Yves Dudal

Polymeric cyclodextrin-based nanoparticles: synthesis, characterization and sorption properties of three selected pharmaceutically active ingredients

The reaction of three cyclodextrins, namely α-, β- and γ-cyclodextrins, with toluene-2,4-diisocyanate yields water-insoluble polymers that in the case of the α- and β-derivatives self-assemble in aqueous and ethanolic solutions as polydisperse polymeric nanoparticles. The so-produced nanomaterials have been characterized by means of scanning electron microscopy, BET (Brunauer, Emmett and Teller) nitrogen adsorption technique and ζ-potential measurements. The interactions of these nanoparticles with three selected pharmaceutically active ingredients (levofloxacin, aspirin and acetaminophen) have been studied in aqueous solution. It is demonstrated that in all cases the interactions of the studied drugs with the produced polymeric nanomaterials follow the well-established Freundlich model suggesting that the polymers act as heterogeneous sorbents in aqueous phase. It is demonstrated that the β-cyclodextrin-based polymer exhibits the highest sorption capacity for all three pharmaceuticals compared to the α- and γ-analogues, with a higher affinity for aspirin. The influence of the chemical structure of the guest molecule on the interactions of the produced nanoparticulate polymers is discussed.

Enzyme Shielding in an Enzyme-thin and Soft Organosilica Layer.

The fragile nature of most enzymes is a major hindrance to their use in industrial processes. Herein, we describe a synthetic chemical strategy to produce hybrid organic/inorganic nanobiocatalysts; it exploits the self-assembly of silane building blocks at the surface of enzymes to grow an organosilica layer, of controlled thickness, that fully shields the enzyme. Remarkably, the enzyme triggers a rearrangement of this organosilica layer into a significantly soft structure. We demonstrate that this change in stiffness correlates with the biocatalytic turnover rate, and that the organosilica layer shields the enzyme in a soft environment with a markedly enhanced resistance to denaturing stresses.

Cyclodextrin-based polyurethanes act as selective molecular recognition materials of active pharmaceutical ingredients (APIs)

A series of highly cross-linked water insoluble polyurethanes have been produced using β-cyclodextrin and/or 2,2-bis(hydroxymethyl)propionic acid as monomers and toluene-2,4-diisocyanate or hexamethylene diisocyanate as cross-linkers. It is demonstrated that the binding specificities of the produced polymers for selected active pharmaceutical ingredients (APIs) are considerably different; the introduction of H-bond donor and acceptor systems and the chemical nature of the cross-linker are shown to influence the binding capabilities of the produced polymers for the studied APIs.

Design and high-throughput synthesis of cyclodextrin-based polyurethanes with enhanced molecular recognition properties

51 highly cross-linked cyclodextrin-based polyurethanes were produced using a high-throughput synthesis method. The reaction was carried out in a multiwell plate using three different cyclodextrins, namely α-, β- and γ-cyclodextrin, four different diisocyanate crosslinkers (1,4-phenylene diisocyanate, toluene 2,4-diisocyanate, isophorone diisocyanate, and hexamethylene diisocyanate), and four different carboxyl-containing dihydroxy monomers (2,2-bis(hydroxymethyl)propionic acid, 2,5-dihydroxybenzoic acid, 2,5-dihydroxyterephthalic acid, and 1,4-dihydroxy-2-naphthoic acid). The interactions of the produced polyurethanes with a mixture of molecules of interest, namely acetaminophenol, atenolol, caffeine, ofloxacin, ciprofloxacin, tetracycline, sulfamethoxazole, chloramphenicol, (±)-propranolol and diclofenac, were studied in water. It was demonstrated that the binding properties of the produced polyurethanes could be tuned by selecting the monomers and crosslinkers used for their synthesis. In addition to the hydrophobic inclusion of the target into the cyclodextrin macrocycle, a set of synergistic interactions were shown to influence the sorption behavior of the produced polyurethanes. Two selected formulations were upscaled at the gram quantity; the binding results showed a similar behavior as that of the polyurethanes produced using the high-throughput method, thus demonstrating the suitability of the method to produce polymers with enhanced molecular recognition properties.

A cyclodextrin-based polymer for sensing diclofenac in water.

An assay for the determination of diclofenac concentration, in the micromolar range in water, was developed. It is based on the use of a recently developed cyclodextrin-based polymer that possesses an inherent affinity for the target pharmaceutical. This competitive assay is exploiting the possibility to displace a fluorescent dye, adsorbed in the cyclodextrin-based polymer, by the target drug. This displacement is followed by measuring the increase in fluorescence polarization of the dye released in solution. The assay was successfully tested on a real wastewater sample with a limit of detection of 1 μM.

Surface Immobilization and Shielding of a Transaminase Enzyme for the Stereoselective Synthesis of Pharmaceutically Relevant Building Blocks

Transaminases are enzymes capable of stereoselective reductive amination; they are of great interest in the production of chiral building blocks. However, the use of this class of enzymes in industrial processes is often hindered by their limited stability under operational conditions. Herein, we demonstrate that a transaminase enzyme from Aspergillus terreus can be immobilized at the surface of silica nanoparticles and protected in an organosilica shell of controlled thickness. The so-protected enzyme displays a high biocatalytic activity, and additionally provides the possibility to be retained in a reactor system for continuous operation and to be recycled.

Engineering Nanosized Organosilica for Molecular Recognition and Biocatalysis Applications

A series of synthetic nanomaterials capable of molecular recognition and/or biocatalysis have been produced by exploiting the self-sorting, self-assembly and polycondensation of organosilane building blocks around protein templates. The established methodology allows for the production of thin organosilica layers of controlled thickness, down to nanometer precision. Fully synthetic virus recognition materials have been shown to specifically bind their target virus down to picomolar concentrations. The shielding of natural enzymes allowed producing nanobiocatalysts functioning under harsh operational conditions.

A Biocatalytic Nanomaterial for the Label‐Free Detection of Virus‐Like Particles

The design of nanomaterials that are capable of specific and sensitive biomolecular recognition is an on‐going challenge in the chemical and biochemical sciences. A number of sophisticated artificial systems have been designed to specifically recognize a variety of targets. However, methods based on natural biomolecular detection systems using antibodies are often superior. Besides greater affinity and selectivity, antibodies can be easily coupled to enzymatic systems that act as signal amplifiers, thus permitting impressively low detection limits. The possibility to translate this concept to artificial recognition systems remains limited due to design incompatibilities. Here we describe the synthesis of a synthetic nanomaterial capable of specific biomolecular detection by using an internal biocatalytic colorimetric detection and amplification system. The design of this nanomaterial relies on the ability to accurately grow hybrid protein‐organosilica layers at the surface of silica nanoparticles. The method allows for label‐free detection and quantification of targets at picomolar concentrations.