 × 10⁵ M⁻¹ and 1.0 × 10⁴ M⁻¹ as the association constants of the protonated metronidazole inclusion in CB7 and SCX4, whereas the unprotonated guests had values more than one order of magnitude lower, respectively. The preferential binding of the protonated metronidazole resulted in 1.91 pH unit pK_a diminution upon encapsulation in CB7, but the complexation with SCX4 led to a pK_a decrease of only 0.82 pH unit. The produced protonated metronidazole–SCX4 complex induced nanoparticle formation with protonated chitosan by supramolecular crosslinking of the polysaccharide chains. The properties of the aqueous nanoparticle solutions and the micron-sized solid composite produced therefrom by nano spray drying were unraveled. The results of the present work may find application in the rational design of tailor-made self-assembled drug carrier systems. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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14 pages, 1477 KiB

Open AccessCommunication

Controlled Anchoring of (Phenylureido)sulfonamide-Based Receptor Moieties: An Impact of Binding Site Multiplication on Complexation Properties

by Karolína Salvadori, Alena Krupková, Lucie Červenková Šťastná, Monika Müllerová, Václav Eigner, Tomáš Strašák and Petra Cuřínová

Molecules 2021, 26(18), 5670; https://doi.org/10.3390/molecules26185670 - 18 Sep 2021

Cited by 3 | Viewed by 2098

Abstract

The repetition of urea-based binding units within the receptor structure does not only lead to monomer properties multiplication. As confirmed by spectroscopic studies, UV-Vis and ¹H-NMR in classical or competitive titration mode, the attachment to a carrier allocates the active moieties to mutual positions predetermining the function of the whole receptor molecule. Bivalent receptors form self-aggregates. Dendritic receptors with low dihydrogen phosphate loadings offer a cooperative complexation mode associated with a positive dendritic effect. In higher dihydrogen phosphate concentrations, the dendritic branches act independently and the binding mode changes to 1:1 anion: complexation site. Despite the anchoring, the dendritic receptors retain the superior efficiency and selectivity of a monomer, paving the way to recyclable receptors, desirable for economic and ecological reasons. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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15 pages, 3056 KiB

Open AccessArticle

Encapsulation of Risperidone by Methylated β-Cyclodextrins: Physicochemical and Molecular Modeling Studies

by Laura Sbârcea, Ionuț-Mihai Tănase, Adriana Ledeți, Denisa Cîrcioban, Gabriela Vlase, Paul Barvinschi, Marinela Miclău, Renata-Maria Văruţ, Cristina Trandafirescu and Ionuț Ledeți

Molecules 2020, 25(23), 5694; https://doi.org/10.3390/molecules25235694 - 3 Dec 2020

Cited by 13 | Viewed by 2866

Abstract

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 β-cyclodextrins, namely heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-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—thermogravimetry/DTG—derivative thermogravimetry/HF—heat flow), powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy and saturation solubility studies. Job’s method was employed for the determination of the stoichiometry of the inclusion complexes, which was found to be 2:1 for both guest–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-β-CD as host; the guest–host system RSP/DM-β-CD can thus be a starting point for further research in developing new formulations containing RSP, with enhanced bioavailability. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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11 pages, 2070 KiB

Open AccessArticle

Encapsulation of Cinnamic Acid by Cucurbit[7]uril for Enhancing Photoisomerization

by Na’il Saleh, Muna S. Bufaroosha, Ziad Moussa, Rukayat Bojesomo, Hebah Al-Amodi and Asia Al-Ahdal

Molecules 2020, 25(16), 3702; https://doi.org/10.3390/molecules25163702 - 14 Aug 2020

Cited by 3 | Viewed by 4646

Abstract

Cis- or Z-configuration is required for the plant growth-promoting activity of cinnamic acid (CA), whereas the E-form is inactive. Herein, we describe the encapsulation of E-CA by cucurbit[7]uril (CB7) and show that photoisomerization reactions can be more efficiently controlled in aqueous solutions by utilizing this supramolecular approach. Measurements of UV–visible absorption and proton NMR spectra at different pH values confirm that E-CA and its methyl ester, methyl-E-cinnamate (MC), form stronger 1:1 host–guest complexes with CB7 compared to cucurbit[8]uril (CB8) or three cyclodextrins (α-, β-, and γ-CD). Irradiation of (300 nm) UV light to an aqueous solution of the CB7-bound E isomers induces E to Z photoisomerization and the dissociation of the complex. When the same solution is irradiated by (254 nm) UV light, Z to E conformational changes of the unbound Z isomers are observed and are accompanied by restoring the host–guest complex formation. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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17 pages, 6336 KiB

Open AccessArticle

Delivery of Alpha-Mangostin Using Cyclodextrins through a Biological Membrane: Molecular Dynamics Simulation

by Wiparat Hotarat, Bodee Nutho, Peter Wolschann, Thanyada Rungrotmongkol and Supot Hannongbua

Molecules 2020, 25(11), 2532; https://doi.org/10.3390/molecules25112532 - 29 May 2020

Cited by 10 | Viewed by 3745

Abstract

α-Mangostin (MGS) exhibits various pharmacological activities, including antioxidant, anticancer, antibacterial, and anti-inflammatory properties. However, its low water solubility is the major obstacle for its use in pharmaceutical applications. To increase the water solubility of MGS, complex formation with beta-cyclodextrins (βCDs), particularly with the native βCD and/or its derivative 2,6-dimethyl-β-CD (DMβCD) is a promising technique. Although there have been several reports on the adsorption of βCDs on the lipid bilayer, the release of the MGS/βCDs inclusion complex through the biological membrane remains unclear. In this present study, the release the MGS from the two different βCDs (βCD and DMβCD) across the lipid bilayer was investigated. Firstly, the adsorption of the free MGS, free βCDs, and inclusion complex formation was studied by conventional molecular dynamics simulation. The MGS in complex with those two βCDs was able to spontaneously release free MGS into the inner membrane. However, both MGS and DMβCD molecules potentially permeated into the deeper region of the interior membrane, whereas βCD only adsorbed at the outer membrane surface. The interaction between secondary rim of βCD and the 1-palmitoeyl-2-oleoyl-glycero-3-phosphocholine (POPC) phosphate groups showed the highest number of hydrogen bonds (up to 14) corresponding to the favorable location of βCD on the POPC membrane. Additionally, the findings suggested that electrostatic energy was the main driving force for βCD adsorption on the POPC membrane, while van der Waals interactions played a predominant role in DMβCD adsorption. The release profile of MGS from the βCDs pocket across the lipid bilayer exhibited two energy minima along the reaction coordinate associated with the permeation of the MGS molecule into the deeper region of the POPC membrane. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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10 pages, 1656 KiB

Open AccessArticle

Solvent Switched Weak Interaction of a 4-Quinazolinone with a Cavitand Derivative

by Zoltán Nagymihály, Beáta Lemli, László Kollár and Sándor Kunsági-Máté

Molecules 2020, 25(8), 1915; https://doi.org/10.3390/molecules25081915 - 21 Apr 2020

Cited by 2 | Viewed by 2206

Abstract

Interaction of 4-quinazolinone with tetrakis (3,5-dicarboxylatophenoxy)-cavitand derivative has been studied in methanol and dimethylformamide media using fluorescence spectroscopy and molecular modeling methods. Results show temperature dependent complex formation: either the entropy gain or the high enthalpy changes are responsible for the formation of stable complexes in two separated temperature regions. However, different thermodynamic parameters are associated to different conformations of the complexes: while the high entropy gain associated to the formation of deeply included guest in methanol, the high entropy gain is associated with the formation of weakly included guest in dimethylformamide solvent. This finding highlights the importance of dynamic properties of the species interacted in different solvents. Full article

(This article belongs to the Special Issue Molecular Encapsulation)

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