Hélène Parrot-Lopez

FORMATION OF AMPHIPHILIC CYCLODEXTRINS VIA HYDROPHOBIC ESTERIFICATION AT THE SECONDARY HYDROXYL FACE

Abstract Esterification at the O2 and O3 positions of β-cyclodextrin has been achieved in high overall yield via protection by the Bu t Me 2 Si- group at the O6 position and the use of the dimethylaminopyridine as an acylation catalyst. The silyl protecting group was removed by use of BF 3 ·Et 2 O to give the novel amphiphilic β-cyclodextrin derivatives. The resulting amphiphilic compounds form mixed vesicules with phospholipids.

Vectorised transport of drugs: Synthesis of a new glycosyl derivative of β-cyclodextrin.

Abstract Monosubstitution at the O-6 position of β-cyclodextrin by a β-N-glucosyl residue has been achieved with a spacer C 9 diamide as the interglycosidic linkage. The new glycosyl derivative has been characterised by 1 H N.M.R. (COSY-RCT), is much more soluble (200g.1 −1 ) in water and has been shown to retain the capacity to include and to enhance the solubility of pharmacologically active molecules.

Design, synthesis, and in vitro evaluation of new amphiphilic cyclodextrin-based nanoparticles for the incorporation and controlled release of acyclovir

Acyclovir possesses low solubility in water and in lipid bilayers, so that its dosage forms do not allow suitable drug levels at target sites following oral, local, or parenteral administration. In order to improve this lack of solubility, new cyclodextrin-based amphiphilic derivatives have been designed to form nanoparticles, allowing the efficient encapsulation of this hydrophobic antiviral agent. The present work first describes the synthesis and characterization of five new O-2,O-3 permethylated O-6 alkylthio- and perfluoroalkyl-propanethio-amphiphilic β-cyclodextrins. These derivatives have been obtained with good overall yields. The capacity of these molecules to form nanoparticles in water and to encapsulate acyclovir has then been studied. The nanoparticles prepared from the new β-cyclodextrin derivatives have been characterized by dynamic light scattering and have an average size of 120nm for the fluorinated derivatives and 220nm for the hydrogenated analogs. They all allowed high loading and sustained release of acyclovir.

Novel nanoparticles made from amphiphilic perfluoroalkyl α-cyclodextrin derivatives: Preparation, characterization and application to the transport of acyclovir

The preparation of aqueous suspensions of nanoparticles of the fluorinated amphiphilic alpha-cyclodextrins hexakis[6-deoxy-6-(3-perfluoroalkylpropanethio)-2,3-di-O-methyl]-alpha-cyclodextrin and their hydrocarbon analogues was studied. The complexation of acyclovir by modified alpha-cyclodextrin, the encapsulation efficiency and release profile were measured as an assessment of the properties of such nanoparticles regarding drug delivery applications. Stable aqueous suspensions of nanoparticles were prepared using nanoprecipitation method without using surface-active agent. The organic solvent (ethanol) and cyclodextrin concentration (0.4 mM) were carefully selected. The nanoparticles prepared from these new amphiphilic alpha-cyclodextrin derivatives according to optimized conditions have an average diameter of 100 nm for fluorinated derivatives and 150 nm for hydrocarbon analogues. Suspensions were stable over at least 9 months. Acyclovir forms inclusion complexes of 1:1 stoichiometry and high stability constants (from 700 mol L(-1) to 4000 mol L(-1) in ethanol) as assessed from UV/vis spectroscopy and Electrospray Ionization Mass Spectroscopy. Satisfactory loading of acyclovir inside the nanoparticles was achieved according to the highly loaded preparation method (encapsulation efficiency approximately 40%). Nanoparticles based on the fluorinated compounds delayed the drug release up to 3 h with little initial burst release. Fluorinated amphiphilic alpha-cyclodextrins self-assemble in the form of nanospheres that encapsulate acyclovir and allow sustained release, showing their potential for applications to drug delivery.

Preparation and characterization of CK2 inhibitor-loaded cyclodextrin nanoparticles for drug delivery

Casein Kinase 2 (CK2) is a ubiquitous kinase protein currently targeted for the treatment of some cancers. Recently, the series of indeno[1,2-b]indoles has revealed great interest as potent and selective CK(2) ATP-competitive inhibitors. Among them, 1-amino-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (CM1) was selected for an encapsulation study in order to improve its biodisponibility. Its complexation was evaluated at the molecular scale, with a series of fluorinated or hydrocarbonated amphiphilic cyclodextrins (CDs). Then the encapsulation of CM1 within CD nanoparticles at the supramolecular level was achieved. Nanoparticles formed between CM1 and hexakis[6-deoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl]-α-cyclodextrin, a fluorinated amphiphilic α-cyclodextrin, gave the best results in terms of encapsulation rate, stability and drug release. These nanospheres showed an encapsulation efficiency of 65% and a sustained release of the entrapped drug over 3h. Based on these results, encapsulation within fluorinated amphiphilic CD nanoparticles could be considered as a potential drug delivery system for indenoindole-type CK2 inhibitors, allowing better biodisponibility and offering perspectives for tumor targeting development.

Synthesis and characterisation of O-6-alkylthio- and perfluoroalkylpropanethio-α-cyclodextrins and their O-2-, O-3-methylated analogues

The synthesis of twelve alkylthio- or perfluoroalkylpropanethio-α-cyclodextrin derivatives and their O-2-, O-3-methylated analogues are described. The coupling reaction involves firstly the basic in situ hydrolysis of alkylperfluoropropane isothiouronium iodide or alkylisothiouronium bromide, then reaction with an α-cyclodextrin modified at the C-6 position by an iodine or methylsulfonyl group. The interfacial properties of these new compounds have been determined by the studies of their mono-molecular layer at the air–water interface.

Synthesis, solid state structures and interfacial properties of new para-phosphonato-O-alkoxy-calix[8]arene derivatives

The synthesis of six para-phosphonato-alkoxy-calix[8]arene derivatives are described. Here, a total of 24 intermediates have been isolated, and X-ray structures of the octabromo-octamethoxy-calix[8]arene and octabromo-octabutoxy-calix[8]arene have been resolved. The interfacial properties of the para-phosphonato-alkoxy-calix[8]arene derivatives and their di-iso-propoxy-protected analogues have been determined.

Fluorescent amino acids as reporter systems in peptido-cyclodextrin inclusion compounds

The inclusion behaviour of mono-6-(N-acetyltyrosinyl)amino-6-deoxy-β-cyclodextrin and mono-6-(N-acetyltryptophanyl)amino-6-deoxy-β-cyclodextrin with regard to borneol, menthol and 5-methoxypsoralen have been investigated by fluorescence spectroscopy, circular dichroism and NMR spectroscopy. For mono-6-(N-acetyltryptophanyl)amino-6-deoxy-β-cyclodextrin, the weakly self-included indole residue is disincluded, and for 5-methoxypsoralen, fluorescence resonant energy transfer is observed. In contrast, for mono-6-(N-acetyltyrosinyl)amino-6-deoxy-β-cyclodextrin the self-inclusion is sufficiently strong that no disinclusion occurs. A binary complex is postulated to arise from hydrogen bonding between borneol and mono-6-(N-acetyltyrosinyl)amino-6-deoxy-β-cyclodextrin.

Insulated molecular wires of polyaniline pseudopolyrotaxane

High density threading of cyclodextrins to conducting poly(aniline) as its emeraldine salt was achieved. Such insulated molecular wires were obtained using a strongly complexing chemically modified β-cyclodextrin. Inclusion complexation of the aniline monomer, polymerization of the inclusion complex, physicochemical characterizations of the polyaniline pseudopolyrotaxane and the electrical properties of its thin films are reported.