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Supramolecular assembly of helical homopolymers to form stable chiral entities in water is highly valuable for creating chiral nanostructures and fabricating chiral biomaterials. Here we report on thermally induced supramolecular assembly of helical dendronized poly(phenylacetylene)s (PPAs) in aqueous solutions, and their in-situ photo-crosslinking at elevated temperatures to afford crosslinked nano-assemblies with hierarchical structures and stabilized helicities. These helical dendronized homopolymers carry cinnamate-cored dendritic oligoethylene glycol (OEG) pendants, which exhibit characteristic thermoresponsive behavior. Their thermal aggregation confers hexagonal packing of the polymer chains, and simultaneously resulting in enhancement of their chiralities. Assisted by radial amphiphilicity and worm-like molecular geometry, these dendronized PPAs form supramolecular twisted fibers, spheroid particles or toroids via thermal aggregation. Through UV photoirradiation above their cloud points (Tcps), cycloaddition of cinnamate moieties from the dendritic pendants promotes intermolecular crosslinking of dendronized PPA chains within the thermal aggregates, and simultaneously, the dynamic morphologies and supramolecular chirality from the dendronized PPAs through thermally induced aggregation can be fixed. In addition, photo-crosslinking can be occurred solely within individual aggregates due to the protection of densely packed dendritic OEGs. Therefore, various crosslinked assemblies from the dendronized homopolymers with tailorable morphologies and stabilized chirality are fabricated by tuning their thermally induced dynamic aggregations followed by in-situ photo-crosslinking. We believe that this work paves a convenient route to fabricate chiral assemblies with stabilized morphologies and fixed chiralities from dynamic helical homopolymers through intermolecular crosslinking, which can be promising for various chiral applications.
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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.
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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.
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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.
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Corneal stromal fibrosis is a common cause of visual impairment resulting from corneal injury, inflammation and surgery. Therefore, there is an unmet need for inhibiting corneal stromal fibrosis. However, bioavailability of topical eye drops is very low due to the tear and corneal barriers. In situ delivery offers a unique alternative to improve efficacy and minimize systemic toxicity. Herein, a drug delivery platform based on thermoresponsive injectable hydrogel/nano-micelles composite with in situ drug-controlled release and long-acting features is developed to prevent corneal scarring and reduce corneal stromal fibrosis in lamellar keratoplasty. The in-situ gelation hydrogels enabled direct delivery of celastrol to the corneal stroma. In vivo evaluation with a rabbit anterior lamellar keratoplasty model showed that hydrogel/micelles platform could effectively inhibit corneal stromal fibrosis. This strategy achieves controlled and prolonged release of celastrol in the corneal stroma of rabbit. Following a single corneal interlamellar injection, celastrol effectively alleviated fibrosis via mTORC1 signal promoting autophagy and inhibiting TGF-ß1/Smad2/3 signaling pathway. Overall, this strategy demonstrates promise for the clinical application of celastrol in preventing corneal scarring and reducing corneal stromal fibrosis post-lamellar keratoplasty, highlighting the potential benefits of targeted drug delivery systems in ocular therapeutics.
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Trasplante de Córnea , Hidrogeles , Triterpenos Pentacíclicos , Animales , Conejos , Triterpenos Pentacíclicos/administración & dosificación , Hidrogeles/administración & dosificación , Trasplante de Córnea/métodos , Cicatriz/prevención & control , Cicatriz/tratamiento farmacológico , Preparaciones de Acción Retardada , Fibrosis , Sistemas de Liberación de Medicamentos , Córnea/efectos de los fármacos , Córnea/metabolismo , Triterpenos/administración & dosificación , Liberación de Fármacos , Sustancia Propia/efectos de los fármacos , HumanosRESUMEN
Tailoring the amphiphilicity of a molecule through external stimuli can alter the balance between self-association and repulsion, resulting in different propensities for its assembly. Here we report on the supramolecular assembly of a series of dendronized spiropyrans (DSPs) in water. These DSPs carry 3-fold dendritic oligoethylene glycols (OEGs) with either methoxyl or ethoxyl terminals for different hydrophilicities, and contain an Ala-Gly dipeptide to provide the chirality. These dendronized amphiphiles form supramolecular nanospheres in aqueous solutions with remarkable induced chirality to a level of 1.0 × 106 deg cm2 dmol-1. They can be tuned reversibly through photoisomerization of the spiropyran moieties from the hydrophobic SP form into the hydrophilic MC form, and can even become chirally silent through thermally mediated collapse of the dendritic OEGs. Photoisomerization of the spiropyran moieties in these DSPs is accompanied by simultaneous changes of UV absorption, fluorescence emission, supramolecular chirality and aqueous solution colors. These supramolecular nanospheres exhibit characteristic thermoresponsive behavior due to thermal collapse of the dendritic OEGs with their cloud point temperatures (Tcps) being dependent on the overall hydrophilicity of the molecules and also the aggregate morphologies resulting from how dendritic OEGs are wrapped around the aggregates. Both photo-irradiation-mediated isomerization of the spiropyran moieties and thermally mediated dehydration and collapse of the dendritic OEGs influence the amphiphilicity of these DSPs and their solvation by water, leading to varied driving forces for their assembly. NMR, circular dichroism (CD) and fluorescence spectroscopy techniques, as well as DLS and AFM techniques are combined to follow the supramolecular assembly and illustrate the aggregation mechanism. All experimental results demonstrate that the reversible chirality of the aggregates originates from the balance between dendritic OEGs and spiropyran moieties against water solvation.
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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.
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Convenient chemical modification of biomacromolecules to create novel biocompatible functional materials satisfies the current requirements of sustainable chemistry. Dendronization of chitosan with dendritic oligoethylene glycols (OEGs) paves a strategy for the preparation of functional dendronized chitosans (DCSs) with unprecedent thermoresponsive behavior, which inherit biological features from polysaccharides and the topological features from dendritic OEGs. In addition, densely packed dendritic OEG chains around the backbone provide efficient cooperative interactions and form an intriguing confined microenvironment based on the degradable biopolymers. In this perspective, we describe the principle for the preparation of the thermoresponsive DCSs, and focus on the molecular envelop effect from the hydrophobic microconfinement to the encapsulated guest molecules or moieties. Particular attention is put on their capacity to regulate behavior and the functions of the encapsulated guests through thermally-mediated dehydration and collapse of the densely packed dendritic OEGs. We believe that the methodology described here may provide prospects for the fabrication of functional materials from biomacromolecules, especially when used as environmentally friendly nanomaterials or in accurate diagnosis and therapy.
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Quitosano , Nanoestructuras , Quitosano/química , Materiales Biocompatibles , GlicolesRESUMEN
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.
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Gelatin-based microgels are intriguing for various biomedical applications, which are conventionally prepared through photopolymerization of gelatin methacrylamide (GelMA). Here, we report on the modification of gelatin through acrylamidation to form gelatin acrylamide (GelA) with different substitution degrees, which was found to exhibit fast photopolymerization kinetics, better gelation, steady viscosity at elevated temperatures, and satisfying biocompatibility when compared to GelMA. By the online photopolymerization strategy with a home-made microfluidic setting, microgels of uniform sizes from GelA by blue light were obtained and their swollen properties were investigated. Compared to the microgels from GelMA, they showed an enhanced cross-linking degree and have better shape stability when swollen in water. Cell toxicities of the hydrogels from GelA and cell encapsulation from the corresponding microgels were investigated, which were found to exhibit superior properties than those from GelMA. We therefore believe that GelA has potential for constructing scaffolds for bioapplications and can be an excellent substitute for GelMA.
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Gelatina , Microgeles , Microfluídica , Materiales Biocompatibles , Encapsulación Celular , Ingeniería de Tejidos , Acrilamida , Luz , AcrilamidasRESUMEN
Regulation of protein activity is important in their applications for biomedicine and therapeutics. Here, an approach for the regulation of protein bioactivity through molecular confinement provided by oligoethylene glycol (OEG)-based dendronized chitosan (DCS) hydrogels is reported. Structural effects on their thermoresponsiveness are investigated. The highly transparent hydrogels are formed from thermoresponsive DCSs through their thermal dehydration and exhibit an intriguing reversible sol-gel transition property when triggered at physiological temperatures. The thermo-gelling behavior and mechanical strength of these hydrogels are investigated, and possible effects from hydrophobicity of the OEG dendrons, grafting rates of the dendrons on the chitosan main chain, and solid content of polymers are examined. These DCS hydrogels are found to have lamellar morphologies and can provide characteristic hydrophobicity microenvironments formed through the crowded OEG dendrons, which show a higher level of confinement to guest proteins. This allows the DCS hydrogels remarkable activity protection capability to proteins. Furthermore, these DCS hydrogels inherit the degradability from chitosan, allowing protein release from these hydrogels through the controllable ways without impairing their activities.
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Quitosano , Dendrímeros , Quitosano/farmacología , Coloides , Hidrogeles , PolímerosRESUMEN
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.
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Dendrímeros , Nanopartículas del Metal , Dendrímeros/química , Gelatina , Glicoles , Oro/química , Hidrogeles , Nanopartículas del Metal/química , MetacrilatosRESUMEN
C3-symmetric molecules carrying a conjugated diacetylene (DA) core are found to self-assemble into well-defined supramolecular fibers with enhanced supramolecular chirality in both organic and aqueous solutions. The conjugated core affords these amphiphiles characteristic fluorescence properties, which can be quenched partially due to the aggregation. Integration of the C3-symmetry with the conjugation provides these novel molecules strong aggregation tendency through solvent-mediated π-π stacking with preferential supramolecular chirality, which is predominately related to steric hindrance from their dipeptide pendants. Highly uniform supramolecular fibers of P and M handedness with thickness consistent in the dimensions of individual C3 molecules are obtained. The increase of concentrations induces these fibers to wrap together to form supramolecular fibrous bundles. Topochemical polymerization of the DA moieties can transform these supramolecular fibers into stable covalent polymers. We therefore believe that self-assembly of these C3-symmetric molecules with extended conjugated DA cores provides new prospects for the construction of supramolecular helical fibers through enhanced π-π stacking and creates a convenient strategy to furnish covalent chiral polymers of hierarchical structures through supramolecular assembly.
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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.
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Glicoles , Interacciones Hidrofóbicas e Hidrofílicas , Sustancias Macromoleculares , Transición de Fase , TemperaturaRESUMEN
BACKGROUND: MiR-29a targets signal transducers and activators of transcription 3 (STAT3) and negatively regulates its expression. Both miR-29a and STAT3 have been implicated in sepsis and upregulated miR-29a was associated with sepsis. However, the regulation of miR-29a in sepsis is not well elucidated. METHODS: We treated TC-1 cells with interleukin (IL)-6 and the expression of miR-29a and STAT3 was measured. We pre-treated TC-1 cells with histone deacetylase inhibitor Trichostatin A, DNA methylation inhibitor 5-Azacytidine or histone acetyltransferase inhibitor A-485, then treated cells with IL-6 and analyzed the expression of miR-29a and STAT3. We measured the expression of histone deacetylases and histone acetyltransferase, and glycolysis in IL-6-treated TC-1 cells. We administrated miR-29a inhibitor or STAT3 inhibitor to septic mice and the survival rate and expression of anti-apoptotic factors were measured. RESUTLS: IL-6 promoted miR-29a expression while suppressed STAT3 expression. Upregulation of miR-29a was associated with sepsis. Histone acetylation promoted miR-29a expression. IL-6 promoted glycolysis in TC-1 cells, which resulted in Acetyl-CoA accumulation. Inhibition of miR-29a promoted survival rate in septic mice while inhibiting STAT3 exacerbated death in mice. The protection of miR-29a inhibition against sepsis was abolished when STAT3 was inhibited. CONCLUSION: Histone acetylation promoted miR-29a expression, resulting in downregulation of STAT3 and exacerbation of sepsis.
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Histonas/metabolismo , MicroARNs , Factor de Transcripción STAT3/genética , Sepsis , Acetilación , Animales , Línea Celular Tumoral , Regulación hacia Abajo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Sepsis/genéticaRESUMEN
Balance between self-association of structural units and self-repulsion from crowding-induced steric hindrance accounts for the supramolecular assembly of the amphiphilic entities to form ordered structures, and solvation provides a toolbox to conveniently modulate the assemblies through differential interactions to various structural units. Here we report solvation-modulated supramolecular chiral assembly in aqueous solutions of amphiphilic dendronized tetraphenylethylenes (TPEs) with three-folded dendritic oligoethylene glycols (OEGs) through dipeptide Ala-Gly linkage. These dendronized amphiphiles can form supramolecular spheres with enhanced supramolecular chirality, which is tunable and dependent on solvation. These nanosized spherical aggregates exhibit thermoresponsive behavior, and their cloud point temperatures are dependent on mixed solvent of water and THF. The phase transition temperatures increase with water fractions due to water-driven shifting of OEG moieties from interiors of the aggregates to their peripheries. Furthermore, the thermally induced dehydration and collapse of OEG moieties mediate the reversible aggregation and deaggregation between the spheres, imparting tunable aggregation-induced fluorescent emission (AIE) and supramolecular chirality. Both experimental results and molecular dynamic simulations have highlighted that reversible chirality transformations of the amphiphilic dendronized assemblies mediated by solvation through change solvent quality or thermally dehydration are dependent on the balance between interactions of OEG dendrons with TPE moieties and with the solvent molecules.
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Colorantes , Solventes , TemperaturaRESUMEN
Transformation of supramolecular chiral assemblies into covalent polymers integrates characteristics of supramolecular chemistry together with covalent entities, leading to fabrication of covalent chiral materials through versatile supramolecular chiral assemblies. Here, we report supramolecular assembly of an amphiphilic dendronized 10,12-pentacosadiynoic amide (PCDA) in aqueous solutions to form twisted ribbons, which were transferred into covalent dendronized polydiacetylenes (PDAs) via photopolymerization. These supramolecular dendronized PCDA and the corresponding covalent dendronized PDAs showed unprecedent thermoresponsive properties. The thermally-induced dehydration and aggregations tuned reversibly their chiralities, which can be visually inspected through colour changes.
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Biomimetic scaffolds with transparent, biocompatible, and in situ-forming properties are highly desirable for corneal tissue engineering, which can deeply fill corneal stromal defects with irregular shapes and support tissue regeneration. We here engineer a novel class of corneal scaffolds from oligoethylene glycol (OEG)-based dendronized chitosans (DCs), whose aqueous solutions show intriguing sol-gel transitions triggered by physiological temperature, resulting in highly transparent hydrogels. Gelling points of these hydrogels can be easily tuned, and furthermore, their mechanical strengths can be significantly enhanced when injected into PBS at 37 °C instead of pure water. In vitro tests indicate that these DC hydrogels exhibit excellent biocompatibility and can promote proliferation and migration of keratocyte. When applied in the rabbit eyes with corneal stromal defects, in situ formed DC hydrogels play a positive effect for new tissue regeneration. Overall, this thermo-gelling DCs possess appealing features as corneal tissue substitutes with their excellent biocompatibility and unprecedented thermoresponsiveness.