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Biomedical subjects

J M Fréchet

Publications and source records attributed to J M Fréchet.

At least 19 recordsLinked to original sources

Monolithic porous polymer for on-chip solid-phase extraction and preconcentration prepared by photoinitiated in situ polymerization within a microfluidic device.

Monolithic porous polymers have been prepared by photoinitiated polymerization within the channels of a microfluidic device and used for on-chip solid-phase extraction and preconcentration. The preparation of the monolithic material with hydrophobic and ionizable surface chemistries is easily achieved by copolymerization of butyl methacrylate with ethylene dimethacrylate, or 2-hydroxyethyl methacrylate and [2-(methacryloyloxy)ethyl]trimethylammonium chloride with ethylene dimethacrylate, respectively. The porous properties, and consequently the flow resistance, of the monolithic device are controlled by the use of a mixture of hexane and methanol as a porogenic mixture. This mixture was designed to meet the specific requirements for pore formation within macroporous monoliths useful in the microfluidic formats. The low flow resistance enables high flow rates of up to 10 microL/min, which corresponds to a linear flow velocity of 50 mm/s and far exceeds the flow velocities typical of the common analytical microchips. The function of the monolithic concentration device was first demonstrated using very dilute solutions of Coumarin 519. The performance in a more realistic application was then demonstrated with the enrichment of a hydrophobic tetrapeptide and also of green fluorescent protein for which an increase in concentration by a factor as high as 10(3) was achieved.

Biotechnology↗

Preparation of highly selective stationary phases for high-performance liquid chromatographic separation of enantiomers by direct copolymerization of monomers with single or twin chiral ligands.

Uniformly sized macroporous polymer beads, which can be used as chiral stationary phase (CSP), have been prepared by the staged templated suspension polymerization process using chiral monomer as one of the copolymerization components. This approach enables the preparation of CSPs for which properties such as pore size, pore volume, surface area, chemistry, and chiral ligands can be tuned over a broad range. Several types of well-defined chiral monomers were prepared and allowed to assess synergistic effect of multiple selectors attached to a branched linker as well as the effect of the length and chemistry of the linker. Microscale batch screening was used for simple and rapid evaluation of selectivity. The most promising candidate CSPs were prepared on a larger scale and packed into HPLC columns. Their performance was demonstrated on the separation of racemic N-(3,5-dinitrobenzoyl)-alpha-amino acid alkylamides. The highest separation factors alpha of up to 27 were observed for CSPs prepared from monomers containing the branched spacer. These highly selective CSPs also enabled the separation of larger amounts of the target racemates upon column overload conditions.

Chromatography, High Pressure Liquid↗

Capillary electrochromatography in anion-exchange and normal-phase mode using monolithic stationary phases.

Hydrophilic macroporous weak and strong anion-exchange stationary phases have been prepared in a monolithic format within untreated fused-silica capillaries by the simple thermally or UV-initiated polymerization of 2-dimethylaminoethyl methacrylate, 2-hydroxyethyl methacrylate and ethylene dimethacrylate in the presence of a binary porogenic mixture of dodecanol and cyclohexanol. The tertiary amino functionalities were then alkylated in situ to afford strong anion-exchangers. These new monolithic stationary phases with optimized porous properties were used for the CEC separation of various organic anions. Thus, a mixture of 2-substituted propionic acid drugs (profens) was separated in 13 min and high column efficiencies of up to 231,000 plates/m were achieved. The separation of substituted benzoic acids indicates that the selectivity results primarily from the anion-exchange interactions, while electrophoretic migration contributes only slightly. In addition, these hydrophilic anion-exchangers are also able to separate weakly acidic, neutral and basic compounds such as phenols, xanthines and aromatic amines in normal-phase electrochromatographic mode.

Anion Exchange Resins↗

Fast and convenient divergent synthesis of aliphatic ester dendrimers by anhydride coupling.

A novel divergent approach was developed for the synthesis of dendritic aliphatic polyester structures using an acetal-protected anhydride derivative of 2,2-bis(hydroxymethyl)propionic acid as the acylating agent. This divergent synthesis is remarkable, because unlike all others, it only requires a small excess of reagent to achieve quantitative growth, and it requires no means of purification other than a simple solvent extraction or precipitation. A monodisperse sixth generation dendrimer with molecular weight of 30 711 Dalton and 192 masked hydroxyl groups was prepared in high yield and purity using 1,1,1-tris(hydroxyphenyl)ethane as the core molecule. Linear and star-shaped poly(ethylene glycol) (PEG) derivatives of narrow polydispersity were also used as core molecules in the divergent synthesis of dendritic-linear copolymer hybrids up to the fourth generation without requiring any chromatographic purification.

Journal Article↗

Synthesis of functional aromatic multisulfonyl chlorides and their masked precursors.

The synthesis of functional aromatic bis(sulfonyl chlorides) containing an acetophenone and two sulfonyl chloride groups, i.e., 3,5-bis[4-(chlorosulfonyl)phenyl]-1-acetophenone (16), 3,5-bis(chlorosulfonyl)-1-acetophenone (17), and 3,5-bis(4-(chlorosulfonyl)phenyloxy)-1-acetophenone (18) via a sequence of reactions, involving in the last step the quantitative oxidative chlorination of S-(aryl)- N,N'-diethylthiocarbamate, alkyl- or benzyl thiophenyl groups as masked nonreactive precursors to sulfonyl chlorides is described. A related sequence of reactions was used for the synthesis of the aromatic trisulfonyl chloride 1,1,1-tris(4-chlorosulfonylphenyl)ethane (24). 4-(Chlorosulfonyl)phenoxyacetic acid, 2,2-bis[[[4-(chlorosulfonyl)phenoxyacetyl]oxy]methyl]-1,3-propanediyl ester (27), 5,11,17,23-tetrakis(chlorosulfonyl)-25,26,27,28-tetrakis(ethoxycarbonylmethoxy)calix[4]arene (38), 5,11,17,23,29,35-hexakis(chlorosulfonyl)-37,38,39,40,41,42-hexakis(ethoxycarbonylmethoxy)calix[6]arene (39), 5,11,17,23,29,35,41,47-octakis(chlorosulfonyl)-49,50,51,52,53,54,55,56-octakis(ethoxycarbonylmethoxy)calix[8]arene (40), 5,11,17,23-tetrakis(tert-butyl)-25,26,27,28-tetrakis(chlorosulfonyl phenoxyacetoxy)calix[4]arene (44), 5,11,17,23,29,35-hexakis(tert-butyl)-37,38,39,40,41,42-hexakis(chlorosulfonylphenoxyacetoxy)calix[6]arene (45), and 5,11,17,23,29,35,41,47-octakis(tert-butyl)-49,40,51,52,53,54,55,56-octakis(chlorosulfonylphenoxyacetoxy)calix[8]arene (46) were synthesized by two different multistep reaction procedures, the last step of both methods consisting of the chlorosulfonation of compounds containing suitable activated aromatic positions. 2,4,6-Tris(chlorosulfonyl)aniline (47) was obtained by the chlorosulfonation of aniline. The conformation of two series of multisulfonyl chlorides i.e., 38, 39, 40 and 44, 45, 46, was investigated by (1)H NMR spectroscopy. The masked nonreactive precursor states of the functional aromatic multisulfonyl chlorides and the aromatic multisulfonyl chlorides reported here represent the main starting building blocks required in a new synthetic strategy elaborated for the preparation of dendritic and other complex organic molecules.

Journal Article↗

Encapsulation of functional moieties within branched star polymers: effect of chain length and solvent on site isolation.

Porphyrin and pyrene photoactive cores have been encapsulated within an isolating polymeric shell using an efficient and general strategy based on the use of dendritic initiators for the ring-opening polymerization of epsilon-caprolactone to yield functional core star polymers. The isolation of the core functionalities has been studied using fluorescence quenching and fluorescence resonance energy transfer (FRET) techniques as well as solvatochromic probes. With increasing chain length as well as solvent polarity, enhanced site isolation of the core has been observed. These findings have been correlated to actual molecular dimensions independently measured by pulsed field gradient spin-echo (PGSE) NMR. The developed synthetic methodology offers a rapid route to efficient encapsulation of functional moieties and therefore has potential for the design of new materials.

Journal Article↗

Porous polymer monoliths: simple and efficient mixers prepared by direct polymerization in the channels of microfluidic chips.

Porous monolithic polymers have been prepared by photoinitiated polymerization of mixtures consisting of 2-hydroxyethyl methacrylate, ethylene dimethacrylate, UV-sensitive free radical initiator and porogenic solvent within channels of specifically designed microfluidic chips and used as micromixers. Substituting azobisisobutyronitrile with 2,2-dimethoxy-2-phenylacetophenone considerably accelerated the kinetics of the polymerization. Mixtures of cyclohexanol and 1 -dodecanol and of hexane and methanol were used, respectively, to control the porous properties and therefore the mixing efficiency of the device. The performance of the monolithic mixers has been tested by pumping aqueous solutions of two fluorescent dyes at various flow rates and monitoring the point at which the boundary of both streams completely disappears. Best results were achieved with a monolithic mixer containing very large irregular pores.

Acetophenones↗

Chiral monolithic columns for enantioselective capillary electrochromatography prepared by copolymerization of a monomer with quinidine functionality. 1. Optimization of polymerization conditions, porous properties, and chemistry of the stationary phase.

Monolithic columns for chiral capillary electrochromatography have been prepared within the confines of untreated fused-silica capillaries in a single step by a simple copolymerization of mixtures of O-[2-(methacryloyloxy)ethylcarbamoyl]-10,11-dihydroquinidine , ethylene dimethacrylate, and glycidyl methacrylate or 2-hydroxyethyl methacrylate in the presence of mixture of cyclohexanol and 1-dodecanol as a porogenic solvent. The porous properties of the monolithic columns can easily be controlled through changes in the composition of the binary porogenic solvent. Although both thermal- and UV light-initiated polymerizations afford useful capillary columns, monoliths prepared using the former approach exhibit better chromatographic properties. The ability to control pore size independently of the polymerization mixture composition enables the preparation of monoliths with varying percentages of the chiral monomer and cross-linker, as well as the optimization of their separation properties. Very good separations of model racemate (R,S)-N-3,5-dinitrobenzoylleucine were achieved using an optimized monolithic CEC column, with high efficiencies of up to 74000 plates/m for the retained peaks.

Chromatography, Liquid↗

Chiral monolithic columns for enantioselective capillary electrochromatography prepared by copolymerization of a monomer with quinidine functionality. 2. Effect of chromatographic conditions on the chiral separations.

The effect of chromatographic conditions on the performance of chiral monolithic poly(O-[2-(methacryloyloxy)-ethylcarbamoyl]-10,11-dihydroqui nidine-co-ethylene dimethacrylate-co-2-hydroxyethyl methacrylate) columns in the capillary electrochromatography of enantiomers has been studied. The flow velocity was found to be proportional to the pore size of the monolith and both the pH and the composition of the mobile phase. The length of both open and monolithic segments of the capillary column was found to exert a substantial effect on the run times. The use of monoliths as short as 8.5 cm and the "short-end" injection technique enabled the separations to be achieved in approximately 5 min despite the high retentitivity of the quinidine selector. Very high column efficiencies of close to 250000 plates/m and good selectivities were achieved for the separations of numerous enantiomers using the chiral monolithic capillaries with the optimized chromatographic conditions.

Chromatography, Liquid↗

Design of the monolithic polymers used in capillary electrochromatography columns.

Monolithic columns for capillary electrochromatography (CEC) are receiving quite remarkable attention. Both the simplicity of the in situ preparation and the large number of readily available chemistries make the monolithic separation media a vital alternative to capillary columns packed with particulate materials. This review summarizes the current state-of-the-art in this rapidly growing area of CEC with a focus on monolithic capillary columns prepared from synthetic polymers. Recent achievements in column technologies for both high-performance liquid chromatography and capillary electrophoresis are used as the starting point to highlight the influence of these well established analytical methods on the development of monolithic capillary columns for CEC. The effects of individual variables on the separation properties of monolithic capillaries are discussed in detail. The analytical potential of these columns is demonstrated with separations involving various families of compounds in different chromatographic modes.

Electrophoresis, Capillary↗

Water-soluble dendritic unimolecular micelles: their potential as drug delivery agents.

To explore the potential of dendritic unimolecular micelles in drug delivery systems, dendritic unimolecular micelles with a hydrophobic core surrounded by a hydrophilic shell were prepared by coupling dendritic hypercores with poly(ethylene glycol) [PEG] mesylate. The monomer selected to build the dendritic cores was 4, 4-bis(4'-hydroxyphenyl) pentanol as this large monomer unit provides flexibility to the dendritic structure while contributing to the "container" capacity of the overall structure. Four generations of dendritic hypercores with six, 12, 24, and 48 phenolic end groups were prepared. Subsequent coupling reactions with PEG mesylate afforded four generations of dendritic unimolecular micelles. The micelles were characterized by Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS), 1H-NMR and Gel Permeation Chromatography (GPC). The "container" property of micelles was demonstrated by solubilizing pyrene in aqueous solution. Entrapment of the model drug indomethacin in the dendritic micelles was achieved at 11 wt.% loading level, and preliminary in vitro release tests showed that sustained release characteristics were achieved.

Anti-Inflammatory Agents, Non-Steroidal↗

"Reactive filtration": use of functionalized porous polymer monoliths as scavengers in solution-phase synthesis.

[reaction: see text] Solid functionalized porous monolithic disks with reactive polymer chains grafted to their inner pore surface have been developed for scavenging excess reagents from reaction mixtures. A poly(chloromethylstyrene-co-divinylbenzene) monolith was cut into disks and activated by graft polymerizing 4-vinyl-2,2-dimethylazlactone to its pore surface. In contrast to the direct copolymerization of reactive monomers, grafting increases the accessibility of the reactive groups. Application of the reactive disks is demonstrated in the scavenging of excess amines from reaction mixtures in different solvents.

Chemical Phenomena↗

Towards stationary phases for chromatography on a microchip: molded porous polymer monoliths prepared in capillaries by photoinitiated in situ polymerization as separation media for electrochromatography.

Photoinitiated free radical polymerization has been used for the preparation of porous polymer monoliths within UV transparent fused silica capillaries and quartz tubes. These formats were used as models for the preparation of the separation media within channels of microfabricated devices. A mixture of ethylene dimethacrylate, butyl methacrylate, and 2-acrylamido-2-methyl-1-propanesulfonic acid was polymerized in the presence of a porogenic solvent consisting of 1-propanol, 1,4-butanediol, and water at room temperature under UV irradiation. Modification of the porogen composition enables the tailoring of pore size within the broad range from ca. 100 to 4000 nm. Scanning electron micrographs confirmed the homogeneity of the porous structure of the materials prepared, even in a quartz tube with a diameter as large as 4 mm. Separation properties of the resulting capillary columns were tested in capillary electrochromatography (CEC) mode using a mixture of thiourea and eight aromatic compounds. Plate number as high as 210 000 plates/m were found for a capillary column with optimized porous properties. The monolithic columns were also able to separate mixtures of peptides.

Animals↗

Rapid reversed-phase separation of proteins and peptides using optimized 'moulded' monolithic poly(styrene-co-divinylbenzene) columns.

Monolithic macroporous poly(styrene-co-divinylbenzene) stationary phases have been prepared by free radical polymerization within the confines of 4.6-mm I.D. chromatographic columns. The optimized porous properties allow the mobile phase to flow through these columns at flow-rates of up to 10 ml/min. As opposed to the simultaneously tested columns packed with either silica or synthetic polymer beads, the monoliths exhibit only modest back pressure. The monolithic columns were able to separate mixtures of peptides and proteins in a very short time. Under the optimized conditions, the separation of five proteins can be easily achieved in less than 20 s.

Chromatography, High Pressure Liquid↗

Separation of oligonucleotides on novel monolithic columns with ion-exchange functional surfaces.

Porous monolithic columns have been prepared by the direct free radical copolymerization of glycidyl methacrylate and ethylene dimethacrylate within the confines of a 50x8 mm I.D. chromatographic column in the presence of porogens. The epoxide groups of these monoliths were modified to different extents by reaction with diethylamine to afford 1-N,N-diethylamino-2-hydroxypropyl functionalities useful for ion-exchange chromatography. Following characterization of the monoliths, the columns were tested in the chromatographic separation of a homologous series of oligodeoxyadenylic [pd(A)(12-18)] and oligothymidylic acids [d(pT)(12-24)] at different flow-rates. Very good separations of the oligonucleotides were achieved even at the high flow-rate of 4 ml/min.

Chromatography, High Pressure Liquid↗

On-bead combinatorial approach to the design of chiral stationary phases for HPLC.

A library of 36 L-amino acid anilides, which are potential selectors for chiral HPLC, was synthesized in solution and attached to functionalized macroporous polymer beads. The best selector from the library was identified by a deconvolution process using the HPLC separation of several racemic N-(3,5-dinitrobenzoyl)-alpha-amino acid alkylamides as a probe. In each deconvolution step, a series of chiral stationary phases (CSPs) containing a subset of the amino acid anilide selector library was screened for enantioselectivity. After the best CSP was chosen, the library was further deconvoluted until the single best selector was found. The highest selectivity was obtained with a L-proline-1-indananilide that exhibited alpha values up to 23 under normal-phase HPLC conditions. In addition, six CSPs were prepared using individual selectors from the library, and screening results indicate that the deconvolution process indeed led to the most selective receptor.

Amino Acids↗