Synthesis of an Ethylenediaminetetraacetic Acid-like Ligand Based on Sucrose Scaffold and Complexation and Proton Relaxivity Studies of Its Gadolinium(III) Complex in Solution.

Sucrose constitutes a non-toxic, biodegradable, low-cost and readily available natural product. To expand its utility, we developed total synthesis for a ligand based on a sucrose scaffold for potential use as a metal chelation agent. The designed target (compound 2) has a metal-chelating functionality at both the C-6 and C-6' positions, which can provide a first coordination sphere of eight valencies. The designed total synthesis was highly efficient. To demonstrate the utility of the ligand, we studied its complexation with Gd(III). Using potentiometric titration and high-resolution mass spectrometry, we confirmed the formation of a 1:1 complex with Gd(III), which has a respectable formation constant of ~1013.4. Further NMR relaxivity studies show that the Gd(III) complex has a relaxivity (r1) of 7.6958 mmol-1 s-1.

Synthesis and Unprecedented Complexation Properties of ß-Cyclodextrin-Based Ligand for Lanthanide Ions.

Here, we report the synthesis and detailed studies on the coordination chemistry of a novel chemically modified polyaminocarboxylate (5) based on ß-cyclodextrin (CD) scaffold for lanthanides. The target ligand is prepared in a highly efficient manner (seven total steps) from ß-CD using the readily available iminodiacetic acid as a starting material. A propargyl group is attached to the iminodiacetate via N-alkylation, and the obtained derivative is efficiently conjugated to the ß-CD scaffold via the copper(I)-mediated 1,3-dipolar cycloaddition. The generated 1,2,3-triazolmethyl residues advantageously provide a competent chelating group while displacing the metal coordination center away from the primary rim of ß-CD, to afford the required conformational flexibility. The functional groups from each of the two adjacent glucopyranosyl units of ß-CD complete a uniquely created octavalent coordination sphere for lanthanides while still sparing one site for dynamic water coordination. To help study the coordination chemistry of CD ligand 5, we also design a relevant maltoside ligand 6, which faithfully represents one submetal-binding section of ligand 5. Thanks to HRMS and NMR studies, we successfully elucidate the coordination chemistries of synthesized ligands. The octavalent coordination sphere of ligand 5 shows strong binding affinity to lanthanides. By potentiometric titration experiments, ligand 5 is found to bind gadolinium(III), forming 1:1, 1:2, and 1:3 multinuclear complexes with lanthanides, thus possessing great capacity for catalyzing the dynamic water-exchange. Further NMR studies also reveal that the formed ligand 5/Gd(III) complexes show significantly better abilities to alter T1 relaxivities of coordinated water than DOTA-Gd(III) and also some of the synthetic CD probes reported in the literature.

Development of cyclodextrin microspheres for pulmonary drug delivery.

PURPOSE: Microparticles of diameter < 5 microm were synthesized by interfacial cross-linking of 7.5% (w/v) beta-cyclodextrins (beta-CD) with 4.5% (w/v) terephtaloyle chloride in 1 M NaOH, in order to provide stable vector for drug encapsulation suitable for administration at the alveolar scale. METHODS: Batches were prepared varying different parameters such as amount of monomer (beta-CD) (5-30% w/v), NaOH concentration (0.5-4 M), reaction time (15-240 min), agitation rate (8000-24000 rpm), amount of cross-linking agent (terephtaloyle chloride: 1.25-10% w/v), surfactant percentage (2.5-10% of Span 85), studying the influence of the freeze-drying step. Microparticles were controlled with respect to their size by a laser diffraction technique, pH of the colloidal suspension, IR spectroscopy, Differential Scanning Calorimetry. After optimization of the microparticles size, complexation with amikacin sulfate was investigated comparing encapsulation efficiency and yield at each step of the preparation (solubilization, emulsification, cross-linking, freeze-drying), contact time and influence of the amount of amikacin. RESULTS: An optimized method was obtained with 1 M NaOH, 4.5% (w/v) cross-linking agent and 5% (w/v) surfactant agent, a 30 min reaction time, a 24000 rpm agitation rate, conducting to microparticles whose size is inferior to 5 microm. Amikacin sulfate encapsulation in polycondensed beta-cyclodextrin showed that better incorporation was obtained during the solubilization step or just before freeze-drying. CONCLUSIONS: Amikacin encapsulation in 5 microm diameter microparticles of beta-CD is achievable for pulmonary drug delivery.

Solubility and dissolution rate of progesterone-cyclodextrin-polymer systems.

This contribution focused on the solubility improvement of the poorly water-soluble steroid hormone progesterone which, in its natural state, presents a reduced oral bioavailability. In the first part of this study, two simple, reproducible methods that were candidates for use in the preparation of inclusion complexes with cyclodextrins were investigated. Solubility capacities of the progesterone complex with hydroxypropyl-beta-CD (HPbeta-CD), hydoxypropyl-gamma-CD (HPgamma-CD), permethyl-beta-CD (PMbeta-CD), and sulfobutylether-beta-CD (SBEbeta-CD), prepared by the freeze-drying and precipitation methods, were evaluated by Higuchi phase solubility studies. The results showed that HPbeta-CD and PMbeta-CD were the most efficient among the four cyclodextrins for the solubilization of progesterone, with the highest apparent stability constants. Therefore, dissolution studies were conducted on these latest progesterone/cyclodextrin complexes and physical mixtures. Two additional natural cyclodextrins, beta-CD and gamma-CD, were taken as references. Hence, the influence of more highly soluble derivatives of beta-CD (HPbeta-CD, PMbeta-CD) on the progesterone dissolution rate, in comparison to pristine beta-CD, alongside an increase in the cavity width for gamma-CD versus beta-CD, were investigated. The dissolution kinetics of progesterone dissolved from HPbeta-CD, PMbeta-CD, and gamma-CD revealed higher constant rates in comparison to beta-CD. Therefore, the aim of the second part of this study was to investigate the possibility of improving the dissolution rate of progesterone/beta-CD binary systems upon formation of ternary complexes with the hydrophilic polymer, PEG 6000, as beta-CD had the smallest progesterone solubility and dissolution capacity among the four cyclodextrins studied (beta-CD, HPbeta-CD, HPgamma-CD and PMbeta-CD). The results indicated that dissolution constant rates were considerably enhanced for the 5% and 10% progesterone/beta-CD complexes in PEG 6000. The interaction of progesterone with the cyclodextrins of interest on the form of the binary physical mixtures, complexes, or ternary complexes were investigated by differential scanning calorimetry (DSC) and Fourier transformed-infrared spectroscopy (FT-IR). The results proved that progesterone was diffused into the cyclodextrin cavity, replacing the water molecules and, in case of ternary systems, that the progesterone beta-cyclodextrin was well dispersed into PEG, thus improving progesterone bioavailability for subsequent oral delivery in the same way as derivatized cyclodextrins. The present work proves that ternary complexes are promising systems for drug encapsulation.