CyD Molecules Research Articles

Design and Evaluation of Folate-Appended α-, β-, and γ-Cyclodextrins Having a Caproic Acid as a Tumor Selective Antitumor Drug Carrier in Vitro and in Vivo

We reported that per-6-folic acid (FA)-appended β-cyclodextrin (β-CyD) possessing two caproic acids between FA and a β-CyD molecule as a spacer (Fol-c2-β-CyD) could be useful as a promising antitumor drug carrier. However, the effects of the cavity size and the spacer length on the carrier ability are not still known. In this study, we designed and evaluated the FA-appended three kinds of CyDs possessing a caproic acid as a spacer between FA and a CyD molecule (Fol-c1-CyDs) as a tumor targeting carrier for antitumor drugs. The stability constant of the Fol-c1-β-CyD/doxorubicin (DOX) complex was much higher than those of Fol-c1-α-CyD and Fol-c1-γ-CyD at pH 7.3. Antitumor activity of DOX was increased by the complexation with Fol-c1-β-CyD, but not with Fol-c1-α-CyD or Fol-c1-γ-CyD in KB cells, a folate receptor-α-positive cell line. Also, Fol-c1-β-CyD increased antitumor activities of paclitaxel and vinblastine, but not 5-fluorouracil. Furthermore, Fol-c1-β-CyD accelerated cellular uptake of DOX and inhibited its efflux from KB cells. The Fol-c1-β-CyD/DOX complex showed much higher antitumor activity than DOX alone after intratumoral and intravenous administrations to tumor-bearing mice with a negligible change of the blood chemistry values. These findings suggest that Fol-c1-β-CyD could be useful as a tumor-selective carrier for antitumor drugs.

Vehicles for oligonucleotide delivery to tumours.

The vasculature of a tumour provides the most effective route by which neoplastic cells may be reached and eradicated by drugs. The fact that a tumour's vasculature is relatively more permeable than healthy host tissue should enable selective delivery of drugs to tumour tissue. Such delivery is relevant to carrier-mediated delivery of genetic medicine to tumours. This review discusses the potential of delivering therapeutic oligonucleotides (ONs) to tumours using cationic liposomes and cyclodextrins (CyDs), and the major hindrances posed by the tumour itself on such delivery. Cationic liposomes are generally 100-200 nm in diameter, whereas CyDs typically span 1.5 nm across. Cationic liposomes have been used for the introduction of nucleic acids into mammalian cells for more than a decade. CyD molecules are routinely used as agents that engender cholesterol efflux from lipid-laden cells, thus having an efficacious potential in the management of atherosclerosis. A recent trend is to employ these oligosaccharide molecules for delivering nucleic acids in cells both in-vitro and in-vivo. Comparisons are made with other ON delivery agents, such as porphyrin derivatives (< 1 nm), branched chain dendrimers (approximately 10 nm), polyethylenimine polymers (approximately 10 nm), nanoparticles (20-1,000 nm) and microspheres (> 1 microm), in the context of delivery to solid tumours. A discourse on how the chemical and physical properties of these carriers may affect the uptake of ONs into cells, particularly in-vivo, forms a major basis of this review.

Physico-chemical characterization of disoxaril–dimethyl-β-cyclodextrin inclusion complex and in vitro permeation studies

In this work we evaluated the ability of 2,6-di- O-methyl-β-cyclodextrin (DM-β-Cyd) to include the anti-rhinovirus drug Disoxaril (WIN 51711), increasing its water solubility and stability. The complex, prepared by kneading method, was characterized in the solid state by differential scanning calorimetry and in aqueous solution using circular dichroism and NMR spectroscopy. The formation of 1:1 and 1:2 drug–Cyd complexes was hypothesized. Stability constants for both complexes were determined on the basis of an Ap-type phase solubility diagrams and evidenced a very high stability for the 1:1 complex. Thermodynamic parameters of the binding process showed the existence of classical hydrophobic interactions in the 1:1 complex with the formation of a less ordered system after complexation. An enthalpic contribution rather than an entropic one accompanied the association of the second Cyd molecule. DM-β-Cyd was able to significantly increase water solubility of WIN 51711, from 0.000123 to 0.47142 mg/ml. Free drug shows a very low water stability, it is completely hydrolyzed after 36 h in PBS (pH 7.0), at 4 °C. In the presence of DM-β-Cyd only a 10% of WIN 51711 was degraded, to the same conditions, after 12 days. DM-β-Cyd increases the permeation of WIN 51711 across excised bovine nasal mucosa mounted on Franz cells, with respect to the free drug. Nevertheless, the permeation process had a lag time of 2 h so that the drug might assure its pharmacological activity on the outer surface of the mucosa. In vivo studies on rabbits evidenced that WIN 51711 is well tolerated, having no observable effect on the nasal mucosa following repeated administration.

Preparation of celecoxib-dimethyl-β-cyclodextrin inclusion complex: characterization and in vitro permeation study

The ability of 2,6-di-O-methyl-β-cyclodextrin (DM-β-Cyd) to include the anti-inflammatory drug celecoxib (CCB) was evaluated. The complex was prepared by kneading and freeze-drying methods and was characterized in the solid state and in aqueous solution. Water solubility and dissolution rate of CCB, in a medium simulating gastric fluid, significantly increased after complexation, with complete dissolution obtained after 30 and 180 min for the freeze-dried and kneaded complexes respectively. Phase solubility studies showed Ap-type diagrams. Stability constants for the 1:1 and 1:2 CCB-DM-β-Cyd complexes and 1H-NMR studies suggested a probable 1:1 inclusion complex and only an external interaction for the second Cyd molecule. Thermodynamic parameters of the binding process showed the existence of van der Waals forces between CCB and DM-β-Cyd. DM-β-Cyd influenced the permeation of CCB through the CaCo-2 cells monolayer. The increase of permeation observed was due to the fast dissolution rate of the included drug and to a destabilizing action exerted by the macrocycle on the biomembrane.

Cyclodextrins and Oligonucleotide Delivery to Solid Tumours

Cyclodextrins (CyDs) have traditionally been used for dissolving hydrophobic chemicals into aqueous media, and more recently, for inducing cholesterol efflux from lipid-laden cells as a proposed mechanism for reversal of cardiovascular disease. This review discusses the potential of delivering therapeutic oligonucleotides to solid tumours using CyD molecules. The physicochemical properties of these oligosaccharide molecules, and the barriers posed by the solid tumour itself, factors that affect may affect the uptake of oligonucleotides by CyDs, are the major foci of this review.

Comparison of nanotube structures constructed from alpha-, beta-, and gamma-cyclodextrins by potential-controlled adsorption.

"Nanotube" structures of the alpha-, beta-, and gamma-cyclodextrins (CyD's), which are similar to that of CyD-polyrotaxane, were constructed by potential-controlled adsorption onto Au(111) surfaces in sodium perchlorate solution without a threaded polymer. CyD molecules adsorbed randomly on bare Au(111) surfaces without potential control and the desorption of CyD's from Au surfaces was observed at a negative potential of less than -0.60 V versus SCE. On the other hand, in the specific range between these potentials, ordered molecular arrays with "nanotube" structures of the CyD's (alpha-, beta-, and gamma-CyD) were observed on Au(111). The range of potentials for formation of the "nanotube" structures of alpha-, beta-, and gamma-CyD was from -0.15 to -0.20 V, from -0.25 to -0.45 V, and from -0.22 to -0.45 V, respectively. beta- and gamma-CyD require a more negative potential for adsorption-induced self-organization (AISO) than alpha-CyD in order to weaken adsorption and induce self-organization. Furthermore, we have succeeded in the visualization of the dynamic process in solution, such as the self-ordering, and the destruction of the nanotube structure. These results indicate that control of the electrode potential facilitates management of the delicate balance of various interactions, resulting in the formation of two-dimensional supramolecular structures on the substrates.

Structure and dynamics of 6-azacytidine by MNDO/H quantum-chemical method

By means of MNDO/H quantum-chemical calculations the structural and dynamic properties of 6-azaCyd were shown to be determined by the co-operative net of intramolecular hydrogen bonds. The 6-azaCyd molecule was found to have four conformations. The variety of conformations is a special feature of 6-azaCyd, which is radically different from the Cyd molecule. It is caused by presence of N6 atom and its ability to form additional intramolecular H-bonds stabilising the new conformations. The conformation of the 6-azaCyd molecule depends on intermolecular interactions and surroundings: formation of intermolecular H-bonds in crystal affects the intramolecular H-bonds net and changes the molecule conformation toward the crystalline field energy minimisation.

Scanning tunneling microscopy on the formation of lipoamide-cyclodextrin monolayer on Au(111)

β-cyclodextrin molecules modified with lipoamide residue (LP-β-CyD) were self-assembled on an Au(111) surface in ethanol solution, and the growth process was studied by scanning tunneling microscopy. At the initial stage, adsorption sites were not only random, but also partially linear ordering, which suggests the existence of some influence by the herringbone structure of the Au(111) surface. According to the macroscopic analysis, the subsequent growth process was explained by the Elovich model, which is based on the repulsive interaction between adsorbed molecules. However, when the immersion time increased, island structures began forming. This result suggests the interaction between LP-β-CyD molecules as attractive, which in fact is more probable in consideration of the possibility of the hydrophobic and the hydrogen bonding interactions between CyD molecules. Finally, formation of a single LP-β-CyD layer was clearly confirmed.

Self-organization of α-cyclodextrin on Au(111) surfaces induced by potential controlled adsorption

Abstract Potential-induced self-organization of α-cyclodextrin (CyD) on Au(111) surfaces in sodium perchlorate has been investigated by using in-situ scanning tunneling microscopy (STM). Near the open circuit potential (approximately +0.0 V vs. SCE), the CyD molecule adsorbs randomly on bare Au(111) surfaces and the desorption of CyD from Au surfaces is observed at negative potentials less than −0.40 V. On the other hand, it was found that the CyD molecules formed an ordered array with a cylindrical structure on the Au(111) surface in the potential region from −0.20 to −0.15 V. The cylindrical structure in which the cavities of CyD face sideways proved that the structure of the adlayer is formed not by simple epitaxy but by self-organization of the molecules.

Monomorphism of cytidine (Cyd) vs. polymorphism of 2′deoxycytidine (dCyd). Structural and functional consequences

It has been found that 2′deoxycytidine (dCyd) crystallizes in different forms, denoted dCyd A, dCyd B and dCyd C·H 2O. In the crystal lattice of the newly discovered form dCydC·H 2O there is a crystalline water molecule present. The monohydrate of dCydC, under suitable conditions (RT, over P 2O 5, 48h), undergoes transformation into the fully dehydrated form—dCydC anhydro. The whole process of de- and re-hydratation has been observed by FTIR-PAS spectroscopy. The nature of the differences and similarities between structural and functional properties of crystalline forms of 2′dCyd and Cyd molecules has been discussed.

Studies of cyclodextrin inclusion complexes. II. Molecular modelling and 1H-NMR evidence for the salbutamol-β-cyclodextrin complex

β-Cyclodextrin (β-CYD) has a hydrophobic cavity in which salbutamol may be clathrated. The ability of a guest molecule to penetrate the CYD host is determined by its size, stereochemistry and polarity. Intermolecular interactions such as the hydrophobic interaction, van der Waals forces, H bonding and other physical forces are involved in the inclusion complexation process. Proton-NMR was employed to assess the mode of inclusion of salbutamol within the β-CYD cavity. The technique is based on the shielding of the CYD and drug protons. If inclusion does occur, protons located within or near the CYD cavity should be strongly shielded. The spectra showed upfield shifts of the CYD protons in the presence of salbutamol and the salbutamol protons shifted downfield in the presence of β-CYD. The downfield shifts of the aromatic protons were greater than those of the aliphatic protons, suggesting that the aromatic ring of salbutamol interacts more strongly with the β-CYD. The interior protons of the CYD molecule were shielded as a result of the anisotropy of the guest aromatic moiety. The highest shifts of β-CYD protons occurred for a molar ratio of 1:1 (salbutamol:β-CYD) indicating the probable stoichiometry of the complex. Molecular graphical computation showed that the minimum van der Waals energy positioning of salbutamol relative to β-CYD occurs when the aromatic ring of salbutamol penetrates the cavity leaving the aliphatic chain externalised.