Catherine Amiel

Association between amphiphilic poly(ethylene oxide) and β-cyclodextrin polymers : aggregation and phase separation

Abstract An original associating system is presented in this paper. It involves the mixing of two polymers: hydrophobically modified polyethylene oxide (PEO) and β-cyclodextrin copolymer. Inclusion complexes between the hydrophobic moieties (naphthalene or adamantane) and β-cyclodextrin cavities are at the origin of the attraction between the two polymers. The strength of the attractive interactions has been tailored by using different architectures for the amphiphilic polymer: linear or multi-arm branched PEO have been used, leading to a variable number of hydrophobic end-groups per chain. Interactions between the host and guest polymer have been demonstrated through both microscopic and macroscopic analysis of the properties of the medium: complexation constants have been determined by fluorescence methods and dialysis, while polymolecular associations have been evidenced by viscoelastic properties. Phase diagram studies have shown that the strength of the interactions between the two polymers is strongly related to the number of hydrophobic moieties per chain: while unmodified PEO and β-cyclodextrin copolymer are phase segregating, associative phase separations are observed for a number of hydrophobes per chain higher than or equal to three.

Aqueous Polysaccharide Associations Mediated by β-Cyclodextrin Polymers

Macromolecular assemblies were elaborated by mixing in water hydrophobically modified dextrans (MDC(n)) and beta-cyclodextrin polymers (pbetaCD) interacting by inclusion complexation between the hydrophobic moieties of MDCn and the beta-cyclodextrin cavities of pbetaCD. Dextrans have been modified by grafting alkyl groups (C(n)) of varying chain lengths (n = 8-16) and grafting ratio (3-6 mol%). Different pbetaCD polymers were synthesized by polycondensation of beta-cyclodextrin and epichlorohydrin. The polymer-polymer interactions have been studied by fluorimetry, isothermal titration microcalorimetry, phase diagrams, and viscosimetry. The viscoelastic properties of the temporary networks (in the semidilute range) have been studied by rheology. The interaction mechanisms between the MDCn and pbetaCD can be understood taking into account the strength of the interaction between the alkyl group and the beta-cyclodextrin cavity (mainly controlled by the alkyl chain length), the density of junctions between the chains (depending on the alkyl grafting density and the pbetaCD molecular weight), and additional cooperative effect (arising for high alkyl grafting density).

ULTRAFILTRATION OF LYSOZYME AND BOVINE SERUM ALBUMIN WITH POLYSULFONE MEMBRANES MODIFIED WITH QUATERNIZED POLYVINYLIMIDAZOLE

Abstract In order to investigate the influence of ionic interactions on protein ultrafiltration, sulfonated polysulfone and polyethersulfone membranes were coated with polyvinylimidazole (PVI) and quarternized by a cross-linking agent bearing Bisphenol A. The apparent PVI thickness, from ATR-FTIR, was in the range from 10 to 40 nm for the polyethersulfone and sulfonated polysulfone membranes. Significant difference in protein retention (positive lysozyme and negative bovine serum albumin) was observed at low ionic strength for oppositely charged protein and (modified) membrane. At high ionic strength, protein retention and membrane flux with modified and unmodified membranes were similar due to protein adsoption on the membrane and interactions of adsorbed protein to free protein. Hydrophobic interactions between Bisphenol A and protein were demonstrated with similarly modified HPLC silica. Hence, the hydrophobic interactions could partly explain the unexpected high protein retention observed both with the unmodified and modified membrane at high ionic strength.

Polymers of malic acid conjugated with the 1-adamantyl moiety as lipophilic pendant group

Abstract Ethyladamantyl malolactonate and butyladamantanamide malolactonate were prepared, starting from malic acid, following the usual synthesis route described for different malolactonic acid esters. Despite the steric hindrance of both adamantyl groups, the three-step synthesis led to the corresponding lactones with a quite good yield and high purity. Otherwise, ethyladamantyl malolactonate has been obtained by chemical modification of the lateral car☐ylic acid function of malolactonic acid. Both ethyladamantyl malolactonate and butyladamantanamide malolactonate were homopolymerized by anionic ring opening polymerization using tetramethylammonium benzoate as initiator. Expected high molecular weight homopolymers were obtained and characterized by 1 H nuclear magnetic resonance (n.m.r.) and size exclusion chromatography (s.e.c.). Furthermore, ethyladamantyl malolactonate was copolymerized with benzyl malolactonate in the molar ratio 5/95. The resulting copolymer was studied by 1 H and 13 C n.m.r., s.e.c. and differential scanning calorimetry. After deprotection of the benzyl protecting groups by catalytic hydrogenolysis, the corresponding poly(β-malic acid- co -ethyladamantyl β-malate) displayed a water solubility.

Associative network based on cyclodextrin polymer: a model system for drug delivery.

Associative networks have been elaborated by mixing in aqueous media a cyclodextrin polymer to a dextran bearing adamantyl groups. The two polymers interact mainly via inclusion complexes between adamantyl groups and cyclodextrin cavities, as evidenced by the high complexation constants determined by isothermal titration microcalorimetry (approximately 10(4) L mol(-1)). Additional interaction mechanisms participating in the strength of the network, mainly hydrogen bonding and electrostatic interactions, are sensitive to the pH and ionic strength of the medium, as shown by pH-dependent rheological properties. The loading and release of an apolar model drug, benzophenone, has been studied at two pH values and different cyclodextrin polymer content. Slow releases have been obtained (10-12 days) with slower kinetics at pH 2 than at pH 7. Analysis of the experiments at pH 7 shows that drug release is controlled both by diffusion in the network and by inclusion complex interactions with cyclodextrin cavities.

Development and Characterization of New Cyclodextrin Polymer-Based DNA Delivery Systems

In this study, we investigated whether a cyclodextrin polymer (polybetaCD) complexed with cationic adamantyl derivatives (Ada) could be used as a vector for gene delivery. DNA compaction as a function of adamantyl/DNA phosphate ratio (A/P) by this new class of vector was demonstrated using surface enhanced Raman spectroscopy, zeta potential measurements, and DNA retardation assays. Transfection data highlight the relationship between in vitro gene delivery efficiency and the combination of several physical properties of the polybetaCD/Ada/DNA polyplexes, including cationic polar headgroup valency and chemical structure of the spacer arm of Ada connectors, the adamantyl/DNA phosphate ratio (A/P) of the polybetaCD/Ada/DNA polyplexes, and the ionic strength of the medium. Finally, when associating the best formulation with a fusogenic peptide, we reached transfection levels which were of the same order as those obtained with DOTAP.

Evaluation of a cationic calix[4]arene: Solubilization and self-aggregation ability.

Water-soluble calixarenes are promising macrocyclic compounds which have found numerous applications in chemistry and biology. However, these compounds have been less studied in regard to their behavior in aqueous solutions and mechanisms of drug solubilization. The present work is devoted to the evaluation of the solubilizing properties and estimation of self-aggregation ability of positively charged 5,11,17,23-tetrakis(trimethylammoniomethyl)-25,26,27,28-tetrapropoxy-calix[4]arene tetrachloride (aminocalix), including comparisons with a series of pharmaceutically relevant cyclodextrins. Phase-solubility measurements of the drugs with aminocalix and various cyclodextrins were carried out. Aminocalix showed a solubilizing ability comparable to the cyclodextrins. The drug solubility enhancement caused by the aminocalix was studied and was found to be maximal for steroid drugs. An attempt to understand the solubilizing mechanism of aminocalix was undertaken based on correlation analysis between physical and physico-chemical properties of the drugs from one side and the solubilizing ability of aminocalix from the other. Correlation analysis supports the supposition that the solubilizing effect of aminocalix is based on interaction of the drug with aminocalix aggregates rather than on inclusion complexation. UV-absorbance, osmolality and surface tension concentration dependences of aminocalix showed an inflection at 1% (w/v) which was initially related to the transition from monomers to micelles. However, dynamic light scattering and transmission electron microscopy measurements revealed that likely vesicles of diverse size exist at 0.1% (w/v) concentration. Thus the 1% (w/v) inflection point was interpreted to be spontaneous reordering of the vesicles between two different size populations.

Comparison of the Complexation of Cosmetical and Pharmaceutical Compounds with γ-Cyclodextrin, 2-Hydroxypropyl-β-cyclodextrin and Water-Soluble β-Cyclodextrin-co-epichlorhydrin Polymers

The ability of different cyclodextrins (CDs): γCD, 2-hydroxypropyl βCD to complex drugs like 3-β-hydroxy-11-oxoolean- 12-en-30-oic acid, 2-ethylhexyl-3-(4-methoxyphenyl)-2-propanoate and menthol was compared to that of water-soluble polymers: βCD-co-epichlorhydrin polymer (pβCD/EP) and βCD-co-epichlorhydrin polymer partially modified with trimethylammonium groups (pβCD/EPN+). 3-β-Hydroxy-11-oxoolean-12-en-30-oic acid was poorly solubilized by γCD compared with other CD derivatives, however the determination of the complexation constants was possible for pβCD/EP, K11 = 740, K12 = 4, for pβCD/EPN+, K11 = 681, for γCD, K11 = 16 and for hydroxypropyl βCD, K11 = 114, K12 = 3.4. A significant increase of the solubility was observed for 2-ethylhexyl-3-(4-methoxyphenyl)-2-propanoate with all host molecules, it was 916 times its solubility in pure water with pβCD/EPN+, 1116 and 1300 times with 2-hydroxypropyl βCD and pβCD/EP respectively. The association constants are K11 = 7970, K11 = 4700, K11 = 1470, K11 = 230 and K12 = 200 with pβCD/EP, pβCD/EPN+, γCD, 2-hydroxypropyl βCD respectively. An increase of the solubility of menthol was observed with all CD derivatives, up to 36–37 times, except for γCD. The complexation constants are similar equal to about 200.

Cyclodextrin-Mediated Hierarchical Self-Assembly and Its Potential in Drug Delivery Applications

Hierarchical self-assembly exploits various non-covalent interactions to manufacture sophisticated organized systems at multiple length scales with interesting properties for pharmaceutical industry such as possibility of spatially controlled drug loading and multiresponsiveness to external stimuli. Cyclodextrin (CD)-mediated host-guest interactions proved to be an efficient tool to construct hierarchical architectures primarily due to the high specificity and reversibility of the inclusion complexation of CDs with a number of hydrophobic guest molecules, their excellent bioavailability, and easiness of chemical modification. In this review, we will outline the recent progress in the development of CD-based hierarchical architectures such as nanoscale drug and gene delivery carriers and physically cross-linked supramolecular hydrogels designed for a sustained release of actives.

Association of hydrophobically modified poly (N,N-dimethylacrylamide hydroxyethylmethacrylate) with water soluble β-cyclodextrin polymers

Abstract Hydrophobically associating polymers have been obtained by chemical modification of poly (N,N-dimethyl acrylamide hydroxyethylmethacrylate) consisting in the introduction of adamantyl groups (Ad). Viscosity studies of dilute solutions of modified polymers show lower reduced viscosities than precursor solutions attributed to intramolecular hydrophobic associations. At higher concentrations intermolecular associations take place. In all cases, the viscosities are of limited value. Hydrophobic microdomains were evidenced by static fluorescence measurements in the presence of pyrene and critical aggregation concentrations determined. A study of fluorescence versus temperature has shown a modification of hydrophobic properties above 40°C corresponding to a coiling of the molecules, masking the hydrophobic groups. When these modified polymers are added to solutions of β-cyclodextrin epichlorhydrin polymer (βCD/EP), associations take place between the two polymers due to inclusion of adamantyl groups in cyclodextrin cavities. High viscosity enhancements are observed which are maximum for a precise composition of both polymers. This composition corresponds to the stoechiometry 1 adamantyl group for 1 CD cavity and varies with molecular weight and hydrophobe content of the modified polymer. Associative phase diagrams were stated which confirm the strong association of both polymers via inclusion of adamantyl groups in the β-cyclodextrin cavities.