Polymeric nanoparticles are widely used in biomedical applications due to their ability to protect cargo, enhance bioavailability and enable controlled cargo release. Polymerization-induced self-assembly (PISA) is a versatile and scalable approach for nanoparticle preparation. However, the majority of PISA-derived systems lack degradability, which limits their potential for biomedical applications. Herein, we report a radical ring-opening polymerization-induced self-assembly (rROPISA) strategy to prepare redox-responsive degradable vinyl copolymer nanoparticles incorporating up to 30 mol% ethyl lipoate (LpEt). LpEt is the ethyl ester of the naturally occurring small molecule lipoic acid (LA), which can ring open to introduce reduction-labile disulfide-containing units along the polymer backbone. Well-defined nanoparticles with spherical, worm-like and pearl-necklace-like morphologies were readily obtained. The incorporation of disulfide linkages in the polymer chains was confirmed by reductive degradation of both copolymers and nanoparticles. The nanoparticles exhibited up to 75% loss in molecular weight upon treatment with 10 mM dithiothreitol (DTT) at 37 degrees C. Cell viability study also confirmed the cytocompatibility of the polymeric particles, with all formulations demonstrating greater than 75% cell viability at solid contents up to 1.0 mg mL-1. This strategy provides a versatile platform for the preparation of degradable, redox-responsive PISA nanoparticles, offering new opportunities for the design of stimuli-responsive polymeric nanomaterials for potential drug delivery applications.

The ability to revert polymers to their original monomers represents a crucial chemical recycling technique, promoting sustainability and offering the chance to convert used materials into valuable products. In recent years, numerous studies have explored the use of polymers synthesized via reversible deactivation radical polymerization (RDRP) techniques to facilitate efficient depolymerization reactions. Herein, we report the use of a photocatalyst, zinc tetraphenylporphyrin (ZnTPP), along with light irradiation to accelerate depolymerization of polymers prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. We explore various parameters affecting depolymerization efficiency, including solvents, reaction temperature (80, 100, and 120 degrees C), the presence of photocatalysts (ZnTPP and Eosin Y), and the type of RAFT end-groups, namely trithiocarbonate, dithiobenzoate, and 1H-pyrazole-1-carbodithioate. For instance, when PMMA was diluted to 25 mM in 1,4-dioxane and heated to 120 degrees C under green light irradiation in the presence of ZnTPP (200 ppm), rapid depolymerization exceeding 70% occurred within 1 h. Without ZnTPP, under similar conditions, the reaction required over 8 h to achieve a slightly lower yield. Furthermore, this method confers moderate oxygen tolerance to the system, enabling depolymerization to proceed without the need of deoxygenation, albeit at a lower rate and consequently lesser monomer recovery (31%). image

Reversible addition-fragmentation chain transfer polymerization (RAFT) is a popular method for the synthesis of well-defined macromolecules, but its sensitivity to oxygen is a major limitation for many industrial applications. Recent research has focused on developing strategies to confer oxygen tolerance onto RAFT polymerization, eliminating the need for deoxygenation steps and allowing for simpler reaction conditions. This minireview highlights several promising approaches to achieve oxygen tolerance in RAFT polymerization, including enzyme-mediated, alkylborane-initiated, and photomediated methods. The potential applications of oxygen-tolerant RAFT polymerization are also discussed, demonstrating the promise for significant advances in large-scale industrial polymer synthesis.

An oxygen-tolerant SI-PhotoRAFT technique has been developed for the efficient synthesis of surface-tethered polymer brushes under low-energy near-infrared (NIR) light. This technique takes advantage of the unique properties of NIR light, in particular enhanced penetration, to effectively prepare polymeric coatings, even through barriers that are opaque to visible light. The NIR-mediated SI-PhotoRAFT polymerization technique was utilized to precisely modulate brush height in direct correlation with the irradiation time. Additionally, this technique facilitated sequential chain extension, enabling the fabrication of block copolymer brushes. Moreover, the incorporation of a photoresponsive monomer, 7-[4-(trifluoromethyl)coumarin]acrylamide [2-(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)acrylamide, TCAm], within the poly(N,N-dimethylacrylamide) brushes enables orthogonal control over polymerization and cross-linking processes through the use of two different wavelengths (NIR and UV light). When exposed to a UV source (? = 365 nm, 18.2 mW/cm2), the TCAm undergoes dimerization triggering cross-linking of the grafted brush "arms". Furthermore, by utilizing the enhanced penetration of NIR light, a polymeric coating was prepared on the inner walls of a tube that was opaque to visible light. Finally, this process is successfully applied to the synthesis of antifouling surfaces on poly(dimethylsiloxane)-coated silicon wafers, leading to inhibition of biofouling.

Triblock copolymers containing an ionophilic polymerized ionic liquid block, sandwiched between two ionophobic polystyrene blocks, were investigated as solid polymer electrolytes (SPE) to simultaneously provide mechanically robust, free-standing membranes with high lithium conductivity and an optimized electrolyte composition. The conductivity reached 8 x 10-5 S cm-1 and 6.5 x 10-4 S cm-1 at 30 and 80 degrees C, respectively, with an anodic stability above 4.5 V. Highly stable Li metal symmetric cycling was demonstrated, with an overpotential of 130 mV for over 300 h at 50 degrees C at a current density of 0.5 mA cm-2/0.5 mAh cm-2. Attempts were also made to incorporate the SPE as the binder in an LMO cathode formulation. The best cell performance, however, was obtained when substituting the SPE in the LMO cathode formulation with a PMA solid-state gel electrolyte, resulting in a high-performance solid-state Li|polymer eletrolyte|LMO device with stable cycling at C/5, and an impressive capacity retention (i.e., 105 mAh g-1 after 150 cycles at 0.1 mA cm-2) with a Coulombic efficiency around 99.4%.

In this work we use RAFT crosslinking polymerisation coupled with a Chemspeed robotic synthesis platform to optimise conditions to produce PDMS-arm star polymers by an arm-first strategy.

A well-defined AB diblock copolymer of 2-vinyl-4,4-dimethylazlactone (VDA) and N,N-dimethylacrylamide (DMA) was generated by reversible addition-fragmentation chain transfer (RAFT) radical polymerization. The VDA-DMA diblock copolymer was reacted with 2-(methylthio)ethylamine (MTEA) and 3(methylthio)propylamine (MTPA) to yield two novel thioether functional diblock copolymers whose structure was confirmed using H-1 NMR and FTIR spectroscopy. Both diblock copolymers formed micelles (20-30 nm) in aqueous media as confirmed by dynamic light scattering (DLS) and transmission electron microscopy. The self-assembled micelles were loaded with Nile Red, a model hydrophobic drug to study their ROS-triggered release mechanism. On addition of hydrogen peroxide (H2O2), the most common ROS species, the hydrophobic thioether core of these micelles oxidized, and both diblock copolymers became more hydrophilic. This triggered their disassembly and subsequent cargo release as characterized by UV evisible spectroscopy. The Nile Red loaded micelles demonstrated similar in-vitro ROS-mediated release when exposed to endogenous oxidants in a model inflammation environment simulated by the presence of activated macrophages. The responsive nanomaterials developed in this article have promising potential as drug carriers in applications where ROS-triggered delivery of cargo is required such as in inflammatory conditions. (C) 2021 Elsevier Ltd. All rights reserved.

We report on two important advances in radical polymerization with reversible addition–fragmentation chain transfer (RAFT polymerization). (1) Electrochemically initiated emulsion RAFT (eRAFT) polymerization provides rapid polymerization of styrene at ambient temperature. The electrolytes and mediators required for eRAFT are located in the aqueous continuous phase separate from the low-molar-mass-dispersity macroRAFT agent mediator and product in the dispersed phase. Use of a poly(N,N-dimethylacrylamide)-block-poly(butyl acrylate) amphiphilic macroRAFT agent composition means that no added surfactant is required for colloidal stability. (2) Direct photoinitiated (visible light) RAFT polymerization provides an effective route to high-purity, low-molar-mass-dispersity, side chain liquid-crystalline polymers (specifically, poly(4-biphenyl acrylate)) at high monomer conversion. Photoinitiation gives a product free from low-molar-mass initiator-derived by-products and with minimal termination. The process is compared with thermal dialkyldiazene initiation in various solvents. Numerical simulation was found to be an important tool in discriminating between the processes and in selecting optimal polymerization conditions.

3D bioprinting is a recent technique that can create complex cell seeded scaffolds and therefore holds great promise to revolutionize the biomedical sector by combining materials and structures that more closely mimic the 3D cell environment in tissues. The most commonly used biomaterials for printing are hydrogels, however, many of the hydrogels used still present issues of printability, stability, or poor cell-material interactions. We propose that bioinks with intrinsic self-assembling and shear thinning properties, such as xanthan gum, can be methacrylated (XGMA) and combined with a bio-functional material such as gelatin methacryloyl (GelMa) to create a stable, cell-interactive bioink with improved properties for 3D bioprinting. These biomaterials have reduced viscosity under high shear and recover their viscosity rapidly after the shear is removed, retaining their shape, which translates to easier extrusion whilst maintaining accurate fidelity after printing. This was confirmed in printing studies, with measured normalized strand widths of 1.2 obtained for high gel concentrations (5+5 % XGMA-GelMA). Furthermore, the introduction of a secondary photo-cross-linking method allowed tuning of the mechanical properties of the hydrogel with stiffness between 15 and 30 kPa, as well as improving the stability of the hydrogel with retention of 75 % of its mass after 90 d. The hydrogel was shown to be biocompatible and bio-active with 97 % cell viability, and cell spreading after 7 d of culture for low gel concentrations (3+3 % XGMA-GelMA). Shear stresses were relatively low while printing (1 kPa) as a result of the shear thinning property of the material, which supported cell viability during extrusion. Finally, printed hydrogels retained high cell viability for lower gel concentrations, and showed improved cell viability for more concentrated hydrogels when compared to cells cultured in bulk hydrogels, presumably due to improved nutrient/oxygen diffusion and cell migration. In conclusion, stability and formulation of a XGMA-GelMA shear thinning composite hydrogel has been optimized to create a bio-functional bioink, with improved printability, and in vitro culture stability via secondary photo-induced cross-linking, making this composite a promising bioink for 3D bioprinting.

Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafe-namide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/10(6) cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications.

A goal in applying electrochemical methods to reversible addition-fragmentation chain transfer (RAFT) polymerization is to use electrochemical reduction to activate RAFT agents (S=C(Z)S-R) to also act as initiators. The use of a mediator can limit side reactions that would otherwise inhibit polymerization. In this work, we present the use of anthraquinone (AQ) to mediate the electrochemical reduction of a trithiocarbonate RAFT agent, 4-cyano-4-(((dodecylthio)carbonothioyl)thio)-pentanoic acid, and thereby initiate RAFT polymerization of methyl methacrylate (MMA). In a representative eRAFT reaction conducted in DMSO with a target degree of polymerization (DP) of 100, conversion reached 67% in 24 h at ambient temperature, with D = 1.19. The effect of reaction conditions on polymerization was studied-in general, the conversion rate was found to decrease as target DP increases. Dispersity increases as (i) target DP increases and (ii) mediator concentration increases. The livingness of AQ-mediated eRAFT polymerization was confirmed by eRAFT chain extension with MMA and by thermally initiated RAFT with styrene to form a block copolymer. AQ-mediated eRAFT was found to be unsuitable for polymerization of monosubstituted monomers (styrene, butyl acrylate, N,N-dimethylacrylamide, and N-vinylpyrrolidone). These results support the hypothesis that mediated electrochemical reduction of RAFT agents can yield an initiating species (R-.), although polymerization is strongly dependent on diffusion and fragmentation kinetics.

In this work, we present a polymerized ionic liquid block copolymer (PBCP) film where relevant properties such as ionic conductivity and electrochemical parameters are tailored by using a ternary system comprised of poly(styrene-b-1-((2-acryloyloxy)ethyl)−3-butylimidazolium bis(tri-fluoromethanesulfonyl)imide), LiFSI salt and ethylene carbonate (EC) as a cosolvent. It was found that EC efficiently decreases the glass transition temperature of the ionic block, resulting in an improved ionic conductivity and efficient platting/stripping of lithium. By using an optimal ratio of EC/LiFSI at relatively high LiFSI amount, Li∣Li symmetrical cells at 50 °C show an overpotential as low as 70 mV at 0.1 mA.cm−2 along with a high lithium transport number of 0.56 (tLi+ ). All-solid-state full cells based on lithium iron phosphate cathode paired with a lithium metal anode reveal a rather stable cycling at both 50 °C and 70 °C. A negligible capacity fading is observed up to 30 cycles where a specific capacity as high as 161 mAh.g−1 is achieved with a coulombic efficiency of 99.9%. Thus, this work demonstrates an important pathway for tailoring the properties of solid state polymer electrolytes for emerging and specially designed block copolymer architectures comprising domains that give both excellent ionic conduction along with desirable mechanical properties.

Amphiphilic copolymers capable of extracting membrane proteins directly from lipid bilayers into "native nanodiscs" promise a simpler membrane protein sample preparation procedure for structural and functional studies. Unfortunately, the selection of nanodisc-forming copolymers is currently limited to molecules that are heterogeneous in terms of molecular weight and monomer sequence, limiting their efficacy in extracting membrane proteins. Here, we report the development of a highly alternating copolymer composed of acrylic acid and styrene by taking advantage of the fundamental reactivity ratios of these monomers. We show that these copolymers, which we term AASTY, are effective solubilizers of membrane proteins expressed in mammalian cells by virtue of their structured amphiphilicity. These AASTY copolymers are promising alternatives to styrene-maleic acid copolymers and provide a new chemical platform for structural and functional characterization of integral membrane proteins in native nanodiscs.

The molecular weight distribution (MWD) has a significant impact on the properties of polymeric materials; however, the characterization of polymer MWDs has been limited to statistical parameters such as the number average molecular weight (Mn) and dispersity (D). These parameters do not fully express the features of polymer MWDs, thus limiting the ability to rationally design complex polymeric materials with tailored MWDs. Herein, a platform for the design and synthesis of arbitrary polymer MWDs is developed and experimentally validated. The platform is based on the description of polymer MWDs as a mathematical function, rather than individual statistical parameters. As such, the complete shape of arbitrary polymer MWDs can be designed using developed software. The software requires only a calibration using model monomodal MWDs directly obtained from GPC to design theoretical MWD. Using this platform in conjunction with a flow-mediated polymerization approach, a range of arbitrarily shaped polymer MWDs were successfully designed and prepared. Finally, complex triblock copolymer mixtures with tailored compositions and overall MWD were fabricated via one-pass flow-mediated polymerization using this computer-guided approach.

Amphiphilic polymers bearing cationic moieties are an emerging alternative to traditional antibiotics given their broad-spectrum activity and low susceptibility to the development of resistance. To date, however, much remains unclear regarding their mechanism of action. Using functional assays (ATP leakage, cell viability, DNA binding) and super-high resolution structured illumination microscopy (OMX-SR) of fluorescently tagged polymers, we present evidence for a multimodal mechanism, involving membrane permeation as well as cellular uptake, interaction with intracellular targets and competitive binding to bacterial DNA.

Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput-controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.

Electrochemical activation of thiocarbonylthio reversible addition-fragmentation chain transfer (RAFT) agents (S=C(Z)S-R) is explored as a potential method for initiating RAFT polymerization under mild conditions without producing initiator-derived byproducts. Herein we apply cyclic voltammetry to establish a predominant reduction mechanism, where electrochemical reduction is coupled to an irreversible first-order chemical reaction. Structure-dependent trends in cyclic voltammograms (CVs), and comparison to absorption spectra, clarify the role of R- and Z-groups in determining reduction processes. The major reduction peak moves to more cathodic potentials in the series dithiobenzoates > trithiocarbonates > heteroaromatic dithiocarbamates > xanthates ∼ N-alkyl-N-aryldithiocarbamates, due to the Z-group influence on thiocarbonyl bond reactivity. More active (electron-withdrawing, radical stabilizing) R-groups shift the reduction peak anodically, in part due to their influence on the rate of the coupled chemical reaction. Analysis of CVs across a range of scan rates revealed that kinetic control over the reduction mechanism is influenced by both the charge transfer rate and chemical reaction rate.

The two diastereoisomers of 4,4′-azobis(4-cyanopentanoic acid) decompose at different rates in aqueous media. The major products (>50%) are amides produced by trapping the ketenimines formed by C–N coupling.

The photocatalyst Zn(II) meso-tetra(4-sulfonatophenyl)porphyrin (ZnTPPS) is found to substantially accelerate visible-light-initiated (red, yellow, green light) single unit monomer insertion (SUMI) of N,N-dimethylacrylamide into the reversible addition-fragmentation chain transfer (RAFT) agent, 4-((((2-carboxyethyl)thio)carbonothioyl)thio)-4-cyanopentanoic acid (RAFT1 ), in aqueous solution. Thus, under irradiation with red (633 nm) or yellow (593 nm) light with 50 mpm (moles per million mole of monomer) ZnTPPS at 30 °C, the rate enhancement provided by photoinduced energy or electron transfer (PET) is ≈sevenfold over the rate of direct photoRAFT-SUMI (without catalyst), which corresponds to achieving full and selective reaction in hours versus days. Importantly, the selectivity, as judged by the absence of oligomers, is retained. Under green light at similar power, higher rates of SUMI are also observed. However, the degree of enhancement provided by PET-RAFT-SUMI over direct photoRAFT-SUMI as a function of catalyst concentration is less and some oligomers are formed.