Development of an Efficient Thionolactone for Radical Ring-Opening Polymerization by a Combined Theoretical/Experimental Approach.

The environmental impact of plastic waste has been a real problem for the past decades. The incorporation of cleavable bonds in the polymer backbone is a solution to making a commodity polymer degradable. When radical polymerization is used, this approach is made possible by radical ring-opening polymerization (rROP) of a cyclic monomer that allows for the introduction of a weak bond into the polymer backbone. Among the various cyclic monomers that could be used in rROP, thionolactones are promising structures due to the efficiency of the C═S bond to act as a radical acceptor. Nevertheless, only a few structures were reported to be efficient. In this work, we used DFT calculations to gain a better understanding of the radical reactivity of thionolactones, and in particular, we focused on the transfer rate constant ktr value and its ratio with the propagation rate constant kp of the vinyl monomer. The closer to 1, the better is the statistical incorporation of the two comonomers into the backbone. These theoretical results were in good agreement with all of the experimental data reported in the literature. We thus used this approach to understand the key parameters to tune the reactivity of thionolactone to prepare random copolymers. We identified and prepared the 7-phenyloxepane-2-thione (POT) thionolactone that led to statistical copolymers with styrene and acrylate derivatives that were efficiently degraded under accelerated conditions (KOH in THF/MeOH, TBD in THF, or mCPBA in THF), confirming the theoretical approach. The compatibility with RAFT polymerization as well as the homopolymerization behavior of POT was established. This theoretical approach paves the way for the in-silico design of new efficient thionolactones for rROP.

RAFT-Mediated Emulsion Polymerization-Induced Self-Assembly for the Synthesis of Core-Degradable Waterborne Particles.

Poly(N-acryloylmorpholine) (PNAM)-decorated waterborne nanoparticles comprising a core of either degradable polystyrene (PS) or poly(n-butyl acrylate) (PBA) were synthesized by polymerization-induced self-assembly (PISA) in water. A PNAM bearing a trithiocarbonate chain end (PNAM-TTC) was extended via reversible addition-fragmentation chain transfer (RAFT)-mediated emulsion copolymerization of either styrene (S) or n-butyl acrylate (BA) with dibenzo[c,e]oxepane-5-thione (DOT). Well-defined amphiphilic block copolymers were obtained. The in situ self-assembly of these polymers resulted in the formation of stable nanoparticles. The insertion of thioester units in the vinylic blocks enabled their degradation under basic conditions. The same strategy was then applied to the emulsion copolymerization of BA with DOT using a poly(ethylene glycol) (PEG) equipped with a trithiocarbonate end group, resulting in PEG-decorated nanoparticles with degradable PBA-based cores.

Evaluation of the Efficiency of Random and Diblock Methacrylate-Based Amphiphilic Cationic Polymers against Major Bacterial Pathogens Associated with Cystic Fibrosis.

Cystic fibrosis (CF) is associated with repeated lung bacterial infection, mainly by Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobacterium abscessus, all known to be or becoming resistant to several antibiotics, often leading to therapeutic failure and death. In this context, antimicrobial peptides and antimicrobial polymers active against resistant strains and less prompt to cause resistance, appear as a good alternative to conventional antibiotics. In the present study, methacrylate-based copolymers obtained by radical chemistry were evaluated against CF-associated bacterial strains. Results showed that the type (Random versus Diblock) and the size of the copolymers affected their antibacterial activity and toxicity. Among the different copolymers tested, four (i.e., Random10200, Random15000, Random23900, and Diblock9500) were identified as the most active and the safest molecules and were further investigated. Data showed that they inserted into bacterial lipids, leading to a rapid membranolytic effect and killing of the bacterial. In relation with their fast bactericidal action and conversely to conventional antibiotics, those copolymers did not induce a resistance and remained active against antibiotic-resistant strains. Finally, the selected copolymers possessed a preventive effect on biofilm formation, although not exhibiting disruptive activity. Overall, the present study demonstrates that methacrylate-based copolymers are an interesting alternative to conventional antibiotics in the treatment of CF-associated bacterial infection.

Thionolactone as a Resin Additive to Prepare (Bio)degradable 3D Objects via VAT Photopolymerization.

Three-dimensional (3D) printing and especially VAT photopolymerization leads to cross-linked materials with high thermal, chemical, and mechanical stability. Nevertheless, these properties are incompatible with requirements of degradability and re/upcyclability. We show here that thionolactone and in particular dibenzo[c,e]-oxepane-5-thione (DOT) can be used as an additive (2 wt %) to acrylate-based resins to introduce weak bonds into the network via a radical ring-opening polymerization process. The low amount of additive makes it possible to modify the printability of the resin only slightly, keep its resolution intact, and maintain the mechanical properties of the 3D object. The resin with additive was used in UV microfabrication and two-photon stereolithography setups and commercial 3D printers. The fabricated objects were shown to degrade in basic solvent as well in a homemade compost. The rate of degradation is nonetheless dependent on the size of the object. This feature was used to prepare 3D objects with support structures that could be easily solubilized.

One-Step Synthesis of Degradable Vinylic Polymer-Based Latexes via Aqueous Radical Emulsion Polymerization.

Aqueous emulsion copolymerizations of dibenzo[c,e]oxepane-5-thione (DOT) were performed with n-butyl acrylate (BA), styrene (S) and a combination of both. In all cases, stable latexes were obtained in less than two hours under conventional conditions; that is in the presence of sodium dodecyl sulfate (SDS) used as surfactant and potassium persulfate (KPS) as initiator. A limited solubility of DOT in BA was observed compared to S, yielding to a more homogeneous integration of DOT units in the PS latex. In both cases, the copolymer could be easily degraded under basic conditions. Emulsion terpolymerization between DOT, BA and S allowed us to produce stable latexes not only composed of degradable chains but also featuring a broad range of glass transition temperatures.

Polyesters by a Radical Pathway: Rationalization of the Cyclic Ketene Acetal Efficiency.

Radical ring-opening polymerization (rROP) of cyclic ketene acetals (CKAs) combines the advantages of both ring-opening polymerization and radical polymerization thereby allowing the robust production of polyesters coupled with the mild polymerization conditions of a radical process. rROP was recently rejuvenated by the possibility to copolymerize CKAs with classic vinyl monomers leading to the insertion of cleavable functionality into a vinyl-based copolymer backbone and thus imparting (bio)degradability. Such materials are suitable for a large scope of applications, particularly within the biomedical field. The competition between the ring-opening and ring-retaining propagation routes is a major complication in the development of efficient CKA monomers, ultimately leading to the use of only four monomers that are known to completely ring-open under all experimental conditions. In this article we investigate the radical ring-opening polymerization of model CKA monomers and demonstrate by the combination of DFT calculations and kinetic modeling using PREDICI software that we are now able to predict in silico the ring-opening ability of CKA monomers.

Degradable Copolymer Nanoparticles from Radical Ring-Opening Copolymerization between Cyclic Ketene Acetals and Vinyl Ethers.

2-Methylene-1,3-dioxepane (MDO) and different vinyl ether (VE) monomers were successfully copolymerized by free-radical radical ring-opening copolymerization (rROP) to yield P(MDO- co-VE) copolymers with Mn = 7 000-13 000 g·mol-1 and high molar fractions of MDO ( FMDO = 0.7-0.9). By using VE derivatives of different aqueous solubilities or by grafting PEG chains onto the copolymers by "click" chemistry via azide-containing VE units, hydrophobic, amphiphilic and water-soluble copolymers were obtained. The different copolymers were then formulated into nanoparticles by nanoprecipitation using Pluronics for hydrophobic copolymers, without surfactant for amphiphilic copolymers, or blended with PMDO for water-soluble copolymers. Most of the copolymers led to nanoparticles with average diameters in the 130-250 nm with narrow particle size distributions and satisfying colloidal stability for a period of at least 1-2 weeks and up to 6 months. The copolymers were successfully degraded under accelerated, hydrolytic or enzymatic conditions. Hydrophobic copolymers led to degradation kinetics in PBS similar to that of PCL and complete degradation (-95% in Mn decrease) was observed in the presence of enzymes (lipases). Preliminary cytotoxicity assays were performed on endothelial cells (HUVEC) and macrophages (J774.A1) and revealed high cell viabilities at 0.1 mg·mL-1.

Simulation of the Degradation of Cyclic Ketene Acetal and Vinyl-Based Copolymers Synthesized via a Radical Process: Influence of the Reactivity Ratios on the Degradability Properties.

The radical copolymerization of vinyl and cyclic ketene acetal (CKA) monomers is a promising way to prepare degradable vinyl polymers. The reactivity of the comonomer pair is known to be dependent of the vinyl monomer structure that requires to play with experimental conditions (feed ratio, overall monomer conversion, etc.) to target a desired cumulative (average) copolymer composition. Even if the materials are completely degradable, there is no information about the homogeneity of the degraded products. This theoretical study, using kinetic Monte Carlo simulations, allows simulating degradation at the molecular level. It is shown that disparate reactivity ratios (styrene/CKA, etc.) and also a composition drift at high conversion can lead to an inhomogeneous degraded product compared to systems with similar reactivity ratios (vinyl ether/CKA, etc.). The use of reversible deactivation radical polymerization techniques does not influence the final degraded products and is only useful for the design of advanced macromolecular architectures before degradation.

Radical Copolymerization of Vinyl Ethers and Cyclic Ketene Acetals as a Versatile Platform to Design Functional Polyesters.

Free-radical copolymerization of cyclic ketene acetals (CKAs) and vinyl ethers (VEs) was investigated as an efficient yet simple approach for the preparation of functional aliphatic polyesters. The copolymerization of CKA and VE was first predicted to be quasi-ideal by DFT calculations. The theoretical prediction was experimentally confirmed by the copolymerization of 2-methylene-1,3-dioxepane (MDO) and butyl vinyl ether (BVE), leading to rMDO =0.73 and rBVE =1.61. We then illustrated the versatility of this approach by preparing different functional polyesters: 1) copolymers functionalized by fluorescent probes; 2) amphiphilic copolymers grafted with poly(ethylene glycol) (PEG) side chains able to self-assemble into PEGylated nanoparticles; 3) antibacterial films active against Gram-positive and Gram-negative bacteria (including a multiresistant strain); and 4) cross-linked bioelastomers with suitable properties for tissue engineering applications.

Radical Ring-Opening Polymerization: Scope, Limitations, and Application to (Bio)Degradable Materials.

Cyclic monomers bearing either vinyl or exomethylene groups have the ability to be polymerized through a radical pathway via a ring-opening mechanism (addition-fragmentation process), leading to the introduction of functionalities in the polymer backbone. Radical ring-opening polymerization (rROP) combines the advantages of both ring-opening polymerization and radical polymerization, that is the preparation of polymers bearing heteroatoms in the backbone but with the ease and robustness of a radical process. This current review presents a comprehensive description of rROP by detailing: (i) the various monomers that polymerize through rROP; (ii) the main parameters that govern the rROP mechanism; (iii) the copolymerization by conventional or controlled/living radical polymerization between rROP monomers and traditional vinyl monomers to obtain copolymers with advanced properties; (iv) the different applications (low shrinkage materials and preparation of (bio)degradable materials) of rROP monomer-containing materials, and (v) the main alternatives to rROP to induce degradability to materials obtained by a radical polymerization.

Anomerization of Acrylated Glucose During Traveling Wave Ion Mobility Spectrometry.

Anomerization of simple sugars in the liquid phase is known as an acid- and base-catalyzed process, which highly depends on solvent polarity. This reaction is reported here to occur in the gas phase, during traveling wave ion mobility spectrometry (TWIMS) experiments aimed at separating α- and ß-anomers of penta-acrylated glucose generated as ammonium adducts in electrospray ionization. This compound was available in two samples prepared from glucose dissolved in solvents of different polarity, namely tetrahydrofuran (THF) and N,N-dimethylacetamide (DMAC), and analyzed by electrospray tandem mass spectrometry (ESI-MS/MS) as well as traveling wave ion mobility (ESI-TWIMS-MS). In MS/MS, an anchimerically-assisted process was found to be unique to the electrosprayed α-anomer, and was only observed for the THF sample. In ESI-TWIMS-MS, a signal was measured at the drift time expected for the α-anomer for both the THF and DMAC samples, in apparent contradiction to the MS/MS results, which indicated that the α-anomer was not present in the DMAC sample. However, MS/MS experiments performed after TWIMS separation revealed that ammonium adducts of the α-anomer produced from each sample, although exhibiting the same collision cross section, were clearly different. Indeed, while the α-anomer actually present in the THF sample was electrosprayed with the ammonium adducted at the C2 acrylate, its homologue only observed when the DMAC sample was subjected to TWIMS hold the adducted ammonium at the C1 acrylate. These findings were explained by a ß/α inter-conversion upon injection in the TWIMS cell, as supported by theoretical calculation and dynamic molecular modeling.

Real-time monitoring of peptide grafting onto chitosan films using capillary electrophoresis.

Chitosan, being antimicrobial and biocompatible, is attractive as a cell growth substrate. To improve cell attachment, arginine-glycine-aspartic acid-serine (RGDS) peptides were covalently grafted to chitosan films, through the widely used coupling agents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC-HCl) and N-hydroxysuccinimide (NHS), via the carboxylic acid function of the RGDS molecule. The grafting reaction was monitored, for the first time, in real time using free-solution capillary electrophoresis (CE). This enabled fast separation and determination of the peptide and all other reactants in one separation with no sample preparation. Covalent RGDS peptide grafting onto the chitosan film surface was demonstrated using solid-state NMR of swollen films. CE indicated that oligomers of RGDS, not simply RGDS, were grafted on the film, with a likely hyperbranched structure. To assess the functional properties of the grafted films, cell growth was compared on control and peptide-grafted chitosan films. Light microscopy and polymerase chain reaction (PCR) analysis demonstrated greatly improved cell attachment to RGDS-grafted chitosan films.

Stability of SG1 nitroxide towards unprotected sugar and lithium salts: a preamble to cellulose modification by nitroxide-mediated graft polymerization.

The range of applications of cellulose, a glucose-based polysaccharide, is limited by its inherently poor mechanical properties. The grafting of synthetic polymer chains by, for example, a "grafting from" process may provide the means to broaden the range of applications. The nitroxide-mediated polymerization (NMP) method is a technique of choice to control the length, the composition and the architecture of the grafted copolymers. Nevertheless, cellulose is difficult to solubilize in organic media because of inter- and intramolecular hydrogen bonds. One possibility to circumvent this limitation is to solubilize cellulose in N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) with 5 to 10 wt % of lithium salts (LiCl or LiBr), and carry out grafted polymerization in this medium. The stability of nitroxides such as SG1 has not been studied under these conditions yet, even though these parameters are of crucial importance to perform the graft modification of polysaccharide by NMP. The aim of this work is to offer a model study of the stability of the SG1 nitroxide in organic media in the presence of unprotected glucose or cellobiose (used as a model of cellulose) and in the presence of lithium salts (LiBr or LiCl) in DMF or DMA. Contrary to TEMPO, SG1 proved to be stable in the presence of unprotected sugar, even with an excess of 100 molar equivalents of glucose. On the other hand, lithium salts in DMF or DMA clearly degrade SG1 nitroxide as proven by electron-spin resonance measurements. The instability of SG1 in these lithium-containing solvents may be explained by the acidification of the medium by the hydrolysis of DMA in the presence of LiCl. This, in turn, enables the disproportionation of the SG1 nitroxide into an unstable hydroxylamine and an oxoammonium ion. Once the conditions to perform an SG1-based nitroxide-mediated graft polymerization from cellobiose have been established, the next stage of this work will be the modification of cellulose and cellulose derivatives by NMP.

Separation of poly(acrylic acid) salts according to topology using capillary electrophoresis in the critical conditions.

Branching was detected in polyacrylates synthesised through radical polymerization via solution-state NMR, while inconsistencies have been reported for the determination of the molar mass of hydrophilic polyacrylates using aqueous-phase and organic-phase size-exclusion chromatography. In this work, poly(sodium acrylate)s, PNaAs, of various topologies were separated for the first time using free-solution capillary electrophoresis (CE). Free-solution CE does not separate the PNaAs by their molar mass, similarly to separations by liquid chromatography in the critical conditions, rather by different topologies (linear, star branched, and hyperbranched). The electrophoretic mobility of PNaAs increases as the degree of branching decreases. Separation is shown to be not only by the topology but also by the end groups as expected for a separation in the critical conditions: replacing a relatively bulky nitroxide end group with hydrogen atom yielded a higher electrophoretic mobility. This novel method, capillary electrophoresis in the critical conditions enabled, for the first time, the separation of hydrophilic polyacrylates according to their topology (branching) and their chain ends. This will allow meaningful and accurate characterization of their branched topologies as well as molar masses and progress in for advanced applications such as drug delivery or flocculation.

Aqueous suspension of amphiphilic diblock copolymer nanoparticles prepared in situ from a water-soluble poly(sodium acrylate) alkoxyamine macroinitiator.

The simple, one step synthesis of aqueous suspensions of amphiphilic nanoparticles is presented. Those particles are prepared in the batch heterophase polymerization of styrene or -butyl acrylate, using a water-soluble poly(sodium acrylate) alkoxyamine macroinitiator. The nitroxide-mediated controlled growth of the hydrophobic block leads to the formation of poly(sodium acrylate)--polystyrene or poly(sodium acrylate)--poly(-butyl acrylate) amphiphilic diblock copolymers, able to self-assemble in water simultaneously to the growth step. When the diblock copolymers become strongly asymmetrical, with a short poly(sodium acrylate) block and a long hydrophobic one, the formed hairy nanoparticles are analogous to amphiphilic diblock copolymer crew-cut micelles.

Surfactant-free synthesis of amphiphilic diblock copolymer nanoparticles via nitroxide-mediated emulsion polymerization.

Amphiphilic hairy nanoparticles are prepared in a one step, batch, heterogeneous polymerization of styrene or n-butyl acrylate, using a water-soluble poly(sodium acrylate) alkoxyamine macroinitiator based on the SG1 nitroxide.