Effects of Drug Conjugation on the Biological Activity of Single-Chain Nanoparticles.

The field of single-chain nanoparticles (SCNPs) continues to mature, and an increasing range of reports have emerged that explore the application of these small nanoparticles. A key application for SCNPs is in the field of drug delivery, and recent work suggests that SCNPs can be readily internalized by cells. However, limited attention has been directed to the delivery of small-molecule drugs using SCNPs. Moreover, studies on the physicochemical effects of drug loading on SCNP performance is so far missing, despite the accepted view that such small nanoparticles should be significantly affected by the drug loading content. To address this gap, we prepared a library of SCNPs bearing different amounts of a covalently conjugated therapeutic drug-sulfasalazine (SSZ). We evaluated the impact of the conjugated drug loading on both the synthesis and biological activity of SCNPs on pancreatic cancer cells (AsPC-1). Our results reveal that covalent drug conjugation to the side chains of the SCNP polymer precursor interferes with chain collapse and cross-linking, which demands optimization of reaction conditions to reach high degrees of cross-linking efficiencies. Small-angle neutron scattering and diffusion-ordered spectroscopy nuclear magnetic resonance (DOSY NMR) analyses reveal that SCNPs with a higher drug loading display larger sizes and looser structures, as well as increased hydrophobicity associated with a higher SSZ content. Increased SSZ loading led to reduced cellular uptake when assessed in vitro, whereby SCNP aggregation on the surface of AsPC-1 cells led to reduced toxicity. This work highlights the effects of drug loading on the drug delivery efficiency and biological behavior of SCNPs.

Polydopamine as a Visible-Light Photosensitiser for Photoinitiated Polymerisation.

Polydopamine (PDA) is a synthetic model for melanin and has a wide range of opto-electronic properties that underpin its utility in applied and biological settings, from broadband light absorbance to possessing stable free radical species. Here, we show that PDA free radicals are photo-responsive under visible light irradiation, enabling PDA to serve as a photo-redox catalyst. Steady-state and transient electron spin resonance spectroscopy reveals a reversible amplification in semiquinone radical population within PDA under visible light. This photo-response modifies the redox potential of PDA and supports sensitisation of exogenous species via photoinduced electron transfer (PET). We demonstrate the utility of this discovery by employing PDA nanoparticles to photosensitise a common diaryliodonium photoinitiator and initiate free-radical polymerisation (FRP) of vinylic monomers. In situ 1 H nuclear magnetic resonance spectroscopy reveals an interplay between PDA-driven photosensitising and radical quenching during FRP under blue, green, and red light. This work provides crucial insights into the photoactive free radical properties of melanin-like materials and reveals a promising new application for polydopamine as a photosensitiser.

Mechanically Activated Solid-State Radical Polymerization and Cross-Linking via Piezocatalysis.

Piezocatalysis offers a means to transduce mechanical energy into chemical potential, harnessing physical force to drive redox reactions. Working in the solid state, we show here that piezoelectric BaTiO3 nanoparticles can transduce mechanical load into a flux of reactive radical species capable of initiating solid state free radical polymerization. Activation of a BaTiO3 powder by ball milling, striking with a hammer, or repeated compressive loading generates highly reactive hydroxyl radicals (⋅OH), which readily initiate radical chain growth and crosslinking of solid acrylamide, acrylate, methacrylate and styrenic monomers. Control experiments indicate a critical role for chemisorbed water on the BaTiO3 nanoparticle surface, which is oxidized to ⋅OH via mechanoredox catalysis. The force-induced production of radicals by compressing dry piezoelectric materials represents a promising new route to harness mechanical energy for solid state radical synthesis.

Rapid Online Analysis of Photopolymerization Kinetics and Molecular Weight Using Diffusion NMR.

Online, high-throughput molecular weight analysis of polymerizations is rare, with most studies relying on tedious sampling techniques and batchwise postanalysis. The ability to track both monomer conversion and molecular weight evolution in real time could underpin precision polymer development and facilitate study of rapid polymerization reactions. Here, we use a single time-resolved diffusion nuclear magnetic resonance (NMR) experiment to simultaneously study the kinetics and molecular weight evolution during a photopolymerization, with in situ irradiation inside the NMR instrument. As a model system, we used a photoinduced electron transfer reversible addition-fragmentation chain transfer (PET-RAFT) polymerization. The data allow diffusion coefficients and intensities to be calculated every 14 s from which the polymer size and monomer conversion can be extracted. Key to this approach is (1) the use of shuffled gradient amplitudes in the diffusion NMR experiment to access reactions of any rate, (2) the addition of a relaxation agent to increase achievable time resolution and, (3) a sliding correction that accounts for viscosity changes during polymerization. Diffusion NMR offers a uniquely simple, translatable handle for online monitoring of polymerization reactions.

Polymer Grafting to Polydopamine Free Radicals for Universal Surface Functionalization.

Modifying surfaces using free radical polymerization (FRP) offers a means to incorporate the diverse physicochemical properties of vinyl polymers onto new materials. Here, we harness the universal surface attachment of polydopamine (PDA) to "prime" a range of different surfaces for free radical polymer attachment, including glass, cotton, paper, sponge, and stainless steel. We show that the intrinsic free radical species present in PDA can serve as an anchor point for subsequent attachment of propagating vinyl polymer macroradicals through radical-radical coupling. Leveraging a straightforward, twofold soak-wash protocol, FRP over the PDA-functionalized surfaces results in covalent polymer attachment on both porous and nonporous substrates, imparting new properties to the functionalized materials, including enhanced hydrophobicity, fluorescence, or temperature responsiveness. Our strategy is then extended to covalently incorporate PDA nanoparticles into organo-/hydrogels via radical cross-linking, yielding tunable PDA-polymer composite networks. The propensity of PDA free radicals to quench FRP is studied using in situ 1H nuclear magnetic resonance and electron paramagnetic resonance spectroscopy, revealing a surface area-dependent macroradical scavenging mechanism that underpins PDA-polymer conjugation. By combining the arbitrary surface attachment of PDA with the broad physicochemical properties of vinyl polymers, our strategy provides a straightforward route for imparting unlimited new functionality to practically any surface.

Effect of cell culture media on photopolymerizations.

Radical polymerization is one of the most widely used methods for the synthesis of polymeric materials for biomedical applications, such as drug delivery, 3D cell culture, and regenerative medicine. Among radical polymerization reactions, thiol-ene click chemistry has shown excellent orthogonality in diverse reaction conditions. However, our preliminary investigations revealed that it fails in cell culture environment. Herein, we investigate the mechanisms by which cell culture media interfere with radical photoreactions. Three different models including free radical linear photopolymerization (N,N-dimethylacrylamide photopolymerization), free radical photohydrogelation (poly(ethylene glycol) diacrylate photohydrogelation), and thiol-ene photohydrogelation (4-arm poly(ethylene glycol)-norbornene thiol-ene photohydrogelation) were investigated. We showed that common cell culture media ingredients can interfere with radical polymerization by two different pathways; namely, radical chain transfer and radical scavenging effects. Thiol-ene photoclick hydrogelation was seriously affected by cell culture media especially under the alkaline conditions of many of them, due to the impact of deprotonation of the thiol reactant. We intend these findings to serve as a reference guide to researchers employing free radical-based molecular synthesis in cell culture settings. The nonbenign impact of media components, pH, and concentration should provide a cue for future studies that aim to prepare well-defined polymeric materials in the presence of cell culture media.

Ultrapermeable Composite Membranes Enhanced Via Doping with Amorphous MOF Nanosheets.

Thin-film composite (TFC) polymeric membranes have attracted increasing interest to meet the demands of industrial gas separation. However, the development of high-performance TFC membranes within their current configuration faces two key challenges: (i) the thickness-dependent gas permeability of polymeric materials (mainly poly(dimethylsiloxane) (PDMS)) and (ii) the geometric restriction effect due to the limited pore accessibility of the underlying porous substrate. Here we demonstrate that the incorporation of trace amounts (∼1.8 wt %) of amorphous metal-organic framework (MOF) nanosheets into the gutter layer of TFC assemblies can simultaneously address these two limitations by the creation of rapid, transmembrane gas diffusion pathways. The resultant PDMS&MOF membrane displayed excellent CO2 permeance of 10450 GPU and CO2/N2 selectivity of 9.1. Leveraging this strategy, we successfully fabricate a novel TFC membrane, consisting of a PDMS&MOF gutter and an ultrathin (∼54 nm) poly(ethylene glycol) top selective layer via surface-initiated atom transfer radical polymerization. The complete TFC membrane exhibits excellent processability and remarkable CO2/N2 separation performance (1990 GPU with a CO2/N2 ideal selectivity of 39). This study reveals a strategy for the design and fabrication of a new TFC membrane system with unprecedented gas-separation performance.

Bacterial Redox Potential Powers Controlled Radical Polymerization.

Microbes employ a remarkably intricate electron transport system to extract energy from the environment. The respiratory cascade of bacteria culminates in the terminal transfer of electrons onto higher redox potential acceptors in the extracellular space. This general and inducible mechanism of electron efflux during normal bacterial proliferation leads to a characteristic fall in bulk redox potential (Eh), the degree of which is dependent on growth phase, the microbial taxa, and their physiology. Here, we show that the general reducing power of bacteria can be subverted to induce the abiotic production of a carbon-centered radical species for targeted bioorthogonal molecular synthesis. Using two species, Escherichia coli and Salmonella enterica serovar Typhimurium as model microbes, a common redox active aryldiazonium salt is employed to intervene in the terminal respiratory electron flow, affording radical production that is mediated by native redox-active molecular shuttles and active bacterial metabolism. The aryl radicals are harnessed to initiate and sustain a bioorthogonal controlled radical polymerization via reversible addition-fragmentation chain transfer (BacRAFT), yielding a synthetic extracellular matrix of "living" vinyl polymers with predetermined molecular weight and low dispersity. The ability to interface the ubiquitous reducing power of bacteria into synthetic materials design offers a new means for creating engineered living materials with promising adaptive and self-regenerative capabilities.

Progress and Perspectives Beyond Traditional RAFT Polymerization.

The development of advanced materials based on well-defined polymeric architectures is proving to be a highly prosperous research direction across both industry and academia. Controlled radical polymerization techniques are receiving unprecedented attention, with reversible-deactivation chain growth procedures now routinely leveraged to prepare exquisitely precise polymer products. Reversible addition-fragmentation chain transfer (RAFT) polymerization is a powerful protocol within this domain, where the unique chemistry of thiocarbonylthio (TCT) compounds can be harnessed to control radical chain growth of vinyl polymers. With the intense recent focus on RAFT, new strategies for initiation and external control have emerged that are paving the way for preparing well-defined polymers for demanding applications. In this work, the cutting-edge innovations in RAFT that are opening up this technique to a broader suite of materials researchers are explored. Emerging strategies for activating TCTs are surveyed, which are providing access into traditionally challenging environments for reversible-deactivation radical polymerization. The latest advances and future perspectives in applying RAFT-derived polymers are also shared, with the goal to convey the rich potential of RAFT for an ever-expanding range of high-performance applications.

A multifunctional surfactant catalyst inspired by hydrolases.

The remarkable power of enzymes to undertake catalysis frequently stems from their grouping of multiple, complementary chemical units within close proximity around the enzyme active site. Motivated by this, we report here a bioinspired surfactant catalyst that incorporates a variety of chemical functionalities common to hydrolytic enzymes. The textbook hydrolase active site, the catalytic triad, is modeled by positioning the three groups of the triad (-OH, -imidazole, and -CO2H) on a single, trifunctional surfactant molecule. To support this, we recreate the hydrogen bond donating arrangement of the oxyanion hole by imparting surfactant functionality to a guanidinium headgroup. Self-assembly of these amphiphiles in solution drives the collection of functional headgroups into close proximity around a hydrophobic nano-environment, affording hydrolysis of a model ester at rates that challenge α-chymotrypsin. Structural assessment via NMR and XRD, paired with MD simulation and QM calculation, reveals marked similarities of the co-micelle catalyst to native enzymes.

Self-deoxygenating glassware.

The removal of dissolved oxygen (O2) from solution is a prerequisite for many reactions, frequently requiring specialized equipment/reagents or expertise. Herein, we introduce a range of reusable, shelf-stable enzyme-functionalized glassware, which biocatalytically removes O2 from contained aqueous solutions. The effectiveness of the activated glassware is demonstrated by facilitating several O2-intolerant RAFT polymerizations.

Postcombustion Carbon Capture Using Thin-Film Composite Membranes.

Climate change due to anthropogenic carbon dioxide emissions (e.g., combustion of fossil fuels) represents one of the most profound environmental disasters of this century. Equipping power plants with carbon capture and storage (CCS) technology has the potential to reduce current worldwide CO2 emissions. However, existing CCS schemes (i.e., amine scrubbing) are highly energy-intensive. The urgent abatement of CO2 emissions relies on the development of new, efficient technologies to capture CO2 from existing power plants. Membrane-based CO2 separation is an attractive technology that meets many of the requirements for energy-efficient industrial carbon capture. Within this domain, thin-film composite (TFC) membranes are particularly attractive, providing high gas permeance in comparison with conventional thicker (∼50 µm) dense membranes. TFC membranes are usually composed of three layers: (1) a bottom porous support layer; (2) a highly permeable intermediate gutter layer; and (3) a thin (<1 µm) species-selective top layer. A key challenge in the development of TFC membranes has been to simultaneously maximize the transmembrane gas permeance of the assembled membrane (by minimizing the gas resistance of each layer) while maintaining high gas-specific selectivity. In this Account, we provide an overview of our recent development of high-performance TFC membrane materials as well as insights into the unique fabrication strategies employed for the selective layer and gutter layer. Optimization of each layer of the membrane assembly individually results in significant improvements in overall membrane performance. First, incorporating nanosized fillers into the selective layer (poly(ethylene glycol)-based polymers) and reducing its thickness (to ca. 50 nm) through continuous assembly of polymers technology yields major improvements in CO2 permeance without loss of selectivity. Second, we focus on optimization of the middle gutter layer of TFC membranes. The development of enhanced gutter layers employing two- and three-dimensional metal-organic framework materials leads to considerable improvements in both CO2 permeance and selectivity compared with traditional poly(dimethylsiloxane) materials. Third, incorporation of a porous, flexible support layer culminates in a mechanically robust high-performance TFC membrane design that exhibits unprecedented CO2 separation performance and holds significant potential for industrial CO2 capture. Alternative strategies are also emerging, whereby the selective layer and gutter layer may be combined for enhanced membrane efficiency. This Account highlights the CO2 capture performance, current challenges, and future research directions in designing high-performance TFC membranes.

Highly Living Stars via Core-First Photo-RAFT Polymerization: Exploitation for Ultra-High Molecular Weight Star Synthesis.

Star polymers are highly functional materials that display unique properties in comparison to linear polymers, making them valuable in a wide range of applications. Currently, ultra-high molecular weight (UHMW) star polymers synthesized using controlled radical polymerization are prone to termination reactions that have undesirable effects, such as star-star coupling. Herein, we report the synthesis of the largest star polymers to date using controlled radical techniques via xanthate-mediated photo-reversible addition-fragmentation chain transfer (RAFT) polymerization using a core-first approach. Polymerization from xanthate-functionalized cores was highly living, enabling the synthesis of well-defined star polymers with molecular weights in excess of 20 MDa.

Ultrathin Metal-Organic Framework Nanosheets as a Gutter Layer for Flexible Composite Gas Separation Membranes.

Ultrathin metal-organic framework (MOF) nanosheets show great potential in various separation applications. In this study, MOF nanosheets are incorporated as a gutter layer in high-performance, flexible thin-film composite membranes (TFCMs) for CO2 separation. Ultrathin MOF nanosheets (∼3-4 nm) were prepared via a surfactant-assisted method and subsequently coated onto a flexible porous support by vacuum filtration. This produced an ultrathin (∼25 nm), extremely flat MOF layer, which serves as a highly permeable gutter with reduced gas resistance when compared with conventional polydimethylsiloxane gutter layers. Subsequent spin-coating of the ultrathin MOF gutter layer with a polymeric selective layer (Polyactive) afforded a TFCM exhibiting the best CO2 separation performance yet reported for a flexible composite membrane (CO2 permeance of ∼2100 GPU with a CO2/N2 ideal selectivity of ∼30). Several unique MOF nanosheets were examined as gutter layers, each differing with regard to structure and thickness (∼10 and ∼80 nm), with results indicating that flexibility in the ultrathin MOF layer is critical for optimized membrane performance. The inclusion of ultrathin MOF nanosheets into next-generation TFCMs has the potential for major improvements in gas separation performance over current composite membrane designs.

Blood-Catalyzed RAFT Polymerization.

The use of hemoglobin (Hb) contained within red blood cells to drive a controlled radical polymerization via a reversible addition-fragmentation chain transfer (RAFT) process is reported for the first time. No pre-treatment of the Hb or cells was required prior to their use as polymerization catalysts, indicating the potential for synthetic engineering in complex biological microenvironments without the need for ex vivo techniques. Owing to the naturally occurring prevalence of the reagents employed in the catalytic system (Hb and hydrogen peroxide), this approach may facilitate the development of new strategies for in vivo cell engineering with synthetic macromolecules.

Tunable, Quantitative Fenton-RAFT Polymerization via Metered Reagent Addition.

A continuous supply of radical species is a key requirement for activating chain growth and accessing quantitative monomer conversions in reversible addition-fragmentation chain transfer (RAFT) polymerization. In Fenton-RAFT, activation is provided by hydroxyl radicals, whose indiscriminate reactivity and short-lived nature poses a challenge to accessing extended polymerization times and quantitative monomer conversions. Here, an alternative Fenton-RAFT procedure is presented, whereby radical generation can be finely controlled via metered dosing of a component of the Fenton redox reaction (H2 O2 ) using an external pumping system. By limiting the instantaneous flux of radicals and ensuring sustained radical generation over tunable time periods, metered reagent addition reduces unwanted radical "wasting" reactions and provides access to consistent quantitative monomer conversions with high chain-end fidelity. Fine tuning of radical concentration during polymerization is achieved simply via adjustment of reagent dose rate, offering significant potential for automation. This modular strategy holds promise for extending traditional RAFT initiation toward more tightly regulated radical concentration profiles and affords excellent prospects for the automation of Fenton-RAFT polymerization.

Effects of Tailored Dispersity on the Self-Assembly of Dimethylsiloxane-Methyl Methacrylate Block Co-Oligomers.

The effect of dispersity on block polymer self-assembly was studied in the monodisperse limit using a combination of synthetic chemistry, matrix-assisted laser desorption ionization spectroscopy, and small-angle X-ray scattering. Oligo(methyl methacrylate) (oligoMMA) and oligo(dimethylsiloxane) (oligoDMS) homopolymers were synthesized by conventional polymerization techniques and purified to generate an array of discrete, semidiscrete, and disperse building blocks. Coupling reactions afforded oligo(DMS-MMA) block polymers with precisely tailored molar mass distributions spanning single molecular systems (D = 1.0) to low-dispersity mixtures (D ≈ 1.05). Discrete materials exhibit a pronounced decrease in domain spacing and sharper scattering reflections relative to disperse analogues. The order-disorder transition temperature (TODT) also decreases with increasing dispersity, suggesting stabilization of the disordered phase, presumably due to the strengthening of composition fluctuations at the low molar masses investigated.

A Versatile and Scalable Strategy to Discrete Oligomers.

A versatile strategy is reported for the multigram synthesis of discrete oligomers from commercially available monomer families, e.g., acrylates, styrenics, and siloxanes. Central to this strategy is the identification of reproducible procedures for the separation of oligomer mixtures using automated flash chromatography systems with the effectiveness of this approach demonstrated through the multigram preparation of discrete oligomer libraries (D = 1.0). Synthetic availability, coupled with accurate structural control, allows these functional building blocks to be harnessed for both fundamental studies as well as targeted technological applications.