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Application of redox-active polymers (RAPs) in redox flow batteries (RFBs) can potentially reduce the stack cost through substitution of costly ion-exchange membranes by cheap size-exclusion membranes. However, intermolecular interactions of polymer molecules, i.e. , entanglements, particularly in concentrated solutions, result in relatively high electrolyte viscosities. Furthermore, the large size and limited mobility of polymers lead to slow diffusion and more sluggish heterogeneous electron transfer rates compared to quickly diffusing small molecules. Although a number of RAPs with varying electrolyte viscosities have been reported in the literature, the relation between the RAP structure and the hydrodynamic properties has not been thoroughly investigated. Herein, hyperbranched 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO)-based polymers intended for application as low-viscosity catholytes for RFBs are presented and the influence of the structure and the molar mass distribution on the hydrodynamic properties is investigated. A new synthesis approach for TEMPO-based polymers is established based on step-growth polymerization of a TEMPO-containing monomer using an aza-Michael addition followed by a postpolymerization modification to improve solubility in aqueous solutions. The compact structure of hyperbranched polymers was demonstrated using size-exclusion chromatography (SEC) with viscometric detection and the optimum molar mass was found based on the results of viscometric and crossover investigations. The resulting RAP revealed a viscosity of around 21 mPas at a concentration corresponding to around 1 M TEMPO-containing units, according to the calculated mass of the repeating unit, showing potential for high capacity polymer-based catholytes for RFBs. Nevertheless, possible partial deactivation of TEMPO units lowered the active TEMPO concentration of the hyperbranched RAPs. A faster diffusion and higher charge transfer rate were observed for the hyperbranched polymer compared to the previously reported linear polymers. However, in RFB tests, a poor performance was observed, which is attributed to the side reactions of the oxidized TEMPO moieties. Finally, pathways for overcoming the main remaining challenges, i.e. , high loss of material during dialysis as an indication of being prone to crossover, the partial deactivation of TEMPO moieties, and the subsequent side reactions under battery conditions, are suggested., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Hypothesis: Host rock weathering and incipient pedogenesis result in the exposition of minerals, e.g., clay minerals in sedimentary limestones. Once exposed, these minerals provide the surfaces for fluid-solid interactions that control the fate of dissolved or suspended compounds such as organic matter and colloids. However, the functional and compositional diversity of organic matter and colloids limits the assessment of reactivity and availability of clay mineral interfaces. Such assessment demands a mobile compound with strong affinity to clay surfaces that is alien to the subsurface., Experiment: We approached this challenge by using poly(ethylene glycol) (PEG) as interfacial tracer in limestone weathering experiments., Findings: PEG adsorption and transport was dependent on the availability of clay mineral surfaces and carbonate dissolution dynamics. In addition, PEG adsorption featured adsorption-desorption hysteresis which retained PEG mass on clay mineral surfaces. This resulted in different PEG transport for experiments conducted consecutively in the same porous medium. As such, PEG transport was reconstructed with a continuum-scale model parametrized by a Langmuir-type isotherm including hysteresis. Thus, we quantified the influence of exposed clay mineral surfaces on the transport of organic colloids in carbonate media. This renders PEG a suitable model colloid tracer for the assessment of clay surface exposition in porous media., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The in-depth analytical characterization of polymers, in particular regarding intended biomedical applications, is becoming increasingly important to elucidate their structure-property relationships. Specifically, end group analysis of e.g. polymers featuring a 'stealth effect' towards the immune system is of particular importance because of their use in coupling reactions to bioactive compounds. Herein, we established a liquid chromatography (LC) protocol to analyse bicyclo[6.1.0]nonyne-functionalized poly(2-alkyl-2-oxazoline)s (POx)s as promising functional polymers that can be applied in strain-promoted click reactions. This work involved the synthesis of poly(2-methyl-2-oxazoline) (PMeOx) and poly(2-ethyl-2-oxazoline) (PEtOx) by living cationic ring-opening polymerization (CROP) with different molar masses ranging from 2 up to 17.5 kDa and, to our knowledge, the first liquid chromatographic analysis of PMeOx. The developed analytical protocol enables the quantitative determination of post-polymerization reaction sequences with respect to the conversion of the ω -end groups. All synthesized polymers were straightforwardly analysed on a C18-derivatized silica monolithic column under reversed-phase chromatographic conditions with a binary mobile phase gradient comprising a mixture of acetonitrile and water. Subsequent mass spectrometry of collected elution fractions enabled the confirmation of the desired ω -end group functionalities and the identification of synthetic by-products., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

Hybrid nanoparticles (HNPs) were designed by combining a PLGA core with a lipid shell that incorporated PEG-Lipid conjugates with various functionalities (-RGD, -cRGD, -NH 2 , and -COOH) to create targeted drug delivery systems. Loaded with a neutral lipid orange dye, the HNPs were extensively characterized using various techniques and investigated for their uptake in human monocyte-derived macrophages (MDMs) using FC and CLSM. Moreover, the best-performing HNPs (i.e., HNP-COOH and HNP-RGD as well as HNP-RGD/COOH mixed) were loaded with the anti-inflammatory drug BRP-201 and prepared in two size ranges (d H ~140 nm and d H ~250 nm). The HNPs were examined further for their stability, degradation, MDM uptake, and drug delivery efficiency by studying the inhibition of 5-lipoxygenase (5-LOX) product formation, whereby HNP-COOH and HNP-RGD both exhibited superior uptake, and the HNP-COOH/RGD (2:1) displayed the highest inhibition.

Leukotrienes are pro-inflammatory lipid mediators generated by 5-lipoxygenase aided by the 5-lipoxygenase-activating protein (FLAP). BRP-201, a novel benzimidazole-based FLAP antagonist, inhibits leukotriene biosynthesis in isolated leukocytes. However, like other FLAP antagonists, BRP-201 fails to effectively suppress leukotriene formation in blood, which limits its therapeutic value. Here, we describe the encapsulation of BRP-201 into poly(lactide-co-glycolide) (PLGA) and ethoxy acetalated dextran (Ace-DEX) nanoparticles (NPs), aiming to overcome these detrimental pharmacokinetic limitations and to enhance the bioactivity of BRP-201. NPs loaded with BRP-201 were produced via nanoprecipitation and the physicochemical properties of the NPs were analyzed in-depth using dynamic light scattering (size, dispersity, degradation), electrophoretic light scattering (effective charge), NP tracking analysis (size, dispersity), scanning electron microscopy (size and morphology), UV-VIS spectroscopy (drug loading), an analytical ultracentrifuge (drug release, degradation kinetics), and Raman spectroscopy (chemical attributes). Biological assays were performed to study cytotoxicity, cellular uptake, and efficiency of BRP-201-loaded NPs versus free BRP-201 to suppress leukotriene formation in primary human leukocytes and whole blood. Both PLGA- and Ace-DEX-based NPs were significantly more efficient to inhibit leukotriene formation in neutrophils versus free drug. Whole blood experiments revealed that encapsulation of BRP-201 into Ace-DEX NPs strongly increases its potency, especially upon pro-longed (≥ 5 h) incubations and upon lipopolysaccharide-challenge of blood. Finally, intravenous injection of BRP-201-loaded NPs significantly suppressed leukotriene levels in blood of mice in vivo. These results reveal the feasibility of our pharmacological approach using a novel FLAP antagonist encapsulated into Ace-DEX-based NPs with improved efficiency in blood to suppress leukotriene biosynthesis., (© 2021. The Author(s).)

Controlling the length of one-dimensional (1D) polymer nanostructures remains a key challenge on the way toward the applications of these structures. Here, we demonstrate that top-down processing facilitates a straightforward adjustment of the length of polyethylene oxide (PEO)-based supramolecular polymer bottlebrushes (SPBs) in aqueous solutions. These cylindrical structures self-assemble via directional hydrogen bonds formed by benzenetrisurea (BTU) or benzenetrispeptide (BTP) motifs located within the hydrophobic core of the fiber. A slow transition from different organic solvents to water leads first to the formation of µm-long fibers, which can subsequently be fragmented by ultrasonication or dual asymmetric centrifugation. The latter allows for a better adjustment of applied shear stresses, and thus enables access to differently sized fragments depending on time and rotation rate. Extended sonication and scission analysis further allowed an estimation of tensile strengths of around 16 MPa for both the BTU and BTP systems. In combination with the high kinetic stability of these SPBs, the applied top-down methods represent an easily implementable technique toward 1D polymer nanostructures with an adjustable length in the range of interest for perspective biomedical applications., (Copyright © 2021, Klein et al.)

Jaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here, we demonstrate that nanocarriers functionalized through DY-635, a fluorescent polymethine dye, and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed the PI3Kγ-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Hypothesis: A prominent fraction of mobile organic matter in natural aqueous soil solutions is formed by molecules in sizes that seamlessly exceed the lower end of what is defined as a colloid. The hydrodynamics and the functional diversity of these molecules result in a transport behavior that is fundamentally different from smaller compounds. However, there is a lack of "reactive tracers" that allow for the study of colloidal transport phenomena appropriately. We hypothesize that tailor-made and well-defined synthetic polymers can overcome this limitation., Experiments: We prepared and characterized the hydrodynamic properties of water-soluble poly(ethylene glycol)s (PEG) and studied their adsorption to mixtures of quartz, illite, and goethite in batch and column experiments., Findings: We used this information to independently predict the transport of PEG with striking agreement to the observed mean breakthrough times in all porous media. As PEG transport can be comprehensively and quantitatively reconstructed, we conclude that functionalized PEGs are promising candidates to be used as tailorable and non-toxic tracers available in the size range of natural organic (macro-)molecules., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor water solubility, and it binds the human ether-à-go-go-related gene (hERG) ion channels, potentially causing deadly arrhythmias. In this case, a targeted delivery of BIM-I is imperative to minimize peripheral side effects. To circumvent these drawbacks BIM-I was encapsulated into nanoparticles prepared from poly(lactic- co -glycolic acid) (PLGA) functionalized by the near-infrared dye DY-635. DY-635 served as an active targeting moiety since it selectively binds the OATP1B1 and OATP1B3 transporters that are highly expressed in liver and cancer cells. PLGA-DY-635 (BIM-I) nanoparticles were produced by nanoprecipitation and characterized using dynamic light scattering, analytical ultracentrifugation, and cryogenic transmission electron microscopy. Particle sizes were found to be in the range of 20 to 70 nm, while a difference in sizes between the drug-loaded and unloaded particles was observed by all analytical techniques. In vitro studies demonstrated that PLGA-DY-635 (BIM-I) NPs prevent the PKC activation efficiently, proving the efficacy of the inhibitor after its encapsulation, and suggesting that BIM-I is released from the PLGA-NPs. Ultimately, our results present a feasible formulation strategy that improved the cytotoxicity profile of BIM-I and showed a high cellular uptake in the liver as demonstrated in vivo by intravital microscopy investigations.

The interrelation of experimental rotational and translational hydrodynamic friction data as a basis for the study of macromolecules in solution represents a useful attempt for the verification of hydrodynamic information. Such interrelation originates from the basic development of colloid and macromolecular science and has proven to be a powerful tool for the study of naturally- and synthetically-based, i.e., artificial, macromolecules. In this tutorial review, we introduce this very basic concept with a brief historical background, the governing physical principles, and guidelines for anyone making use of it. This is because very often data to determine such an interrelation are available and it only takes a set of simple equations for it to be established. We exemplify this with data collected over recent years, focused primarily on water-based macromolecular systems and with relevance for pharmaceutical applications. We conclude with future incentives and opportunities for verifying an advanced design and tailored properties of natural/synthetic macromolecular materials in a dispersed or dissolved manner, i.e., in solution. Particular importance for the here outlined concept emanates from the situation that the classical scaling relationships of Kuhn-Mark-Houwink-Sakurada, most frequently applied in macromolecular science, are fulfilled, once the hydrodynamic invariant and/or sedimentation parameter are established. However, the hydrodynamic invariant and sedimentation parameter concept do not require a series of molar masses for their establishment and can help in the verification of a sound estimation of molar mass values of macromolecules.

Hypothesis: Molecules forming directed intermolecular hydrogen bonds, such as the well-known benzene-1,3,5-tricarboxamides (BTA) motif, are known to self-assemble into long fibrous structures. However, only a few of these systems have so far demonstrated the ability to form such anisotropic nanostructures, if they are combined with hydrophilic polymers to create an amphiphilic material. Here, we designed BTA-polymer conjugates to investigate whether the directionality of the hydrogen bonds or the ratio of hydrophobic to hydrophilic parts of the molecule, and thus the packing parameter, is decisive for obtaining anisotropic supramolecular structures in water., Experiments: Poly(ethylene glycol) was conjugated to BTA moieties with varying lengths of hydrophobic alkyl spacers ranging from two to twelve methylene units. The resulting amphiphilic materials were characterized in aqueous solution by light and small-angle neutron scattering, analytical ultracentrifugation, and cryo-transmission electron microscopy., Findings: While spherical micelles were observed for C 6 and C 10 alkyl spacers, anisotropic structures were only present in case of the C 12 spacer. The comparison to an analogous material, which lacks the directed hydrogen bonds, revealed that the BTA motif cannot provide a sufficient driving force to induce anisotropic structures, but increases the packing density in the hydrophobic part. Therefore, the packing parameter governs the appearance of anisotropic aggregates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The self-assembly of block copolymers in aqueous solution is an important field in modern polymer science that has been extended to double hydrophilic block copolymers (DHBC) in recent years. In here, a significant improvement of the self-assembly process of DHBC in aqueous solution by utilizing a linear-brush macromolecular architecture is presented. The improved self-assembly behavior of poly( N -vinylpyrrolidone)- b -poly(oligo(ethylene glycol) methyl ether methacrylate) (PVP- b -P(OEGMA)) and its concentration dependency is investigated via dynamic light scattering (DLS) (apparent hydrodynamic radii ≈ 100-120 nm). Moreover, the DHBC assemblies can be non-covalently crosslinked with tannic acid via hydrogen bonding, which leads to the formation of small aggregates as well (apparent hydrodynamic radius ≈ 15 nm). Non-covalent crosslinking improves the self-assembly and stabilizes the aggregates upon dilution, reducing the concentration dependency of aggregate self-assembly. Additionally, the non-covalent aggregates can be disassembled in basic media. The presence of aggregates was studied via cryogenic scanning electron microscopy (cryo-SEM) and DLS before and after non-covalent crosslinking. Furthermore, analytical ultracentrifugation of the formed aggregate structures was performed, clearly showing the existence of polymer assemblies, particularly after non-covalent crosslinking. In summary, we report on the completely hydrophilic self-assembled structures in solution formed from fully biocompatible building entities in water., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The determination of diol impurities in methoxy poly(ethylene glycol)s (mPEG)s is of high importance, e.g., in the area of pharmaceutical applications, since mPEGs are considered the gold standard-based on properties of biocompatibility, stealth effect against the immune system, and well-established procedures used in PEGylation reactions. Herein, we communicate a straightforward and fast approach for the resolution of the PEGdiol impurities in mPEG products by liquid chromatography on reversed-phase monolithic silica-rods. Thus, we utilize fine, in-house prepared and narrow dispersity mPEGs ( Ð ≤ 1.1) and commercial PEGdiol standards as a reference. Most efficient analysis of diol impurities becomes possible with reversed-phase liquid chromatography that results in selective elution of the PEGdiol from mPEG macromolecule populations in partition/adsorption mode. We do this by a minimum selectivity of the population of macromolecules characterizing the narrow molar mass distributions of mPEG. Control experiments with intentionally added water at the start of the well-controlled mPEG synthesis via the living anionic ring opening polymerization of ethylene oxide clearly reconciled the existence of PEGdiol impurity in chromatographed samples. The here-demonstrated methodology allows for the resolution of diol impurities of less than one percent in elution times of only a few minutes, confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) of the collected elution fractions. The unique combination of the open flow-through pore structure of the monolithic silica rods and resultant varying accessibility of C18-derivatized pore surfaces indicates beneficial properties for robust and end-group-specific adsorption/partition liquid chromatography of synthetic macromolecules.

Depending on the degree of grafting (DG) and the side chain degree of polymerization (DP), graft copolymers may feature properties similar to statistical copolymers or to block copolymers. This issue is approached by studying aqueous solutions of PMMA- g -OEtOx graft copolymers comprising a hydrophobic poly(methyl methacrylate) (PMMA) backbone and hydrophilic oligo(2-ethyl-2-oxazoline) (OEtOx) side chains. The graft copolymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) copolymerization of methyl methacrylate (MMA) and OEtOx-methacrylate macromonomers of varying DP. All aqueous solutions of PMMA- g -OEtOx (9% ≤ DG ≤ 34%; 5 ≤ side chain DP ≤ 24) revealed lower critical solution temperature behavior. The graft copolymer architecture significantly influenced the aggregation behavior, the conformation in aqueous solution and the coil to globule transition, as verified by means of turbidimetry, dynamic light scattering, nuclear magnetic resonance spectroscopy, and analytical ultracentrifugation. The aggregation behavior of graft copolymers with a side chain DP of 5 was significantly affected by small variations of the DG, occasionally forming mesoglobules above the cloud point temperature (T cp ), which was around human body temperature. On the other hand, PMMA- g -OEtOx with elongated side chains assembled into well-defined structures below the T cp (apparent aggregation number (N agg = 10)) that were able to solubilize Disperse Orange 3. The thermoresponsive behavior of aqueous solutions thus resembled that of micelles comprising a poly(2-ethyl-2-oxazoline) (PEtOx) shell (T cp > 60 °C).

Porous polymer monoliths are considered to be one of the major breakthroughs in separation science. These materials are well known to be best suited for the separation of large molecules, specifically proteins, an observation most often explained by convective mass transfer and the absence of small pores in the polymer scaffold. However, this conception is not sufficient to explain the performance of small molecules. This review focuses in particular on the preparation of (macro)porous polymer monoliths by simple free-radical processes and the key events in their formation. There is special focus on the fluid transport properties in the heterogeneous macropore space (flow dispersion) and on the transport of small molecules in the swollen, and sometimes permanently porous, globule-scale polymer matrix. For small molecule applications in liquid chromatography, it is consistently found in the literature that the major limit for the application of macroporous polymer monoliths lies not in the optimization of surface area and/or modification of the material and microscopic morphological properties only, but in the improvement of mass transfer properties. In this review we discuss the effect of resistance to mass transfer arising from the nanoscale gel porosity. Gel porosity induces stagnant mass transfer zones in chromatographic processes, which hamper mass transfer efficiency and have a detrimental effect on macroscopic chromatographic dispersion under equilibrium (isocratic) elution conditions. The inherent inhomogeneity of polymer networks derived from free-radical cross-linking polymerization, and hence the absence of a rigid (meso)porous pore space, represents a major challenge for the preparation of efficient polymeric materials for the separation of small molecules.

Porous polymer monoliths have emerged as unique materials for many applications, including liquid-chromatographic analyses at an unrivaled speed, solid-phase extraction, and enzyme immobilization in capillary and microfluidic chip format. This article reviews the state of the art in the preparation of monoliths in narrow-bore capillaries and microfluidic chips and their miniaturization under conditions of spatial confinement. New developments in their preparation mainly using free radical polymerization techniques with a focus on morphological aspects in view of homogeneous porous materials are described. The suitability of monoliths for analysis of both large and small molecules is also discussed.