Photocontrolled Reversible Amyloid Fibril Formation of Parathyroid Hormone-Derived Peptides.

Peptide fibrillization is crucial in biological processes such as amyloid-related diseases and hormone storage, involving complex transitions between folded, unfolded, and aggregated states. We here employ light to induce reversible transitions between aggregated and nonaggregated states of a peptide, linked to the parathyroid hormone (PTH). The artificial light-switch 3-{[(4-aminomethyl)phenyl]diazenyl}benzoic acid (AMPB) is embedded into a segment of PTH, the peptide PTH25-37, to control aggregation, revealing position-dependent effects. Through in silico design, synthesis, and experimental validation of 11 novel PTH25-37-derived peptides, we predict and confirm the amyloid-forming capabilities of the AMPB-containing peptides. Quantum-chemical studies shed light on the photoswitching mechanism. Solid-state NMR studies suggest that ß-strands are aligned parallel in fibrils of PTH25-37, while in one of the AMPB-containing peptides, ß-strands are antiparallel. Simulations further highlight the significance of π-π interactions in the latter. This multifaceted approach enabled the identification of a peptide that can undergo repeated phototriggered transitions between fibrillated and defibrillated states, as demonstrated by different spectroscopic techniques. With this strategy, we unlock the potential to manipulate PTH to reversibly switch between active and inactive aggregated states, representing the first observation of a photostimulus-responsive hormone.

Fluorinated Linkers Enable High-Voltage Pyrrolidinium-based Dicationic Ionic Liquid Electrolytes.

Novel fluorinated, pyrrolidinium-based dicationic ionic liquids (FDILs) as high-performance electrolytes in energy storage devices have been prepared, displaying unprecedented electrochemical stabilities (up to 7 V); thermal stability (up to 370 °C) and ion transport (up to 1.45 mS cm­1). FDILs were designed with a fluorinated ether linker and paired with TFSI/FSI counterions. To comprehensively asess the impact of the fluorinated spacer on their electrochemical, thermal, and physico-chemical properties, a comparison with their non-fluorinated counterparts was conducted. With a specific focus on their application as electrolytes in next-generation high-voltage lithium-ion batteries, the impact of the Li-salt on the characteristics of dicationic ILs was systematically evaluated. The incorporation of a fluorinated linker demonstrates significantly superior properties compared to their non-fluorinated counterparts, presenting a promising alternative towards next-generation high-voltage energy storage systems.

Stability of Quadruple Hydrogen Bonds in an Ionic Liquid Environment.

Hydrogen bonds (H-bonds) are highly sensitive to the surrounding environments owing to their dipolar nature, with polar solvents kown to significantly weaken H-bonds. Herein, the stability of the H-bonding motif ureidopyrimidinone (UPy) is investigated, embedded into a highly polar polymeric ionic liquid (PIL) consisting of pendant pyrrolidinium bis(trifluoromethylsulfonyl)imide (IL) moieties, to study the influence of such ionic environments on the UPy H-bonds. The content of the surrounding IL is changed by addition of an additional low molecular weight IL to further boost the IL content around the UPy moieties in molar ratios of UPy/IL ranging from 1/4 up to 1/113, thereby promoting the polar microenvironment around the UPy-H-bonds. Variable-temperature solid-state MAS NMR spectroscopy and FT-IR spectroscopy demonstrate that the UPy H-bonds are largely present as (UPy-) dimers, but sensitive to elevated temperatures (>70 °C). Subsequent rheology and DSC studies reveal that the ILs only solvate the polymeric chains but do not interfere with the UPy-dimer H-bonds, thus accounting for their high stability and applicability in many material systems.

Rubber Oxygenase Degradation Assay by UV-Labeling and Gel Permeation Chromatography.

A versatile and robust end-group derivatization approach using oximes has been developed for the detection of oxidative degradation of synthetic polyisoprenes and polybutadiene. This method demonstrates broad applicability, effectively monitoring degradation across a wide molecular weight range through ultraviolet (UV)-detection coupled to gel permeation chromatography. Importantly, it enables the effective monitoring of degradation via derivatization-induced UV-maximum shifts, even in the presence of an excess of undegraded polyene, overcoming limitations previously reported with refractive index detectors. Notably, this oxime-based derivatization methodology is used in enzymatic degradation experiments of synthetic polyisoprenes characterized by a cis: trans ratio with the rubber oxygenase LcpK30. It reveals substantial UV absorption in derivatized enzymatic degradation products of polyisoprene with molecular weights exceeding 1000 g mol-1 - an unprecedented revelation for this enzyme's activity on such synthetic polyisoprenes. This innovative approach holds promise as a valuable tool for advancing research into the degradation of synthetic polyisoprenes and polybutadiene, particularly under conditions of low organocatalytic or enzymatic degradation activity. With its broad applicability and capacity to reveal previously hidden degradation processes, it represents a noteworthy contribution to sustainable polymer chemistry.

A Living Topochemical Ring-Opening Polymerization of Achiral Amino Acid N-Carboxy-Anhydrides in Single Crystals.

A living topochemical ring-opening polymerization (ROP) of achiral amino-acid N-carboxyanhydrides (NCAs) is reported. Single crystals of the NCAs of α-aminoisobutyric acid (Aib) and 1-aminocyclohexanecarboxylic acid (ACHC) were grown, allowing a ring-opening polymerization macroscopically induced by amines. The single crystals could be polymerized at temperatures from 25-50 °C after physically contacting the amine-based initiator with the crystals. Topochemical polymerization of the crystals was proven by MALDI-ToF MS and XRD, generating polymers with chain lengths of up to 40 units and a complete affixation of the initiating amine at the polymer's head. Due to the proper alignment of the reacting groups in the crystal, longer polymer chains with improved purities can be reached, as chain-transfer is reduced as compared to solution polymerization. Simple purification of the polymers can be achieved by separation of the unreacted NCA via dispersion in acetonitrile. Overall, this method enables the preparation of polymers with higher chain length and purities at mild conditions, finally demonstrating a crystal-based ring opening polymerization.

Triggered Crosslinking of Main-Chain Enediyne Polyurethanes via Bergman Cyclization.

Crosslinking chemistries occupy an important position in polymer modification with a particular importance when triggered in response to external stimuli. Enediyne (EDY) moieties are used as functional entities in this work, known to undergo a pericyclic Bergman cyclization (BC) to induce a triggered crosslinking of polyurethanes (PU) via the intermediately formed diradicals. Diamino-EDYs, where the distance between the enyne-moieties is known to be critical to induce a BC, are placed repetitively as main-chain structural elements in isophorone-based PUs to induce reinforcement upon heating, compression, or stretching. A 7-day compression under room temperature results in a ≈69% activation of the BC, together with the observation of an increase in tensile strength by 62% after 25 stretching cycles. The occurrence of BC is further proven by the decreased exothermic values in differential scanning calorimetry, together with characteristic peaks of the formed benzene moieties via IR spectroscopy. Purely heat-induced crosslinking contributes to 191% of the maximum tensile strength in comparison to the virgin PU. The BC herein forms an excellent crosslinking strategy, triggered by heat or force in PU materials.

Tuning the Internal Compartmentation of Single-Chain Nanoparticles as Fluorescent Contrast Agents.

Controlling the internal structures of single-chain nanoparticles (SCNPs) is an important factor for their targeted chemical design and synthesis, especially in view of nanosized compartments presenting different local environments as a main feature to control functionality. We here design SCNPs bearing near-infrared fluorescent dyes embedded in hydrophobic compartments for use as contrast agents in pump-probe photoacoustic (PA) imaging, displaying improved properties by the location of the dye in the hydrophobic particle core. Compartment formation is controlled via single-chain collapse and subsequent crosslinking of an amphiphilic polymer using external crosslinkers in reaction media of adjustable polarity. Different SCNPs with hydrodynamic diameters of 6-12 nm bearing adjustable label densities are synthesized. It is found that the specific conditions for single-chain collapse have a major impact on the formation of the desired core-shell structure, in turn adjusting the internal nanocompartments together with the formation of excitonic dye couples, which in turn increase their fluorescence lifetime and PA signal generation. SCNPs with the dye molecules accumulate at the core also show a nonlinear PA response as a function of pulse energy-a property that can be exploited as a contrast mechanism in molecular PA tomography.

Core-Coordinated Elliptic Polymer Nanoparticles Loading Copper(II) and Chlorambucil for Cooperative Chemodynamic/Chemotherapy.

Chemodynamic therapy (CDT) reflects an innovative cancer treatment modality; however, to enhance its relatively low therapeutic efficiency, rational combination with extra therapeutic modes is highly appreciated. Here, core-coordinated amphiphilic, elliptic polymer nanoparticles (Cu/CBL-POEGEA NPs) are constructed via the self-assembly of a glutathione (GSH)-responsive polymer-drug conjugate, bearing side-chain acylthiourea (ATU) motifs which behave as ligands capable of coordinating Cu(II), such a design is featured by combined chemo (CT)/CDT with dual GSH depletion collectively triggered by the Cu(II) reduction reaction and disulfide bond breakage. To do so, an amphiphilic random copolymer poly[oligo(ethylene glycol)ethyl acrylate-co-thiourea] [P(OEGEA-co-ATU)] is synthesized, followed by conjugation of chlorambucil (CBL) to ATU motifs linked via a disulfide bond, thus yielding the targeted P[OEGEA-co-(ATU-g-CBL)]. In such a system, hydrophilic POEGEA serves as the biocompatible section and ATU motifs coordinate Cu(II), resulting in core-coordinated elliptic Cu/CBL-POEGEA NPs. Benefitting from the GSH-induced reduction reaction, Cu(II) is converted into Cu(I) and subsequently react with endogenous H2O2 to create •OH, realizing GSH-depletion-promoted CDT. Additionally, the disulfide bond endows GSH-responsive CBL release and provokes further GSH decline, finally realizing combined CDT/CT toward enhancing antitumor outcomes, and in vitro as well as in vivo studies indeed reveal remarkable efficacy. Such a system can provide valuable advantages to create novel nanomedicines toward cascade antitumor therapy.

Self-healing nanocomposites via N-doped GO promoted "click chemistry".

N-doped graphene stabilized Cu(I)-catalyzed self-healing nanocomposites are developed. This study found the use of N-doped graphene as both a nanostructured material for enhancing mechanical and conductive properties and a catalyst promoter (a scaffold for catalytic copper(I) particles), helpful to trigger self-healing via "click chemistry". Due to an increase in electron density on nitrogen atom doping, including the coordination of N-doped rGO with Cu+ ions, nitrogen-doped graphene-supported copper particles demonstrate a higher reaction yield at room temperature without adding any external ligand/base. In this study, only one component (an azide moiety containing a healing agent) was encapsulated, whereas another component (an alkyne moiety containing a healing agent) was as such (without encapsulation) homogeneously dispersed in a matrix. Triggered capsule rupture then induces the contact of the healing agents with the N-doped graphene-based catalyst and the alkyne molecules dispersed in the matrix, inducing a "click"-reaction, allowing onsite damage to be repaired as determined by mechanical measurements entirely. Tensile measurements were also performed using molecular dynamics (MD) simulations to support the findings. Given the enormous importance of autonomic repair of materials damage, this concept here reports a trustworthy and reliable chemical system with a high level of robustness.

Hydrogen-Bonds-Mediated Nanomedicine: Design, Synthesis, and Applications.

Among the various challenges in medicine, diagnosis, complete cure, and healing of cancers remain difficult given the heterogeneity and complexity of such a disease. Differing from conventional platforms with often unsatisfactory theranostic capabilities, the contribution of supramolecular interactions, such as hydrogen-bonds (H-bonds), to cancer nanotheranostics opens new perspectives for the design of biomedical materials, exhibiting remarkable properties and easier processability. Thanks to their dynamic characteristics, a feature generally observed for noncovalent interactions, H-bonding (macro)molecules can be used as supramolecular motifs for yielding drug- and diagnostic carriers that possess attractive features, arising from the combination of assembled nanoplatforms and the responsiveness of H-bonds. Thus, H-bonded nanomedicine provides a rich toolbox that is useful to fulfill biomedical needs with unique advantages in early-stage diagnosis and therapy, demonstrating the promising potential in clinical translations and applications. Here the design and synthetic routes toward H-bonded nanomedicines, focus on the growing understanding of the structure-function relationship for efficient cancer treatment are summarized. A guidance for designing new H-bonded intelligent theranostic agents is proposed, to inspire more successful explorations of cancer nanotheranostics and finally to promote potential clinical translations.

Hydrogen-Bonded Supramolecular Polymer Adhesives: Straightforward Synthesis and Strong Substrate Interaction.

High-performance adhesives are of great interest in view of industrial demand. We herein identify a straightforward synthetic strategy towards universal hydrogen-bonded (H-bonded) polymeric adhesives, using a side-chain barbiturate (Ba) and Hamilton wedge (HW) functionalized copolymer. Starting from a rubbery copolymer containing thiolactone derivatives, Ba and HW moieties are tethered as pendant groups via an efficient one-pot two-step amine-thiol-bromo conjugation. Hetero-complementary Ba/HW interactions thus yield H-bonded supramolecular polymeric networks. In addition to an enhanced polymeric network integrity induced by specific Ba/HW association, the presence of individual Ba or HW moieties enables strong binding to a range of substrates, outstanding compared to commercial glues and reported adhesives.

Halogen-Bond Mediated 3D Confined Assembly of AB Diblock Copolymer and C Homopolymer Blends.

Halogen-bond driven assembly, a world parallel to hydrogen-bond, has emerged as an attractive tool for constructing (macro)molecular arrangement. However, knowledge about halogen-bond mediated confined-assembly in emulsion droplets is limited so far. An I…. N bond mediated confined-assembly pathway to enable order-order phase transitions is reported here. Compared to hydrogen bonds, the distinct features of halogen bonds (e.g., higher directionality, hydrophobicity, favored in polar solvents), offers opportunities to achieve novel nanostructures and materials. Polystyrene-b-poly(4-vinyl pyridine) (PS-b-P4VP) AB diblock copolymer is chosen as halogen acceptor, while an iodotetrafluorophenoxy substituted C-type homopolymer, (poly(3-(2,3,5,6-tetrafluoro-4-iodophenoxy)propyl acrylate), PTFIPA) is designed as halogen donor, synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Formation of halogen bonding donor-acceptor pairs between the PTFIPA homopolymer and the P4VP segments presented in PS-b-P4VP, increase the volume of P4VP domains, in turn inducing an order-to-order morphology transition sequence: changing from spherical → cylindrical → lamellar → inverse cylindrical, by tuning the PTFIPA content and choice of surfactant. Subsequent selective swelling/deswelling of the P4VP domains give rise to further internal morphology transitions, creating tailored mesoporous microparticles, disassembled nanodiscs, and superaggregates. It is believed that these results will stimulate further examinations of halogen bonding interactions in emulsion droplets and many areas of application.

Activation of a Copper Biscarbene Mechano-Catalyst Using Single-Molecule Force Spectroscopy Supported by Quantum Chemical Calculations.

Single-molecule force spectroscopy allows investigation of the effect of mechanical force on individual bonds. By determining the forces necessary to sufficiently activate bonds to trigger dissociation, it is possible to predict the behavior of mechanophores. The force necessary to activate a copper biscarbene mechano-catalyst intended for self-healing materials was measured. By using a safety line bypassing the mechanophore, it was possible to pinpoint the dissociation of the investigated bond and determine rupture forces to range from 1.6 to 2.6 nN at room temperature in dimethyl sulfoxide. The average length-increase upon rupture of the Cu-C bond, due to the stretching of the safety line, agrees with quantum chemical calculations, but the values exhibit an unusual scattering. This scattering was assigned to the conformational flexibility of the mechanophore, which includes formation of a threaded structure and recoiling of the safety line.

Nanoscale structure and dynamics of thermoresponsive single-chain nanoparticles investigated by EPR spectroscopy.

We characterize temperature-dependent macroscopic and nanoscopic phase transitions and nanoscopic pre-transitions of water-soluble single chain nanoparticles (SCNPs). The studied SCNPs are based on polymers displaying lower-critical solution temperature (LCST) behavior and show nanoscale compartmentation. SCNPs are amenable to continuous wave electron paramagnetic resonance (CW EPR) spectroscopy to study how amphiphilic, non-covalently added nitroxide spin probes or covalently attached spin labels sample their environment concerning nanoscale structures (polarity, hydrophilicity/-phobicity) and dynamics. These SCNPs are formed through single-chain collapse and have been shown to have nanosized compartments that are rigidified during the crosslinking process. We analyze the temperature-dependent phase transitions of spin-labeled SCNPs by rigorous spectral simulations of a series of multicomponent EPR-spectra that derive from the nanoinhomogeneities (1) that are due to the single-chain compartmentation in SCNPs and (2) the transformation upon temperature change due to the LCST behavior. These transitions of the SCNPs and their respective polymer precursors can be monitored and understood on the nanoscale by following EPR-spectroscopic parameters like hyperfine couplings that depend on the surrounding solvent molecules or Heisenberg spin exchange between small molecule spin probes or covalently attached spin labels in the nanocompartments. In particular, for one SCNP, we find an interesting behavior that we ascribe to the properties of the nanosized inner core with continuous effects before and jump-like changes after the macroscopic thermal collapse, indicating highly efficient desolvation and compaction upon an increase in temperature and aggregation of individual nanoparticles above the collapse temperature.

Multicomponent Stress-Sensing Composites Fabricated by 3D-Printing Methodologies.

The preparation and characterization of mechanoresponsive, 3D-printed composites are reported using a dual-printing setup for both, liquid dispensing and fused-deposition-modeling. The here reported stress-sensing materials are based on high- and low molecular weight mechanophores, including poly(ε-caprolactone)-, polyurethane-, and alkyl(C11)-based latent copper(I)bis(N-heterocyclic carbenes), which can be activated by compression to trigger a fluorogenic, copper(I)-catalyzed azide/alkyne "click"-reaction of an azide-functionalized fluorescent dye inside a bulk polymeric material. Focus is placed on the printability and postprinting activity of the latent mechanophores and the fluorogenic "click"-components. The multicomponent specimen containing both, azide and alkyne, are manufactured via a 3D-printer to place the components separately inside the specimen into void spaces generated during the FDM-process, which subsequently are filled with liquids using a separate liquid dispenser, located within the same 3D-printing system. The low-molecular weight mechanophores bearing the alkyl-C11 chains display the best printability, yielding a mechanochemical response after the 3D-printing process.

Membrane Anchored Polymers Modulate Amyloid Fibrillation.

The nucleating role of cellular membrane components, such as lipid moieties on amyloid beta (Aß1-40 ) fibrillation, has been reported in recent years. The influence of conjugates fabricated from lipid anchors (cholesterol, diacylglycerol) and hydrophilic polymers on Aß1-40 fibrillation is reported here, aiming to understand the impact of polymers cloud point temperature (Tcp ) and its hydrophobic tails on the amyloid fibrillation. Novel lipid-polymer conjugates, consisting of poly(oligo(ethylene glycol)m acrylates) and hydrophobic groups (diacylglyceryl-, cholesteryl-, octyl-, decyl-, hexadecyl-) as anchors are synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization, allowing to tune the hydrophilic-hydrophobic profile of the conjugates by varying both, the degree of polymerization (n) and number of ethylene glycol units (m) in their side chain. The impact of these conjugates on Aß1-40 fibrillation is investigated via in vitro kinetic studies and transmission electron microscopy (TEM). Hydrophobic lipid-anchors are significantly delaying fibrillation (both lag- and half times), observing similar fibrillar structures via TEM when compared to native Aß1-40 . Other hydrophobic end groups are also delaying fibrillation of Aß1-40 , irrespective of their "n" and "m," whereas more hydrophilic polymers (both with longer ethylene glycol-sidechains, m = 3 for octyl, decyl and m = 5 for cholesterol) are only marginally inhibited fibrillation.

Comparing C2=O and C2=S Barbiturates: Different Hydrogen-Bonding Patterns of Thiobarbiturates in Solution and the Solid State.

Carbonyl-centered hydrogen bonds with various strength and geometries are often exploited in materials to embed dynamic and adaptive properties, with the use of thiocarbonyl groups as hydrogen-bonding acceptors remaining only scarcely investigated. We herein report a comparative study of C2=O and C2=S barbiturates in view of their differing hydrogen bonds, using the 5,5-disubstituted barbiturate B and the thiobarbiturate TB as model compounds. Owing to the different hydrogen-bonding strength and geometries of C2=O vs. C2=S, we postulate the formation of different hydrogen-bonding patterns in C2=S in comparison to the C2=O in conventional barbiturates. To study differences in their association in solution, we conducted concentration- and temperature-dependent NMR experiments to compare their association constants, Gibbs free energy of association ∆Gassn., and the coalescence behavior of the N-H‧‧‧S=C bonded assemblies. In Langmuir films, the introduction of C2=S suppressed 2D crystallization when comparing B and TB using Brewster angle microscopy, also revealing a significant deviation in morphology. When embedded into a hydrophobic polymer such as polyisobutylene, a largely different rheological behavior was observed for the barbiturate-bearing PB compared to the thiobarbiturate-bearing PTB polymers, indicative of a stronger hydrogen bonding in the thioanalogue PTB. We therefore prove that H-bonds, when affixed to a polymer, here the thiobarbiturate moieties in PTB, can reinforce the nonpolar PIB matrix even better, thus indicating the formation of stronger H-bonds among the thiobarbiturates in polymers in contrast to the effects observed in solution.

Fluorescent and Water Dispersible Single-Chain Nanoparticles: Core-Shell Structured Compartmentation.

Single-chain nanoparticles (SCNPs) are highly versatile structures resembling proteins, able to function as catalysts or biomedical delivery systems. Based on their synthesis by single-chain collapse into nanoparticular systems, their internal structure is complex, resulting in nanosized domains preformed during the crosslinking process. In this study we present proof of such nanocompartments within SCNPs via a combination of electron paramagnetic resonance (EPR) and fluorescence spectroscopy. A novel strategy to encapsulate labels within these water dispersible SCNPs with hydrodynamic radii of ≈5 nm is presented, based on amphiphilic polymers with additional covalently bound labels, attached via the copper catalyzed azide/alkyne "click" reaction (CuAAC). A detailed profile of the interior of the SCNPs and the labels' microenvironment was obtained via electron paramagnetic resonance (EPR) experiments, followed by an assessment of their photophysical properties.

Terminal Flow of Cluster-Forming Supramolecular Polymer Networks: Single-Chain Relaxation or Micelle Reorganization?

We correlate the terminal relaxation of supramolecular polymer networks, based on unentangled telechelic poly(isobutylene) linear chains forming micellar end-group clusters, with the microscopic chain dynamics as probed by proton NMR. For a series of samples with increasing molecular weight, we find a quantitative agreement between the terminal relaxation times and their activation energies provided by rheology and NMR. This finding corroborates the validity of the transient-network model and the special case of the sticky Rouse model, and dismisses more dedicated approaches treating the terminal relaxation in terms of micellar rearrangements. Also, we confirm previous results showing reduction of the activation energy of supramolecular dissociation with increasing molecular weight and explain this trend with an increasing elastic penalty, as corroborated by small angle x-ray scattering data.

Peptide-induced RAFT polymerization via an amyloid-ß17-20-based chain transfer agent.

We here describe the synthesis of a novel peptide/polymer-conjugate, embedding the amyloid-ß (Aß) protein core sequence Leu-Val-Phe-Phe (LVFF, Aß17-20) via RAFT polymerization. Based on a novel chain transfer-agent, the "grafting-from" approach effectively generates the well-defined peptide-polymer conjugates with appreciably high monomer conversion rate, resulting in mechanically stiffer peptide-functional cross-linked polymeric hydrogels.