Compressible Hydrogels with Stabilized Chirality from Thermoresponsive Helical Dendronized Poly(phenylacetylene)s.

Fabrication of chiral hydrogels from thermoresponsive helical dendronized phenylacetylene copolymers (PPAs) carrying three-fold dendritic oligoethylene glycols (OEGs) is reported. Three different temperatures, i.e. below or above cloud point temperatures (Tcps) of the copolymers, and under freezing condition, were utilized, affording thermoresponsive hydrogels with different morphologies and mechanical properties. At room temperature, transparent hydrogels were obtained through crosslinking among different copolymer chains. Differently, opaque hydrogels with much improved mechanical properties were formed at elevated temperatures through crosslinking from the thermally dehydrated and collapsed copolymer aggregates, leading to heterogeneity for the hydrogels with highly porous morphology. While crosslinking at freezing temperature synergistically through ice templating, these amphiphilic dendronized copolymers formed hydrogels with highly porous lamellar structures, which exhibited remarkable compressible properties as human articular cartilage with excellent fatigue resistance. Amphiphilicity of the dendronized copolymers played a pivotal role in modulating the network formation during the gelation, as well as morphology and mechanical performance of the resulting hydrogels. Through crosslinking, these dendronized copolymers featured with typical dynamic helical conformations were transformed into hydrogels with unprecedently stabilized helicities due to the restrained chain mobilities in the three-dimensional networks.

Thermoresponsive Helical Dendronized Poly(phenylacetylene)s: Remarkable Stabilization of Their Helicity via Photo-Dimerization of the Dendritic Pendants.

Dynamic helical polymers can change their helicity according to external stimuli due to the low helix-inversion barriers, while helicity stabilization for polymers is important for applications in chiral recognition or chiral separations. Here, we present a convenient methodology to stabilize dynamic helical conformations of polymers through intramolecular cross-linking. Thermoresponsive dendronized poly(phenylacetylene)s (PPAs) carrying 3-fold dendritic oligoethylene glycol pendants containing cinnamate moieties were synthesized. These polymers exhibit typical features of dynamic helical structures in different solvents, that is, racemic contracted conformations in less polar organic solvents and predominantly one-handed stretched helical conformations in highly polar solvents. This dynamic helicity can be enhanced through selective solvation by increasing the polarity of the organic solvents or simply via their thermally mediated dehydration in water. However, through photocycloaddition of the cinnamate moieties between the neighboring pendants via UV irradiation, these dendronized PPAs adopt stable helical conformations either below or above their phase transition temperatures in water, and their helical conformations can even be retained in less polar organic solvents. Spectroscopic and atomic force microscopy measurements demonstrate that photocycloaddition between the cinnamate moieties occurs on the individual molecular level, and this is found to be helpful in restraining the photodegradation of the PPA backbones. Molecular dynamics simulations reveal that the spatial orientation of the pendants along the rigid polyene backbone is crucial for the photodimerization of cinnamates within one helix pitch.

Dual-Responsive Supramolecular Chiral Assemblies from Amphiphilic Dendronized Tetraphenylethylenes.

Supramolecular assembly of amphiphilic molecules in aqueous solutions to form stimuli-responsive entities is attractive for developing intelligent supramolecular materials for bioapplications. Here we report on the supramolecular chiral assembly of amphiphilic dendronized tetraphenylethylenes (TPEs) in aqueous solutions. Hydrophobic TPE moieties were connected to the hydrophilic three-fold dendritic oligoethylene glycols (OEGs) through a tripeptide proline-hydroxyproline-glycol (POG) to afford the characteristic topological structural effects of dendritic OEGs and the peptide linker. Both ethoxyl- and methoxyl-terminated dendritic OEGs were used to modulate the overall hydrophilicity of the dendronized TPEs. Their supramolecular aggregates exhibited thermoresponsive behavior that originated from the dehydration and collapse of the dendritic OEGs, and their cloud point temperatures (Tcps) were tailored by solution pH conditions. Furthermore, aggregation-induced fluorescent emission (AIE) from TPE moieties was used as an indicator to follow the assembly, which was reversibly tuned by temperature variation at different pH conditions. Supramolecular assemblies from these dendronized amphiphiles exhibited enhanced supramolecular chirality, which was dominated mainly by the interaction balance between TPE with dendritic OEG and TPE with POG moieties and was modulated through different solvation by changing solution temperature or pH conditions. More interestingly, ethoxyl-terminated dendritic OEG provided a much stronger shielding effect than its methoxyl-terminated counterpart to prevent amino groups within the peptide from protonation, even in strong acidic conditions, resulting in different responsive behavior to the solution temperature and pH conditions for these supramolecular aggregates.

Thermoresponsive dendritic oligoethylene glycols.

Monodispersed molecules of low molar masses showing thermoresponsiveness are appealing both for mechanism investigation of the thermally-modulated dehydration and aggregation on molecular levels and for designing functional intelligent materials. In the present report, thermoresponsive properties of a homologous series of monodispersed dendritic macromolecules carrying three-, four- or six-fold dendritic oligoethylene glycol (OEG) segments were investigated. These dendritic macromolecules carry either methoxyl or ethoxyl terminals, and have different cores (alcohol, methyl ester or methacryloyl) to exhibit different overall hydrophilicity. They show characteristic thermoresponsive properties with sharp phase transitions when suitable structural units are combined. Three structural factors determine their phase transition temperatures, including the cores, branching density and peripheral terminals. Thermally-induced collapse and aggregation are monitored with temperature-varied NMR spectroscopy at the microscale level and optical microscopy at the macroscale level. At elevated temperature, these dendritic macromolecules undergo fast exchange between the dehydrated and the hydrated states. These dendritic macromolecules afford structure-dependent confinement to guest dyes through their multi-valent interactions.

Dendronized Gelatin-Mediated Synthesis of Gold Nanoparticles.

Thermoresponsive dendronized gelatins (GelG1) or gelatin methacrylates (GelG1MA) were used as precursors to modulate the efficient reduction of Au(III) to form stable gold nanoparticles (AuNPs) through UV irradiation. These dendronized gelatins were obtained through the amidation of gelatin or gelatin methacrylates with dendritic oligoethylene glycols (OEGs). Crowded OEG dendrons along the gelatin backbones create a hydrophobic microenvironment, which promotes the reduction of Au(III). Gelatin backbones act as ligands through the electron-rich groups to facilitate the reduction, while the dendritic OEGs provide shielding effects through crowding to form a hydrophobic microenvironment, which not only enhances the reduction but also stabilize the formed AuNPs through encapsulation. The effects of dendron coverage on the dendronized biomacromolecules and their thermoresponsiveness on the reduction kinetics were examined. Dendronized gelatin/AuNPs hydrogels were further prepared through the in situ photo-crosslinking of GelG1MA. The modification of natural macromolecules through dendronization presented in this report facilitates a novel platform for the environmentally friendly synthesis of noble metal nanoparticles, which may form a new strategy for developing smart nano-biosensors and nano-devices.

Upper Critical Solution Temperature-Type Responsive Cyclodextrins with Characteristic Inclusion Abilities.

Water-soluble and thermoresponsive macrocycles with stable inclusion toward guests are highly valuable to construct stimuli-responsive supramolecular materials for versatile applications. Here, we develop such macrocycles - ureido-substituted cyclodextrins (CDs) which exhibit unprecedented upper critical solution temperature (UCST) behavior in aqueous media. These novel CD derivatives showed good solubility in water at elevated temperature, but collapsed from water to form large coacervates upon cooling to low temperature. Their cloud points are greatly dependent on concentration and can be mediated through oxidation and chelation with silver ions. Significantly, the amphiphilicity of these CD derivatives is supportive to host-guest binding, which affords them inclusion abilities to guest dyes. The inclusion complexation remained nearly intact during thermally induced phase transitions, which is in contrast to the switchable inclusion behavior of lower critical solution temperature (LCST)-type CDs. Moreover, ureido-substituted CDs were exploited to co-encapsulate a pair of guest dyes whose fluorescence resonance energy transfer process can be switched by the UCST phase transition. We therefore believe these novel thermoresponsive CDs may form a new strategy for developing smart macrocycles and allow for exploring smart supramolecular materials.

Amyloid Evolution: Antiparallel Replaced by Parallel.

Several atomic structures have now been found for micrometer-scale amyloid fibrils or elongated microcrystals using a range of methods, including NMR, electron microscopy, and X-ray crystallography, with parallel ß-sheet appearing as the most common secondary structure. The etiology of amyloid disease, however, indicates nanometer-scale assemblies of only tens of peptides as significant agents of cytotoxicity and contagion. By combining solution X-ray with molecular dynamics, we show that antiparallel structure dominates at the first stages of aggregation for a specific set of peptides, being replaced by parallel at large length scales only. This divergence in structure between small and large amyloid aggregates should inform future design of molecular therapeutics against nucleation or intercellular transmission of amyloid. Calculations and an overview from the literature argue that antiparallel order should be the first appearance of structure in many or most amyloid aggregation processes, regardless of the endpoint. Exceptions to this finding should exist, depending inevitably on the sequence and on solution conditions.

Roxadustat (FG-4592) treatment for anemia in dialysis-dependent (DD) and not dialysis-dependent (NDD) chronic kidney disease patients: A systematic review and meta-analysis.

The effect of roxadustat (FG-4592) on individuals with chronic kidney diseases (CKD) patients receiving or not receiving the dialysis was unclear. The aim of this study was to evaluate the efficacy of roxadustat for the treatment of anemia in patients who are dialysis dependent (DD) or dialysis independent (NDD) CKD. We performed a systematic review of randomised controlled trials (RCTs) comparing treatment with roxadustat versus placebo or epoetin alfa up to November 2019. We investigated the efficacy of roxadustat in the levels of hemoglobin and other clinical parameters in renal anemia in patients with NDD and DD-CKD. We estimated weighted-mean difference (WMD) using random effect models. We included six RCTs comprising 1001 patients of whom 70.6 % were treated with roxadustat and 294 controls. The control group for studies of NDD-CKD patients was placebo whereas an active control of epoetin-alfa was used in studies of DD-CKD patients. Median follow-up time was 8 weeks. All trials were industry-sponsored. Overall, roxadustat increased hemoglobin levels by 1.20 g/dl (95 % CI:0.66, 1.75,P < 0.0001,I2 = 99.3 %). Hemoglobin levels increased by 1.99 g/dl in NDD-CKD patients versus placebo and 0.52 g/dl in DD-CKD patients versus epoetin-alfa. Roxadustat was associated with a decrease the levels of hepcidin by -49.3 ng/dl (-38.5 ng/dl in NDD patients versus placebo and -27.7 ng/dl in DD patients versus epoetin alfa), a decrease in ferritin of -49.7 µmol/l (-52.2 µmol/l in NDD patients versus placebo and -7.3 µmol/l in DD patients versus epoetin alfa), and increase in total iron-binding capacity of 32.2 µmol/l (14.1 µmol/l in NDD patients versus placebo and 13.6 µmol/l in DD patients versus epoetin alfa). The percentage change in the transferrin saturation levels was -2.07 % (-6%, NDD patients versus placebo, and +3.7 % in DD patients versus epoetin alfa) in anemia associated CKD patients. This review found roxadustast increases the levels of hemoglobin, serum transferrin, intestinal iron absorption, and reduces hepcidin in both NDD and DD-CKD patients. Safety data is still emerging.

Confined Microenvironments from Thermoresponsive Dendronized Polymers.

Confined microenvironments in biomacromolecules arising from molecular crowding account for their well-defined biofunctions and bioactivities. To mimick this, synthetic polymers to form confined structures or microenvironments are of key scientific value, which have received significant attention recently. To create synthetic confined microenvironments, molecular crowding effects and topological cooperative effects have been applied successfully, and the key is balance between self-association of structural units and self-repulsion from crowding-induced steric hindrance. In this article, formation of confined microenvironments from stimuli-responsive dendronized polymers carrying densely dendritic oligoethylene glycols (OEGs) moieties in their pendants is presented. These wormlike thick macromolecules exhibit characteristic thermoresponsive properties, which can provide constrained microenvironments to encapsulate effectively guest molecules including dyes, proteins, or nucleic acids to prevent their protonation or biodegradation. This efficient shielding effect can also mediate chemical reactions in aqueous phase, and even enhance chirality transferring efficiency. All of these can be switched off simply through the thermally-induced dehydration and collapse of OEG dendrons due to the amphiphilicity of OEG chains. Furthermore, the switchable encapsulation and release of guests can be greatly enhanced when these dendronized polymers are used as major constituents for fabricating bulk hydrogels or nanogels, which provide a higher-level confinement.

pH and Thermo Dual-Responsive Fluorescent Hydrogel Actuator.

As one of the most important smart materials, fluorescent hydrogel actuators can produce both color and shape changes under external stimuli. In the present work, an effective approach to develop a novel fluorescent hydrogel actuator with pH and thermo dual responsiveness is proposed. Through incorporating pH-responsive perylene tetracarboxylic acid (PTCA), which is a typical fluorescent moiety with aggregation-caused quenching (ACQ) effect, into an anisotropic poly(N-isopropylacrylamide)-polyacrylamide (PNIPAm-PAAm) structure, the obtained hydrogel exhibits stable thermoresponsive shape deformation and switchable fluorescence performance upon a pH trigger. Therefore, fluorescence-quenching-based and actuation-based information can be revealed when exposed to UV light and immersed into warm water, respectively. Moreover, the thermoresponsive actuating behavior can be applied to further hide the fluorescence-quenching-based images. The present work may provide new insights into the design and preparation of novel stimuli-responsive hydrogel actuators.

Self-immolative colorimetric, fluorescent and chemiluminescent chemosensors.

Self-immolative chemistry features a cascade of disassembly reactions in response to external stimuli, which provides great opportunities to design new self-immolative chemosensors with advanced performance and/or functions. Self-immolative spacers in these chemosensors not only facilitate the linkage of designed triggers to various chromophores or fluorophores, but can also be used to solve inherent problems associated with native chemosensors, such as low reactivities, poor stabilities and slow response times. Their capacity for stimuli-responsive release through operation of a self-immolative reaction further enables integration of sophisticated functions into chemosensors, including signal amplification, enzyme activity localization, and drug monitoring. Significant advances have been made in the field of self-immolative chemosensors, leading to intriguing applications to sensitive detection of analytes, bioimaging and cancer theranostics. This tutorial review summarizes this recent progress with a focus on their design strategies and sensing mechanisms.

Microfluidic fabrication of microparticles for biomedical applications.

Droplet microfluidics offers exquisite control over the flows of multiple fluids in microscale, enabling fabrication of advanced microparticles with precisely tunable structures and compositions in a high throughput manner. The combination of these remarkable features with proper materials and fabrication methods has enabled high efficiency, direct encapsulation of actives in microparticles whose features and functionalities can be well controlled. These microparticles have great potential in a wide range of bio-related applications including drug delivery, cell-laden matrices, biosensors and even as artificial cells. In this review, we briefly summarize the materials, fabrication methods, and microparticle structures produced with droplet microfluidics. We also provide a comprehensive overview of their recent uses in biomedical applications. Finally, we discuss the existing challenges and perspectives to promote the future development of these engineered microparticles.

pH and Temperature Dual-Responsive Plasmonic Switches of Gold Nanoparticle Monolayer Film for Multiple Anticounterfeiting.

Two-dimensional (2D) gold nanoparticle (Au NP) monolayer film possesses a lot of fascinating peculiarities, and has shown promising applications in photoelectrical devices, catalysis, spectroscopy, sensors, and anticounterfeiting. Because of the localized surface plasmon resonance (LSPR) property predetermined by the natural structure of metal nanoparticles, it is usually difficult to realize the reversible LSPR transition of 2D film. In this work, we report on the fabrication of a large-area free-standing Au NP monolayer film with dual-responsive switchable plasmonic property using a pH- or thermal-responsive dendronized copolymer as a stimuli-sensitive linker. In this system, an oligoethylene-glycol-based (OEG-based) dendronized copolymer (named PG1A) with pH or temperature sensitivity was first modified onto the surface of a Au NP. Then, polyethylene glycol dibenzyl aldehyde (PEG-DA) was introduced to interact with the amino moieties from PG1A before the process of oil-water interfacial self-assembly of NPs, resulting in an elastic, robust, pH- or temperature-sensitive interpenetrating network among Au NPs in monolayer films. In addition, the film could exhibit reversibly plasmonic shifts of about 77 nm and inherent color changes through varying temperature or pH. The obtained free-standing monolayer film also shows an excellent transferable property, which can be easily transferred onto substrates such as plastic molds, PDMS, copper grids, and silicon wafers. In virtue of these peculiarities of the free-standing property, special plasmonic signal, and homologous macroscopic color, the transferred film was primely applied to an anticounterfeiting security label with clear color change at the designed spots, providing a new avenue to plasmonic nanodevices with various applications.

Thermoresponsive cyclodextrins with benzenesulfonamide showing tunable inhibition for carbonic anhydrase.

Monodisperse thermoresponsive cyclodextrins appended with benzenesulfonamides were demonstrated to reversibly regulate the enzymatic activity of carbonic anhydrase, which was found to be dependent on both scaffold effect and thermoresponsiveness.

ILQINS hexapeptide, identified in lysozyme left-handed helical ribbons and nanotubes, forms right-handed helical ribbons and crystals.

Amyloid fibrils are implicated in over 20 neurodegenerative diseases. The mechanisms of fibril structuring and formation are not only of medical and biological importance but are also relevant for material science and nanotechnologies due to the unique structural and physical properties of amyloids. We previously found that hen egg white lysozyme, homologous to the disease-related human lysozyme, can form left-handed giant ribbons, closing into nanotubes. By using matrix-assisted laser desorption ionization mass spectrometry analysis, we here identify a key component of such structures: the ILQINS hexapeptide. By combining atomic force microscopy and circular dichorism, we find that this fragment, synthesized by solid-phase peptide synthesis, also forms fibrillar structures in water at pH 2. However, all fibrillar structures formed possess an unexpected right-handed twist, a rare chirality within the corpus of amyloid experimental observations. We confirm by small- and wide-angle X-ray scattering and molecular dynamics simulations that these fibrils are composed of conventional left-handed ß-sheets, but that packing stresses between adjacent sheets create this twist of unusual handedness. We also show that the right-handed fibrils represent a metastable state toward ß-sheet-based microcrystals formation.

Codendrimer from polyamidoamine (PAMAM) and oligoethylene dendron as a thermosensitive drug carrier.

The efficient synthesis of codendrimer PAMAM-co-OEG (PAG) and its properties in aqueous solution, including particle size and thermosensitivity, are described. PAG is synthesized with well-defined structure through the "attach to" route. In the aqueous solutions, PAG forms unimer and multimolecular aggregates with the respective particle sizes of approximately 8 and 200 nm, depending on the concentration. PAG shows thermosensitive behavior with sharp and fast transition, and the lower critical solution temperature is 38.2 °C. The suitability of codendrimer PAG as the thermosensitive carrier is evaluated with methotrexate (MTX) as the model drug. MTX is encapsulated in PAG with the drug-loading capacity of 39%, among which 30% of MTX is encapsulated in PAMAM core. The release behavior of MTX mediated by temperature is investigated with focus on the effects around the LCST of PAG.

Supramolecular assembly of C3 peptidic molecules into helical polymers.

Self-assembly of C3 discotic molecules bearing dipeptide pendants into helical supramolecular polymers is investigated. The dipeptides are constituted from glycine and alanine with altered sequence, aiming at modulating the steric hindrance and examining the steric effects on the assembly. This steric hindrance effect is further illustrated with a dipeptide formed from glycine and valine, which carries a much larger isopropyl side unit. Their supramolecular polymerization is examined in various organic solvents and at different temperatures. The assembly morphology is directly visualized with atomic force microscopy. It is found that small changes in the dipeptide motifs in combination with solvent structure and the solution concentrations lead to different expression of the supramolecular assembly.

Supramolecular assembly of dendronized diacetylenes into thermoresponsive chiral fibers and their covalent fixation through topochemical polymerization.

By combination of dendritic topological structures with photopolymerizable diacetylene, here we report on supramolecular chiral assembly of the dendronized diacetylenes in water. These dendronized diacetylenes are constituted with three-fold dendritic oligoethylene glycols (OEGs), bridged with a dipeptide from phenylalanine and glycine. These dendronized amphiphiles exhibit intensive propensity to aggregate in water and form helical fibers, which show characteristic thermoresponsive behavior with phase transition temperatures dominated by hydrophilicity of the dendritic OEGs. Topochemical polymerization of these supramolecular fibers through UV irradiation transfers them into the covalent helical dendronized polydiacetylenes. Chirality of these dendronized polydiacetylenes can be mediated through the thermally-induced phase transitions, but is also intriguingly dependent on vortex via stirring. Through stirring the solutions, chiralities of the dendronized polydiacetylenes are inverted, which can be reversibly recovered after keeping still the solution. Hydrogels are formed from these dendronized diacetylenes through concentration-enhanced interactions between the supramolecular fibers. Their mechanical properties can be greatly increased through thermally-enhanced interactions between the fibers with storage moduli increased from 20 Pa to a few hundred Pa. In addition, through photo-polymerization, the supramolecular fibers are transferred into covalent dendronized polydiacetylenes, and the corresponding hydrogels show much improved mechanical properties with storage moduli about 10 kPa.

Visible Light [2 + 2] Cycloadditions of Thermoresponsive Dendronized Styryltriazines To Exhibit Tunable Microconfinement.

Visible light-triggered photochemical reactions in aqueous media are highly valuable to tailor molecular structures and properties in an ecofriendly manner. Here we report visible light-induced catalyst-free [2 + 2] cycloadditions of thermoresponsive dendronized styryltriazines, which show tunable microconfinement to guest dyes in aqueous media. These dendronized styryltriazines are constituted of conjugated mono- or tristyryltriazines, which carry hydrophilic dendritic oligoethylene glycol (OEG) pendants. They underwent efficient [2 + 2] cycloadditions to form dendronized cyclobutane dimers or oligomers in water through irradiation with visible light of 400 nm, and their cycloaddition behavior was dominated by dendritic architectures and solvent conditions. Dendronization with dendritic OEGs also afforded them characteristic thermoresponsive properties with tunable phase transition temperatures in the range 36-65 °C, which can be further modulated through photocycloaddition of styryltriazine chromophores. Importantly, dendronized styryltriazines can form tunable microenvironments in aqueous media, which encapsulate hydrophobic solvatochromic Nile red to exhibit variable photophysical properties. The encapsulated guest dye can be simultaneously released through noninvasive visible light-induced [2 + 2] cycloaddition reactions.