Cyclodextrin Conjugates Research Articles

Study of Self-Assembly of Cyclodextrin Conjugates with Phospholipid by Molecular Dynamics Method

Study of Self-Assembly of Cyclodextrin Conjugates with Phospholipid by Molecular Dynamics Method

Engineered Self-Assembly of Amphiphilic Cyclodextrin Conjugates for Drug Encapsulation.

Cyclodextrins are a group of naturally occurring oligosaccharides that have widely been studied and applied in pharmaceutical formulations forming inclusion complexes with a broad variety of drugs exhibiting different hydrophilicity as well as molecular weights. Grafting aliphatic chains onto native cyclodextrins renders them amphiphilic and enables self-assembly into supramolecular structures that have already been explored for drug delivery. Based on the possibility of controlling the inherent physicochemical properties by modifying their chemical structure, amphiphilic cyclodextrin conjugates hold a great potential to become a drug delivery platform adaptable to the individual needs of specific active drug molecules. In this work, a library of amphiphilic cyclodextrin derivatives was synthesized by conjugating aliphatic chains of different lengths to native β-cyclodextrin via thioether or ester bonds. Upon nanoprecipitation, the synthesized amphiphilic cyclodextrin derivatives spontaneously self-assembled into nanosized supramolecular structures with a monodisperse size distribution. We systematically investigated the relationship between the molecular structure of the amphiphilic cyclodextrin derivatives and the corresponding self-assembly into nanosystems as well as the encapsulation of model drugs with different physicochemical properties. Encapsulation efficiencies up to 97% and pH-dependent release profiles were achieved. We found that both the aliphatic chain length and the linker molecule determine the respective self-assembly and drug encapsulation mechanism of the individual system. The colloidal stability and biocompatibility with human cells of all derivatives were proven. Consequently, amphiphilic cyclodextrin conjugates provide a drug delivery platform with tailor-made control over physicochemical properties and high drug encapsulation efficiency for a broad range of drug molecules, thus offering great potential for the development of future therapeutics with improved therapeutic efficiency.

Twenty Years of Research on Cyclodextrin Conjugates with PAMAM Dendrimers.

Recently, the number of gene and oligonucleotide drugs are increasing. Of various drug delivery systems (DDSs) for gene and oligonucleotide drugs, few examples of the clinical application of polymer as drug carriers are known, despite development of the novel polymers has been progressing. Cyclodextrin (CD) conjugates with starburst polyamidoamine (PAMAM) dendrimer (CDEs), as a new type of polymer-based carriers, were first published in 2001. After that, galactose-, lactose-, mannose-, fucose-, folate-, and polyethyleneglycol (PEG)-appended CDEs have been prepared for passive and active targeting for gene, oligonucleotide, and low-molecular-weight drugs. PEG-appended CDE formed polypsuedorotaxanes with α-CD and γ-CD, which are useful for a sustained release system of gene and oligonucleotide drugs. Interestingly, CDEs were found to have anti-inflammatory effects and anti-amyloid effects themselves, which have potential as active pharmaceutical ingredients. Most recently, CDE is reported to be a useful Cas9-RNA ribonucleoproteins (Cas9 RNP) carrier that induces genome editing in the neuron and brain. In this review, the history and progression of CDEs are overviewed.

Synthesis and biological evaluation of novel β-cyclodextrin-fluvastatin conjugates

Drugs that may regulate lipid metabolism and lower cholesterol, such as statins (drugs that reduce de novo cholesterol synthesis) or cyclodextrins (that promote cholesterol removal), are currently investigated as potential therapeutics for neuronal disorders like Alzheimer’s and Niemann Pick type C disease. Fluvastatin is a member of the statin class widely used in preventing heart diseases as it lowers cholesterol and other lipids. β-cyclodextrin derivatives can also act as cholesterol scavengers to promote cholesterol efflux from cells to extracellular acceptors.This context has inspired us to synthesize and characterize two new cyclodextrin-fluvastatin conjugates representing the first example of cyclodextrin conjugates of statins.We synthesized 3- and 6-functionalized β-cyclodextrin with fluvastatin through an amide bond. We studied the stability, cytotoxicity and protective activity in cells of the new derivatives. We observed that the Fluvastatin cyclodextrin conjugates are stable in plasma and mouse brain homogenates. Moreover, we found that the fluvastain derivatives are well tolerated by cultured neuron cells, and they completely rescue from cell death induced by Aβ oligomers. Overall, the fluvastain derivatives have potential as therapeutic agents in diseases related to cholesterol dyshomeostasis.

Gold Nanoparticles Incorporated with Cyclodextrins and Its Applications

Cyclodextrins are naturally oligosaccharides which had cyclic glucopyranoside units even if six units to form α-cyclodextrin (α-CD), seven units β-cyclodextrin (β-CD) or eight units γ-cyclodextrin (γ-CD) and some other derivatives. It has a truncated cone shape with a hydrophobic cavity and a hydrophilic from the external surface of cyclodextrins. Gold nanoparticles incorporated with cyclodextrins enhanced optical and electrical properties of the resulting conjugates, due to the gold nanoparticles’ unique physical and chemical properties because of their surface plasmon resonance. Here is a review of gold nanoparticles/cyclodextrin’s different applications including sensing, antimicrobial effect, and their variable medical/pharmaceutical applications. Generally, gold nanoparticles and cyclodextrin conjugates showed developed and pronounced advantages due to their biocompatibility and enhanced physical and electric properties.

Preparation and Characterization of Flurbiprofen/β-Cyclodextrin Inclusion Complex

This study aims to ameliorate the water solubility of flurbiprofen by using β-cyclodextrin (β-CD). The drug/ligand 1:1 (M/M) stoichiometry was determined based on the effect of β-CD on the solubility of flurbiprofen. Several methods of preparing flurbiprofen/β-CD inclusion complex were investigated and a solvent method using hot water to dissolve the starting materials was selected. The selected method showed a lot of advantages such as high complexing ability, good product yield, simple and eco-friendly process. The obtained product was characterized using various analytical techniques such as high-performance liquid chromatography, differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy. The product had a predominantly amorphous form with clathrate particles of about 2-7 µm in size, irregular edges and rough surfaces. The study results show that in the complexing process, flurbiprofen replaced water molecules located in the conical cavity of β-CD. The complex contained 19.91% flurbiprofen by mass with water solubility at 37°C was 1,100 µg/ml. The results also show that the complexing with β-CD significantly improved the water solubility of flurbiprofen by both speed and level.
 Keywords
 Flurbiprofen, β-cyclodextrin, inclusion complex, water solubility, preparation, characterization.
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Inhibition of influenza virus infection by multivalent pentacyclic triterpene-functionalized per-O-methylated cyclodextrin conjugates

Multivalent ligands that exhibit high binding affinity to influenza hemagglutinin (HA) trimer can block the interaction of HA with its sialic acid receptor. In this study, a series of multivalent pentacyclic triterpene-functionalized per-O-methylated cyclodextrin (CD) derivatives were designed and synthesized using 1, 3-dipolar cycloaddition click reaction. A cell-based assay showed that three compounds (25, 28 and 31) exhibited strong inhibitory activity against influenza A/WSN/33 (H1N1) virus. Compound 28 showed the most potent anti-influenza activity with IC50 of 4.7 μM. The time-of-addition assay indicated that compound 28 inhibited the entry of influenza virus into host cell. Further hemagglutination inhibition (HI) and surface plasmon resonance (SPR) assays indicated that compound 28 tightly bound to influenza HA protein with a dissociation constant (KD) of 4.0 μM. Our results demonstrated a strategy of using per-O-methylated β-CD as a scaffold for designing multivalent compounds to disrupt influenza HA protein-host receptor protein interaction and thus block influenza virus entry into host cells.

Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

AbstractAlzheimer′s disease represents a daunting challenge for healthcare because it affects millions of people worldwide. The abnormal assembly of amyloid‐beta peptides into amyloid aggregates is a pathological hallmark of Alzheimer's disease. Properly functionalized cyclodextrins modulate amyloidogenesis. Here, we report the synthesis and characterization of a 6‐monofunctionalized cyclodextrin‐bearing a quinoline derivative (IOX1). Moreover, we tested the ability of the new compound and its 3‐monofunctionalized isomer to inhibit self‐induced Aβ aggregation in order to understand if the two isomers differently modulate aggregation process. The results further establish the potential of cyclodextrin conjugates as modulators of Aβ aggregation.

Cyclodextrin 3-Functionalized with 8-Hydroxyquinoline as an Antioxidant Inhibitor of Metal-Induced Amyloid Aggregation.

Cyclodextrins are used increasingly in pharmacotherapy. Experimental and clinical data suggest that cyclodextrins can be used not only as excipients for marketed drugs, but also as active pharmaceutical ingredients to treat neurological diseases including Niemann-Pick type C disease. Disruption of metal and cholesterol homeostasis, protein misfolding, and aggregation are recognized among the major pathological features in triggering neurodegenerative disorders, and therefore it is becoming more and more evident that the next generation of therapies should have multiple functions to combat the multifactorial nature of diseases. A novel class of compounds obtained by conjugating 8-hydroxyquinoline with cyclodextrin has been proposed to combine antioxidant activity, chelating, antiaggregant, and inclusion ability into one compound designed for metal-associated neurodegenerative diseases. Herein, the synthesis and characterization of the new compound 3A -deoxy-3A -[(8-hydroxyquinolyl)-2-methylamino]-2A (S),3A (R)-β-cyclodextrin is reported. Moreover, the interaction of copper-Aβ and zinc-Aβ amyloid with this class of cyclodextrin conjugates was investigated for the first time. New information about the effects of different modified chelating cyclodextrins may be important for further development of drugs against neurodegenerative disorders.

Ligand-functionalized degradable polyplexes formed by cationic poly(aspartic acid)-grafted chitosan-cyclodextrin conjugates.

Polypeptide-based degradable polyplexes attracted considerable attention in drug delivery systems. Polysaccharides including cyclodextrin (CD), dextran, and chitosan (CS) were readily grafted with cationic poly(aspartic acid)s (PAsps). To further enhance the transfection performances of PAsp-based polyplexes, herein, different types of ligand (folic acid, FA)-functionalized degradable polyplexes were proposed based on the PAsp-grafted chitosan-cyclodextrin conjugate (CCPE), where multiple β-CDs were tied on a CS chain. The FA-functionalized CCPE (i.e., CCPE-FA) was obtained via a host-guest interaction between the CD units of CCPE and the adamantane (Ad) species of Ad-modified FA (Ad-FA). The resulting CCPE/pDNA, CCPE-FA/pDNA, and ternary CCPE-FA/CCPE/pDNA (prepared by layer-by-layer assembly) polyplexes were investigated in detail using different cell lines. The CCPE-based polyplexes displayed much higher transfection efficiencies than the CS-based polyplexes reported earlier by us. The ternary polyplexes of CCPE-FA/CCPE/pDNA produced excellent gene transfection abilities in the folate receptor (FR)-positive tumor cells. This work would provide a promising means to produce highly efficient polyplexes for future gene therapy applications.

Photodynamic effects induced by meso-tris(pentafluorophenyl)corrole and its cyclodextrin conjugates on cytoskeletal components of HeLa cells.

The aim of this work was to synthesize new corrole β-cyclodextrin conjugates βCD1 (with one β-cyclodextrin moiety) and βCD2 (with two β-cyclodextrin moieties) from 5,10,15-tris(pentafluorophenyl)corrole (TPFC) and to test invitro the efficacy of these compounds towards tumoral HeLa cells. No dark cytotoxicity was observed for TPFC and βCD1 at the concentration used for PDT cell treatment, even during long incubation periods (24h). Fluorescence microscopy showed that TPFC and βCD1 accumulate in HeLa cells at lysosomes and in the Golgi apparatus, respectively. The cell survival after the PDT treatment with visible light was dependent on light exposure level and compound concentration. βCD1 was able to penetrate efficiently in the cytoplasm of the HeLa cells. In particular, we have analyzed the photodynamic effect of the corrole derivatives on the microtubules of HeLa cells and the morphological alterations on the mitotic spindle. TPFC and βCD1 caused photocytotoxicity in tumoral HeLa cells and induced a rapid metaphase blockage of cells that also showed clearly altered configurations of the mitotic spindle. The results showed that TPFC has the highest photosensitizing efficiency on tumoral cells.

Folate-Cyclodextrin Conjugates as Carriers of the Platinum(IV) Complex LA-12.

Folic acid has emerged as an interesting cell-targeting moiety and a number of drugs have been conjugated to folate. In this context, new conjugates of β-cyclodextrins with folate have been synthesised as drug carriers to improve their selectivity for cells overexpressing the folic acid receptor. In particular, both 3- and 6-functionalised β-cyclodextrins, linked to the α- or γ-carboxylic group of folic acid, have been synthesised and fully characterised. As a proof of concept, the antitumour platinum(IV) complex cis-trans-cis-[PtCl2 (CH3 CO2 )2 (adamantylamine)(NH3 )] (LA-12) has been used as a guest drug. The LA-12-cyclodextrin inclusion complexes have been tested on tumour cells. In the presence of cyclodextrin-folate conjugates, LA-12 exhibited IC50 values four times smaller than those of LA-12 alone in MDA-MB-231 cells, which overexpress folic acid receptors on their membrane. No improvement of LA-12 cytotoxicity was found in control tumour cells that do not overexpress the folate receptor. Thus, the non-covalent approach, based on inclusion complexes with functionalised cyclodextrins, looks very promising for drug targeting.

A novel synthetic luteinizing hormone-releasing hormone (LHRH) analogue coupled with modified β-cyclodextrin: Insight into its intramolecular interactions

BackgroundCyclodextrins (CDs) in combination with therapeutic proteins and other bioactive compounds have been proposed as candidates that show enhanced chemical and enzymatic stability, better absorption, slower plasma clearance and improved dose–response curves or immunogenicity. As a result, an important number of therapeutic complexes between cyclodextrins and bioactive compounds capable to control several diseases have been developed. ResultsIn this article, the synthesis and the structural study of a conjugate between a luteinizing hormone-releasing hormone (LHRH) analogue, related to the treatment of hormone dependent cancer and fertility, and modified β-cyclodextrin residue are presented. The results show that both the phenyl group of tyrosine (Tyr) as well as the indole group of tryptophan (Trp) can be encapsulated inside the cyclodextrin cavity. Solution NMR experiments provide evidence that these interactions take place intramolecularly and not intermolecularly. ConclusionsThe study of a LHRH analogue conjugated with modified β-cyclodextrin via high field NMR and MD experiments revealed the existence of intramolecular interactions that could lead to an improved drug delivery. General significanceNMR in combination with MD simulation is of great value for a successful rational design of peptide–cyclodextrin conjugates showing stability against enzymatic proteolysis and a better pharmacological profile.

Cyclodextrin-scaffolded amphiphilic aminoglucoside clusters: self-assembling and gene delivery capabilities

The self-assembling and gene transfer capabilities of monodisperse amphiphilic aminoglucoside–cyclodextrin conjugates depend on the amino disposition at the glycationic head.

Flavin–cyclodextrin conjugates: effect of the structure on the catalytic activity in enantioselective sulfoxidations

A series of flavin–cyclodextrin conjugates has been prepared and tested in the enantioselective oxidations of prochiral aromatic and aliphatic sulfides with hydrogen peroxide. The newly prepared conjugates contain isoalloxazinium or alloxazinium moieties attached to the primary rim of α- and β-cyclodextrins at the C-6 positions. In addition, flavinium units were attached to the secondary rim of the β-cyclodextrin macrocycle. The relationship between the structural features and the catalytic performance of the conjugates, including those recently reported by us, was analyzed. The rate and enantioselectivity of the sulfoxidations catalyzed by flavin–cyclodextrin conjugates are influenced mainly by the size of the cyclodextrin cavity, the type of flavin unit (alloxazine or isoalloxazine), and by the relative orientation of the flavin and cyclodextrin moieties.

Host–Guest Chemistry of Dendrimer–Cyclodextrin Conjugates: Selective Encapsulations of Guests within Dendrimer or Cyclodextrin Cavities Revealed by NOE NMR Techniques

In this study, G5 PAMAM dendrimer and α-, β-, γ-cyclodextrin (CD) conjugates were synthesized. Host-guest behaviors of the conjugates toward five guest molecules including sodium methotrexate (MTX), amantadine hydrochloride (ADH), sulfamethoxazole (SMZ), sodium deoxycholate (SDC), and sodium dodecyl sulfate (SDS) were analyzed by NOE NMR techniques. Among the five guest molecules, ADH only binds with β-CD in G5-β-CD, SDC shows higher priority to localize within the cavity of γ-CD in G5-γ-CD, while MTX exhibits selective encapsulation within the cavities of G5 dendrimer in G5-α-CD. SDS has high binding affinity with α-CD in G5-α-CD but forms a precipitate in the complex solution. SMZ shows simultaneous encapsulation within CDs (α-, β-, and γ-CD) or G5 in the presence of the three conjugates. The host behavior of G5-CD conjugates depends on CD cavity size, guest size, and hydrophobicity. The results obtained in this study are helpful in the optimization of dendrimer-CD conjugate-based drug delivery systems.

Proline–cyclodextrin conjugates: synthesis and evaluation as catalysts for aldol reaction in water

The synthesis of six conjugates of l-proline and β-cyclodextrin and their evaluation as catalysts of aldol reaction in water are described. The results indicated that the nature of the linker between proline and β-cyclodextrin is important for catalytic activity; the one with the most flexible linker gave the best results. Inhibition experiments showed that the cavity of β-cyclodextrin plays a role in the catalysis. Permethylation of the cyclodextrin hydroxyl groups led to higher conversion rates.

ChemInform Abstract: Alloxazine—Cyclodextrin Conjugates for Organocatalytic Enantioselective Sulfoxidations.

AbstractStructurally different alloxazine‐cyclodextrin conjugates, such as (I) and (II) are prepared and tested as catalysts for the enantioselective oxidation of prochiral sulfides (III) and (V).

ChemInform Abstract: Cyclodextrin‐Based Gene Delivery Systems

AbstractReview: 222 refs.

ChemInform Abstract: Flavin—Cyclodextrin Conjugates as Catalysts of Enantioselective Sulfoxidations with Hydrogen Peroxide in Aqueous Media.

ChemInform Abstract: Flavin—Cyclodextrin Conjugates as Catalysts of Enantioselective Sulfoxidations with Hydrogen Peroxide in Aqueous Media.