Reversible Addition-fragmentation Chain Transfer Research Articles

PH-Triggered, Lymph Node Focused Immunodrug Release by Polymeric 2-Propionic-3-Methyl-maleic Anhydrides with Cholesteryl End Groups.

Gaining spatial control over innate immune activation is of great relevance during vaccine delivery and anticancer therapy, where one aims at activating immune cells at draining lymphoid tissue while avoiding systemic off-target innate immune activation. Lipid-polymer amphiphiles show high tendency to drain to lymphoid tissue upon local administration. Here, pH-sensitive, cholesteryl end group functionalized polymers as stimuli-responsive carriers are introduced for controlled immunoactivation of draining lymph nodes. Methacrylamide-based monomers bearing pendant 2-propionic-3-methylmaleic anhydride groups are polymerized by Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization using a cholesterol chain-transfer agent (chol-CTA). The amine-reactive anhydrides are conjugated with various amines, however, while primary amines afforded irreversible imides, secondary amines provided pH-responsive conjugates that are released upon acidification. This can be applied to fluorescent dyes for irreversibly carrier labeling or immunostimulatory Toll-like receptor (TLR) 7/8 agonists as cargos for pH-responsive delivery. Hydrophilization of remaining anhydride repeating units with short PEG-chains yielded cholesteryl-polymer amphiphiles that showed efficient cellular uptake and increased drug release at endosomal pH. Moreover, reversibly conjugated TLR 7/8 agonist amphiphiles efficiently drained to lymph nodes and increased the number of effectively maturated antigen-presenting cells after subcutaneous injection in vivo. Consequently, cholesteryl-linked methacrylamide-based polymers with pH-sensitive 2-propionic-3-methylmaleic anhydride side groups provide ideal features for immunodrug delivery.

Efficient Synthesis of Ultrahigh Molecular Weight Poly(methyl methacrylate) via Visible Light-Induced RAFT Polymerization in Deep Eutectic Solvent

Efficient Synthesis of Ultrahigh Molecular Weight Poly(methyl methacrylate) via Visible Light-Induced RAFT Polymerization in Deep Eutectic Solvent

Investigating the Formation of Polymer-Nanoparticle Complex Coacervate Hydrogels Using Polymerization-Induced Self-Assembly-Derived Nanogels with a Succinate-Functional Core.

This paper reports polymer-nanoparticle-based complex coacervate (PNCC) hydrogels prepared by mixing anionic nanogels synthesized by polymerization-induced self-assembly (PISA) and cationic branched poly(ethylenimine) (bPEI). Specifically, poly(3-sulfopropyl methacrylate)58-b-poly(2-(methacryloyloxy)ethyl succinate)500 (PKSPMA58-PMES500) nanogels were prepared by reversible addition-fragmentation chain-transfer (RAFT)-mediated PISA. These nanogels swell on increasing the solution pH and form free-standing hydrogels at 20% w/w and pH ≥ 7.5. However, the addition of bPEI significantly improves the gel properties through the formation of PNCCs. Diluted bPEI/nanoparticle mixtures were analyzed by dynamic light scattering (DLS) and aqueous electrophoresis to examine the mechanism of PNCC formation. The influence of pH and the bPEI-to-nanogel mass ratio (MR) on the formation of these PNCC hydrogels was subsequently investigated. A maximum gel strength of 1300 Pa was obtained for 20% w/w bPEI/PKSPMA58-PMES500 PNCC hydrogels prepared at pH 9 with an MR of 0.1, and shear-thinning behavior was observed in all cases. After the removal of shear, these PNCC gels recovered rapidly, with the recovery efficiency being pH-dependent.

Vinyl Ether Maleic Acid Polymers: Tunable Polymers for Self-Assembled Lipid Nanodiscs and Environments for Membrane Proteins.

Native lipid bilayer mimetics, including those that use amphiphilic polymers, are important for the effective study of membrane-bound peptides and proteins. Copolymers of vinyl ether monomers and maleic anhydride were developed with controlled molecular weights and hydrophobicity through reversible addition-fragmentation chain-transfer polymerization. After polymerization, the maleic anhydride units can be hydrolyzed, giving dicarboxylates. The vinyl ether and maleic anhydride copolymerized in a close to alternating manner, giving essentially alternating hydrophilic maleic acid units and hydrophobic vinyl ether units along the backbone after hydrolysis. The vinyl ether monomers and maleic acid polymers self-assembled with lipids, giving vinyl ether maleic acid lipid particles (VEMALPs) with tunable sizes controlled by either the vinyl ether hydrophobicity or the polymer molecular weight. These VEMALPs were able to support membrane-bound proteins and peptides, creating a new class of lipid bilayer mimetics.

Replacing poly(ethylene glycol) with RAFT lipopolymers in mRNA lipid nanoparticle systems for effective gene delivery

Lipid nanoparticles (LNPs) have emerged as promising carriers to efficiently transport mRNA into cells for protein translation, as seen with the mRNA vaccines used against COVID-19. However, they contain a widely used polymer – poly(ethylene glycol) (PEG) – which lacks the functionality to be easily modified (which could effectively control the physicochemical properties of the LNPs such as its charge), and is also known to be immunogenic. Thus, it is desirable to explore alternative polymers which can replace the PEG component in mRNA LNP vaccines and therapeutics, while still maintaining their efficacy. Herein, we employed reversible addition-fragmentation chain transfer (RAFT) polymerisation to synthesise five PEG-lipid alternatives that could stabilise LNPs encapsulating mRNA or pDNA molecules. Importantly, the resultant RAFT lipopolymer LNPs exhibit analogous or higher in vivo gene expression and antigen-specific antibody production compared to traditional PEG-based formulations. Our synthesis strategy which allows the introduction of positive charges along the lipopolymer backbone also significantly improved the in vivo gene expression. This work expands the potential of RAFT polymer-conjugated LNPs as promising mRNA carriers and offers an innovative strategy for the development of PEG-free mRNA vaccines and therapeutics.

Homogeneous Reversible Addition Fragmentation Chain Transfer Synthesis of Amphiphilic Poly(Styrene-b-Acrylamide) Copolymers and Their Solution Characterization: a Thermogelating and Salinity Resistant Viscosifier from Largely Available Monomers

Homogeneous Reversible Addition Fragmentation Chain Transfer Synthesis of Amphiphilic Poly(Styrene-<i>b</i>-Acrylamide) Copolymers and Their Solution Characterization: a Thermogelating and Salinity Resistant Viscosifier from Largely Available Monomers

Optimized gadolinium-DO3A loading in RAFT-polymerized copolymers for superior MR imaging of aging blood-brain barrier.

The development of gadolinium-based contrast agents (GBCAs) has been pivotal in advancing magnetic resonance imaging (MRI), offering enhanced soft tissue contrast without ionizing radiation exposure. Despite their widespread clinical use, the need for improved GBCAs has led to innovations in ligand chemistry and polymer science. We report a novel approach using methacrylate-functionalized DO3A ligands to synthesize a series of copolymers through direct reversible addition-fragmentation chain transfer (RAFT) polymerization. This technique enables precise control over the gadolinium content within the polymers, circumventing the need for subsequent conjugation and purification steps, and facilitates the addition of other components such as targeting ligands. The resulting copolymers were analysed for their relaxivity properties, indicating that specific gadolinium-DO3A loading contents between 12-30 mole percent yield optimal MRI contrast enhancement. Inductively coupled plasma (ICP) measurements corroborated these findings, revealing a non-linear relationship between gadolinium content and relaxivity. Optimized copolymers were synthesized with the claudin-1 targeting peptide, C1C2, to image BBB targeting in aged mice to show imaging utility. This study presents a promising pathway for the development of more efficient GBCA addition to copolymers for targeted drug delivery and bioimaging application.

Reversible Addition-Fragmentation Chain-Transfer Polymerization in Supercritical CO2: A Review.

The development of cleaner, more environmentally friendly processes in polymerization technology is crucial due to the prevalent use of volatile organic solvents (VOCs), which are harmful and toxic. Future regulations are likely to limit or ban VOCs. This review explores the use of supercritical solvents, specifically supercritical CO2 (scCO2), in polymerization processes. The study focuses on reversible addition-fragmentation chain-transfer (RAFT) induced homo-polymerization of various monomers using specific chain transfer agents (CTAs) in scCO2. RAFT polymerization, a reversible deactivation radical polymerization (RDRP) polymerization, relies heavily on the choice of CTA, which significantly influences the dispersity and molar mass of the resulting polymers. Stabilizers are also crucial in controlling product specifications for polymerizations in supercritical CO2, except for fluor-based polymers, although they must be removed and preferably recycled to ensure product purity and sustainability. The review notes that achieving high molar mass through RAFT polymerization in scCO2 is challenging due to solubility limits, which lead to polymer precipitation. Despite this, RAFT polymerization in scCO2 shows promise for sustainable, circular production of low molar mass polymers, although these cannot yet be fully considered green products.

Alteration of the upper critical solution temperature (UCST) behavior of the nonionic polymer poly(N-acryloyl-nipecotamide) by its terminal group

Influences of the terminal group of non-ionic polymer with upper critical solution temperature on cloud points (CPs) has been one of curious research topics, however, detailed investigation has not been conducted so far. This study investigates the effect of the terminal group of poly(N-acryloyl-nipecotamide)s (PNANAms) on their CPs in aqueous solution. PNANAms with different molecular weights (Mn) ranging from 4,100 to 34,300 and different terminal end groups were successfully synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization. The temperature-dependent optical transmittance of aqueous solutions of the PNANAms revealed that their CP was influenced by their terminal group, in addition to their Mn and polymer concentration. PNANAms with low Mn (Mn ≥ 7,500) and a hydrophobic (dodecyl) terminal group exhibited poor solubility, whereas PNANAms with a moderate Mn (Mn ≤ 10,200) and hydrophilic (maleimide or carboxylic) terminal groups were readily soluble in aqueous solution. However, PNANAms with a high Mn (Mn = 34,300) were hardly soluble in aqueous solution. The poor solubility of such PNANAms suggests that strong inter- and intramolecular hydrogen bonds were formed among the polymer chains, increasing their CP. PNANAm with a low Mn (Mn = 4,100) and the hydrophobic terminal and that with a moderate Mn (13,200 ≤ Mn ≤ 18,200) and hydrophilic terminal groups exhibited CPs in aqueous solution. The CP of PNANAms with carboxylic terminal groups was also influenced by the solution pH owing to the deprotonation of these groups. The size of polymeric aggregates was directly observed using phase-contrast microscopy, and the temperature-dependent aggregation and dispersion of the polymers were described in terms of the inter- and intramolecular hydrogen bonds formed among PNANAm chains. Finally, a cell viability assay was conducted to explore the possibility of the applications of PNANAm in the fields of biomaterials and regenerative therapy.

RAFT unchained — Scalable manufacturing of thiocarbonyl chain transfer agents

Here, we report an efficient approach for the manufacturing of chain-transfer agents (CTA) for RAFT polymerization using non-volatile organic compounds (VOC) in one pot with only water-washing as a work-up. Although the RAFT process is scientifically mature, nearly all RAFT CTAs are still produced through multi-step syntheses involving material- and energy-intensive separations. Today’s commercially available RAFT agents are high-value specialty products available only from fine chemical vendors, limiting RAFT’s industrial success. The current work illustrates a single-step one-pot approach to synthesize ethyl (3-oxo-2-butyl) carbonotrithioate and O-ethyl S-(3-oxobutan-2-yl) carbonodithioate at up to 10 L scale in various non-VOC solvents with varied degrees of potential for cross-reactivity: diethyl succinate, tributyl acetyl citrate, castor oil glycidal ether, and glycerol triglycidyl ether. We studied the purity and yield of these CTAs using NMR and LC-MS, and then conducted rigorous polymerization and kinetic studies to evaluate the efficacy of these molecules in maintaining the RAFT equilibrium. We found that the use of these non-VOC solvents impedes neither the synthesis of these molecules nor the RAFT control, thus enabling scalable and low-impact pathways to RAFT CTA manufacturing.

Multi-functional RAFT reagent to prepare fluorescent hyper-branched macromolecular probes for the detection of Fe3+ ions

Reversible addition-fragmentation chain transfer (RAFT) polymerization has the advantages of precise control, high yield, and narrow molecular weight distribution. These merits make it an ideal method for the preparation of hyper-branched fluorescent polymers (FL-HBPs). In this work, a multi-functional RAFT reagent (AVCT-NLP) was prepared for the synthesis of monodisperse FL-HBPs. Firstly, dithionate compound (CN1) containing a CC double bond was synthesized by the reaction of 4-nitrophenol with 1-(bromomethyl)-4-vinylbenzene. Subsequently, the NO2 group on CN1 was reduced to NH2, and the −Br on the 4-bromo-1,8-naphthalic anhydride was substituted to emit fluorescence. Finally, the fluorophore was introduced by the reaction of NH2 with the anhydride on the naphthalene ring to obtain AVCT-NLP which contains fluorophore, dithionate, and CC double bond in one molecule. AVCT-NLP was then used to synthesize the homopolymer (PAVCT-NLP) as both monomer and RAFT reagent. Moreover, PAVCT-NLP served as a macromolecular RAFT reagent, and hydrophilic monomer methacrylic acid (MAA) or 3-butene-1,2-diol were polymerized to obtain amphiphilic hyper-branched polymers (FL-AHBP-1, FL-AHBP-2). All the as-prepared macromolecules (PAVCT-NLP, FL-AHBP-1, and FL-AHBP-2) exhibited specific recognition and high sensitivity for Fe3+. The fluorescence quenching reached up to 74.4 %, with the limit of detection (LOD) as low as 1.82 nM. Additionally, the probe demonstrated pH stability and environmental adaptability. Due to the multi-functional structures of AVCT-NLP, it could be subjected to RAFT polymerization to obtain a monodisperse hyper-branched polymer. All polymers have a high fluorophore density and the polydispersity index (PDI) of the polymer is close to 1.00. This paper provided an effective approach for synthesizing polymer fluorescent probes with versatile structure and fluorescence properties in future applications.

Surface-Initiated Reversible Addition-Fragmentation Chain Transfer Polymerization (SI-RAFT) to Produce Molecularly Imprinted Polymers on Graphene Oxide for Electrochemical Sensing of Methylparathion.

A nonenzymatic redox-responsive sensor was put forward for the detection of methylparathion (MP) by designing globular nanostructures of molecularly imprinted polymers on graphene oxide (GO@MIPs) via surface-initiated reversible addition-fragmentation chain transfer polymerization (SI-RAFT). Fourier transform infrared (FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), and small-angle X-ray scattering (SAXS) studies have confirmed the successful formation of receptor layers of MIPs on RAFT agent-functionalized GO sheets. The electrochemical signal with an amplified current response was attained because of the enhanced diffusion rate of ions at the interface provided by widening the pore size of the MIP film. The analytical response of GO@MIPs, validated by recording square-wave anodic stripping voltammetry (SWASV) at varying MP concentrations, followed the linear response between 0.2 and 200 ng/mL. Under optimized conditions, the sensor exhibited a limit of detection of 4.25 ng/mL with high selectivity over other interfering ions or molecules. The anti-interfering ability and good recovery (%) in food samples directed the use of the proposed sensor toward real-time monitoring and also toward future mimicking of surfaces.

Poly(vinyl alcohol)-Incorporated Core-Shell Polymer Nanogels Functionalized by Block Copolymer Installation for Cisplatin Delivery.

The functionalization approach for nanomaterials is of great importance for their application in drug delivery systems. Herein, an approach based on block copolymer installation into polymer nanogels was newly developed. Poly(vinyl alcohol)-incorporated polymer nanogels were prepared by a two-step dispersion/precipitation polymerization. Poly(methacrylic acid)-block-poly(3-fluorophenylboronic acid methacrylamide) (PMAA-b-PFPBMA) prepared by two-step reversible addition-fragmentation chain transfer polymerization was installed into the polymer nanogels via boronate ester formation. Furthermore, cisplatin as a cancer therapeutic drug was successfully loaded on the block copolymer-installed polymer nanogels, and cell death was achieved by using the resulting cisplatin-loaded nanogels. We believe that the functionality of the nanogels can be changed by varying the installed block copolymer, leading to the functionalization approach of polymer nanogels based on block copolymer installation, which will be of great utility in many fields.

Micelles of poly[oligo(ethylene glycol) methacrylate] as delivery vehicles for zinc phthalocyanine photosensitizers

Drug-loaded polymeric micelles have proven to be highly effective carrier systems for the efficient delivery of hydrophobic photosensitizers (PSs) in photodynamic therapy (PDT). This study introduces the micellization potential of poly(oligoethylene glycol methyl ether methacrylate) (pOEGMA) as a novel approach, utilizing the hydrophobic methacrylate segments of pOEGMA to interact with highly hydrophobic zinc phthalocyanine (ZnPc), thereby forming a potential micellar drug carrier system. The ZnPc molecule was synthesized from phthalonitrile derivatives and its fluorescence, photodegradation, and singlet oxygen quantum yields were determined in various solvents. In solvents such as tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide, the ZnPc compound exhibited the requisite photophysical and photochemical properties for PDT applications. The pOEGMA homopolymer was synthesized via reversible addition-fragmentation chain-transfer polymerization, while ZnPc-loaded pOEGMA micelles were prepared using the nanoprecipitation method. Characterization of the pOEGMA, ZnPc, and micelles was conducted using FTIR,1H-NMR, dynamic light scattering, matrix-assisted laser desorption/ionization time-of-flight mass spectrometries, gel permeation chromatography, and transmission electron microscopy. The critical micelle concentration was determined to be 0.027 mg ml-1using fluorescence spectrometry. The drug loading and encapsulation efficiencies of the ZnPc-loaded micelles were calculated to be 0.67% and 0.47%, respectively. Additionally, the release performance of ZnPc from pOEGMA micelles was monitored over a period of nearly 10 d, while the lyophilized micelles exhibited stability for 3 months. Lastly, the ZnPc-loaded micelles were more biocompatible than ZnPc on L929 cell line. The results suggest that the pOEGMA homopolymer possesses the capability to micellize through its methacrylate segments when interacting with highly hydrophobic molecules, presenting a promising avenue for enhancing the delivery efficiency of hydrophobic PSs in PDT. Moreover, it was also deciphered that obtained formulations were highly biocompatible according to cytotoxicity results and could be safely employed as drug delivery systems in further applications.

Sustainable chitin-derived elastomers via grafting strategy with tunable mechanical and adhesion properties

With increasing environmental awareness and the pursuit of sustainable development goals, environmentally friendly sustainable thermoplastic elastomers (TPEs) derived from natural resources are highly desired to replace traditional TPEs. However, preparing sustainable TPEs with high mechanical properties and multifunctionality from biobased feedstocks remains a significant challenge. In this work, a series of chitin-graft-poly(acrylamide-co-2-ethylhexyl acrylate) (Chitin-g-P(AM-co-EHA)) copolymers were synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerization. The tensile strength of Chitin-g-P(AM-co-EHA) copolymers can be tuned over a wide range from 1.0 to 7.3 MPa by adjusting the chitin and PAM contents. Benefiting from the brush-like architecture, Chitin-g-P(AM-co-EHA) copolymer exhibits improved mechanical properties over its linear counterparts. Moreover, these Chitin-g-P(AM-co-EHA) copolymers show good adhesion performance on different substrates. The shear strength can achieve 7.5 MPa for Chitin0.8-PAM50, which is high enough for commercial applications. The combination of chitin and grafting strategy can promote the development of strong chitin-based sustainable elastomers. This approach can be further utilized to design novel high-performance biobased elastomers and adhesives derived from natural resources.

POSS and PAG Dual-Containing Chemically Amplified Photoresists by RAFT Polymerization for Enhanced Thermal Performance and Acid Diffusion Inhibition

A random copolymer (PTBM), utilized as deep ultra-violet (DUV) photoresist, was prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization with tert-butyl methacrylate (tBMA), methyl methacrylate (MMA), triphenylsulfonium p-styrenesulfonate (TPS-SS), and functional poly (sesquicarbonylsiloxanes) (POSS-MA) as the monomer components, and 4-cyano-4-[(dodecylsulfanylthiocarbonyl) sulfanyl]pentanoic acid (CDSPA) as the RAFT reagent. Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H NMR) proved successful synthesis. Ultraviolet absorption spectroscopy (UV) analysis verified the transparency of the polymer in the DUV band. RAFT polymerization kinetics showed that the polymerization rate conformed to the first-order kinetic relationship, and the polymerization process exhibited a typical controlled free radical polymerization behavior. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and static thermo-mechanical analysis (TMA) showed that the incorporation of POSS groups improved the thermal properties of the copolymer. According to scanning electron microscopy (SEM) images, the copolymerization of photoacid monomers (TPS-SS) resulted in photoresist copolymers exhibiting good resistance to acid diffusion and low roughness.

Organic Donor-Acceptor-Donor Trimers Nanoparticles Stabilized by Amphiphilic Block Copolymers for Photocatalytic Generation of H2.

Photocatalytic generation of H2 via water splitting emerges as a promising avenue for the next generation of green hydrogen due to its low carbon footprint. Herein, a versatile platform is designed to the preparation of functional π-conjugated organic nanoparticles dispersed in aqueous phase via mini-emulsification. Such particles are composed of donor-acceptor-donor (DAD) trimers prepared via Stille coupling, stabilized by amphiphilic block copolymers synthesized by reversible addition-fragmentation chain transfer polymerization. The hydrophilic segment of the block copolymers will not only provide colloidal stability, but also allow for precise control over the surface functionalization. Photocatalytic tests of the resulting particles for H2 production resulted in promising photocatalytic activity (≈0.6mmol g-1 h-1). This activity is much enhanced compared to that of DAD trimers dispersed in the water phase without stabilization by the block copolymers.

Efficient and facile dual post-polymerization modification using acetoacetate-acrylate Michael addition

Post-polymerization modification (PPM) is a valuable strategy for achieving diversified functional polymers; nonetheless, the pursuit of achieving mild and efficient dual modification along the polymeric backbone remains as a challenge. In this work, the Michael addition reaction of acetoacetates and acrylates have been demonstrated as a robust PPM technique. The reversible addition-fragmentation chain transfer polymerization of commercially available 2-(acetoacetoxy)ethyl methacrylate provides a polymer scaffold with controlled molecular weight and acetoacetate groups. These pendant groups are capable of undergoing efficient double addition reactions with acrylates, leading to an increased density of functional moieties within the polymeric backbone. This PPM reaction exhibits unique advantages such as mild reaction conditions (at 40 °C), rapid kinetics (completion within 1 h), and high atom economy. Consequently, a series of polymers with tunable thermal stability, glass transition temperature, and hydrophilicity have been successfully synthesized. Applications have been demonstrated for both the synthesis of polymers exhibiting aggregation-induced luminescence and the preparation of luminescent materials with adjustable mechanical properties. This pioneering work unveils a robust post-polymerization modification technique, significantly advancing the synthesis of innovative functional polymers.

Clustering-Triggered Emission Mechanism of Sulfur Ester-Polyacrylamide Aqueous Solution.

Most nonconventional luminogens enjoy good water solubility and biocompatibility, showing unique application prospects in fields like biological imaging. Although clustering-triggered emission (CTE) mechanisms have been proposed to explain such emissions, it has not been thoroughly elucidated, which limits their development and application. Herein, the photoluminescence properties of polyacrylamide prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization aqueous solution are utilized to further investigate the effects of changes in concentration, in order to elucidate the emission mechanism through transmission electron microscopy (TEM), small angle X-ray scattering (SAXS) and theoretical calculation. The results showed that the size distribution, morphology, and distance between the polymer clusters formed in the water solution are successfully correlated with the cluster emission centers. The emission mechanism of nonconventional luminogens solutions is more clearly and intuitively elucidated, which has a promoting effect on the emission and application of this field. It provides a strategy a strategy to clarify the CTE mechanism of nonconventional luminogens solution more clearly.

Preparation of amphiphilic block copolymers via RAFT polymerization and preliminary properties exploration of blended membranes with PVDF

Preparation of amphiphilic block copolymers via RAFT polymerization and preliminary properties exploration of blended membranes with PVDF