Florence Djedaïni-Pilard

Self-assemblies of amphiphilic cyclodextrins

Cyclodextrins are natural cyclic oligosaccharides widely used as “molecular cages” in the pharmaceutical, agrochemical, food and cosmetical industries. The optimization of their pharmacological properties has led to the synthesis of numerous analogues. Amphiphilic derivatives were designed to improve the cell targeting of the drug-containing cyclodextrin cavities through their transportation in the organism, within self-assembling systems. Amphiphilic cyclodextrins can self-assemble into water-soluble aggregates such as mono or polydisperse micelles, or insert in lipid membranes and liposomes. Polysubstituted amphiphilic cyclodextrins are briefly reviewed, and monosubstituted derivatives of native and methylated β-cyclodextrins are presented in more details, with an emphasis on their self-organization within lipid membranes.

Synthesis of a new molecular carrier: N-(Leu-enkephalin)yl 6-amido-6-deoxy-cyclomaltoheptaose

Abstract The synthesis of N-(Leu-enkephalin)yl 6-amido-6-deoxy-cyclomaltoheptaose has been performed in high yield. The final derivative has been characterized by proton NMR in terms of chemical and inclusion properties and represents a new class of target-directed transporters.

Cyclodextrin nanoassemblies: a promising tool for drug delivery.

Among the biodegradable and nontoxic compounds that can form nanoparticles for drug delivery, amphiphilic cyclodextrins are very promising. Apart from ionic cyclodextrins, which have been extensively studied and reviewed because of their application in gene delivery, our purpose is to provide a clear description of the supramolecular assemblies of nonionic amphiphilic cyclodextrins, which can form nanoassemblies for controlled drug release. Moreover, we focus on the relationship between their structure and physicochemical characteristics, which is crucial for self assembly and drug delivery. We also highlight the importance of the nanoparticle technology preparation for the stability and application of this nanodevice.

Novel Glycolipids Based on Cyclodextrins

Novel amphiphilic cyclodextrins have been prepared by grafting a phospholipid on a modified cyclodextrin through a spacing arm to combine the selectivity in size of cyclodextrins and the transport properties of phospholipids. Synthesis and full characterization by NMR and mass spectrometry have been performed. The aggregation process in water has been characterized by light scattering, DSC and 31P NMR. This compound appears to assemble into large objects and displays a very low CMC. The detergent properties of the phospholipidyl-cyclodextrins have been evaluated.

Inclusion and solubilization properties of 6-S-glycosyl-6-thio derivatives of β-cyclodextrin

The synthesis and physico-chemical properties of branched β-cyclodextrins substituted by one or seven thioglycoside units at the primary hydroxy side are described. The solubilities in water of these compounds are strongly increased compared with the parent β-cyclodextrin although large differences are found between α- and β-anomers, the former exhibiting the larger solubility. The inclusion capacity of these derivatives has been investigated using NMR spectroscopy as the major analytical technique for various host–guest pairs. The apparent discrepancies between the intrinsic solubilities of these host molecules and their ability to solubilize hydrophobic hosts can be explained from geometrical considerations derived from detailed NMR studies. The respective roles of the side of inclusion, of steric effects and of stabilizing interactions are evidenced and allow an a priori selection of the optimal host derivative for a given guest molecule.

POTENTIAL FORMATION OF INTRAMOLECULAR INCLUSION COMPLEXES IN PEPTIDO-CYCLODEXTRINS AS EVIDENCED BY NMR SPECTROSCOPY

Investigations of the structure of β- and γ-cyclodextrin derivatives in solution obtained by grafting amino acids or peptides are presented. These compounds are models for vectorization-dedicated molecular carriers. It is shown that for some amino acids, strong intramolecular self inclusion complexes are formed in aqueous solution. This process strongly depends upon the nature and position of the pertinent amino acid in the peptide sequence. Two dimensional NMR experiments are used in conjunction with competition with external guests to evidence and estimate the strength of these auto-inclusion complexes.

Physico-chemical investigation of asymmetrical peptidolipidyl-cyclodextrins.

A new class of amphiphilic peptidolipidyl-cyclodextrins is reported. The derivatives are chiral due to the presence of an L-leucine in the spacer arm that links a saccharide moiety and a grafted, saturated hydrocarbon chain. Self-assembly properties of the peptidolipidyl-cyclodextrins are characterized by quasi-elastic light scattering, turbidity and UV-visible absorption measurements. NMR experiments give insight into the intermolecular dipolar interactions as a function of temperature and concentration. N-dodecyl-N alpha-(6 I-amidosuccinyl-6 1-deoxy-cyclomaltoheptaose)-L-leucine (1) is poorly soluble in aqueous media. N-dodecyl-N(alpha)-(6 I-amidosuccinyl-6 I-deoxy-2 I,3 I-di-O-methyl-hexakis-(2 II-VII,3 II-VII,6 II-VII-tri-O-methyl)-cyclomaltoheptaose)-L-leucine (2) is found to be more soluble and self-assembles into stable supramolecular colloidal aggregates with nanometric dimensions above a critical aggregation concentration (CAC). It has a propensity for solubilization of hydrophobic species revealing a micellar-like behavior, which is compared to that of the non-ionic detergent octyl glucoside. On the contrary, compound 1 precipitates in a crystalline phase beyond its water solubility limit, and it does not display any solubilizing capacity. The observed behavior corroborates at the molecular level with the NMR results.

Inclusion Complex of n-Octyl β-d-Glucopyranoside and α-Cyclodextrin in Aqueous Solutions: Thermodynamic and Structural Characterization

Complex formation between octyl beta-D-glucopyranoside (OG) and alpha-cyclodextrin (alphaCD) was investigated on the basis of three highly accurate and appropriate experimental techniques. First, surface tension measurements showed that alphaCD directly acts on the surfactant monomers in the aqueous phase, leading to progressive depletion of the air-water interface with increasing cyclodextrin contents. Significant shift of OG critical micelle concentration (cmc) was consequently observed: the higher alphaCD concentration, the higher the cmc value. Experiments performed at surfactant and cyclodextrin concentrations in the Gibbs regime of surface tension versus OG content were performed on one hand to establish Jobs plot that showed 1:1 stoichiometry of the OG-alphaCD complex and on the other hand to calculate the association constant found equal to (1.85 +/- 0.35) x 10(3) L mol(-1). An inclusion process of the surfactant alkyl residue within the cyclodextrin cavity was confirmed by one-dimensional (1)H NMR, and the structure of the mixed assembly was extensively characterized by two-dimensional NOESY (1)H NMR. OG penetrates alphaCD so that its hydrocarbon chain is embedded inside the cyclodextrin cavity, and its polar head as well as the alpha-methylene group emerges outside the alphaCD secondary face. Solubility behavior of the OG-alphaCD complex in a wide range of host-guest ratios and concentrations was finally examined by turbidity recording and optical microscopy. At very low free cyclodextrin levels in the solution, the complex presented high solubility behavior up to more than 70 mM. By increasing nonassociated alphaCD in the mixture, propensity of the cyclodextrin molecules to crystallize was observed at concentrations far below the 100 mM aqueous solubility of the pure cyclodextrin. The hexagonal shape of the crystals seen in the optical microscopy images suggested they were, partially at least, composed of the solid complex.

Specific interaction and stabilization between host and guest : complexation of ellipticine in a nucleobase functionalized cyclodextrin

Abstract A nucleobase derivative of β-cyclodextrin was used to form a highly soluble inclusion complex of ellipticine. The reality of inclusion and the formation of a π-π interaction between host and guest were established by NMR.

High field NMR techniques and molecular modelling study of the inclusion complexes of the nootropic drug tenilsetam (CAS-997) in cyclodextrins

The inclusion complexes of the chiral anti-amnesic drug 3-(2-thienyl)piperazin-2-one (Tenilsetam, CAS-997) with α-, β- and γ-cyclodextrins (CDs) were studied by high resolution 1H NMR spectroscopy and molecular modelling (MACROMODEL interactive computer program). The partial inclusion of the guest from the secondary hydroxyl side of α-CD was observed in aqueous solution, as well as a deeper insertion into β-CD from the same side; no interactions were evidenced with γ-CD. Diastereoisomeric pairs were observed for both α- and β-CD inclusion complexes. ROESY experiments allowed us to detect the dipolar contacts between protons of the thiophene ring and those of the internal cavity of β-CD. The possible geometry of the complex edifice derived from experimental results was consistent with those obtained by molecular modelling. The formation of hydrogen bonds provides specific interaction sites to differentiate the diastereoisomeric intermolecular inclusion complexes in terms of conformational host–guest adaptation according to available experimental NMR data.