Population-based heteropolymer design to mimic protein mixtures.

Biological fluids, the most complex blends, have compositions that constantly vary and cannot be molecularly defined1. Despite these uncertainties, proteins fluctuate, fold, function and evolve as programmed2-4. We propose that in addition to the known monomeric sequence requirements, protein sequences encode multi-pair interactions at the segmental level to navigate random encounters5,6; synthetic heteropolymers capable of emulating such interactions can replicate how proteins behave in biological fluids individually and collectively. Here, we extracted the chemical characteristics and sequential arrangement along a protein chain at the segmental level from natural protein libraries and used the information to design heteropolymer ensembles as mixtures of disordered, partially folded and folded proteins. For each heteropolymer ensemble, the level of segmental similarity to that of natural proteins determines its ability to replicate many functions of biological fluids including assisting protein folding during translation, preserving the viability of fetal bovine serum without refrigeration, enhancing the thermal stability of proteins and behaving like synthetic cytosol under biologically relevant conditions. Molecular studies further translated protein sequence information at the segmental level into intermolecular interactions with a defined range, degree of diversity and temporal and spatial availability. This framework provides valuable guiding principles to synthetically realize protein properties, engineer bio/abiotic hybrid materials and, ultimately, realize matter-to-life transformations.

Self-assembly of emulsion droplets through programmable folding.

In the realm of particle self-assembly, it is possible to reliably construct nearly arbitrary structures if all the pieces are distinct1-3, but systems with fewer flavours of building blocks have so far been limited to the assembly of exotic crystals4-6. Here we introduce a minimal model system of colloidal droplet chains7, with programmable DNA interactions that guide their downhill folding into specific geometries. Droplets are observed in real space and time, unravelling the rules of folding. Combining experiments, simulations and theory, we show that controlling the order in which interactions are switched on directs folding into unique structures, which we call colloidal foldamers8. The simplest alternating sequences (ABAB...) of up to 13 droplets yield 11 foldamers in two dimensions and one in three dimensions. Optimizing the droplet sequence and adding an extra flavour uniquely encodes more than half of the 619 possible two-dimensional geometries. Foldamers consisting of at least 13 droplets exhibit open structures with holes, offering porous design. Numerical simulations show that foldamers can further interact to make complex supracolloidal architectures, such as dimers, ribbons and mosaics. Our results are independent of the dynamics and therefore apply to polymeric materials with hierarchical interactions on all length scales, from organic molecules all the way to Rubik's Snakes. This toolbox enables the encoding of large-scale design into sequences of short polymers, placing folding at the forefront of materials self-assembly.

Demonstrating the Interfacial Polymer Thermal Transition from Coil-to-Globule to Coil-to-Stretch under Shear Flow Using SFG and MD Simulation.

Revealing interfacial shear-induced structural responsiveness has long been an important topic in that most fluids in nature and human life are in motion and cause interesting boundary phenomena. It is amazing how the polymer chain conformation or local structural features at a boundary change under the effective shear condition. In this study, microfluidic-assisted sum frequency generation (SFG) vibrational spectroscopy and all-atom molecular dynamics (MD) simulation are combined to reveal that the shear flow can effectively block the so-called thermal coil-to-globule transition of the poly(N-isopropylacrylamide) (PNIPAM) brushes on the solid substrate, and the normal coil-to-globule transition transfers to a coil-to-stretch one under shear flow with increasing ambient temperature. Such findings are attributed to the balance between the shear flow and the molecular interaction with respect to the polymer chains and adjacent water molecules, thus demonstrating the significant effect of the shear flow on the structural and dynamic behaviors of the polymer chains at the boundaries from the molecular level.

Copolymers of starch, a sustainable template for biomedical applications: A review.

The outstanding versatility of starch offers a source of inspiration for the development of high-performance-value-added biomaterials for the biomedical field, including drug delivery, tissue engineering and diagnostic imaging. This is because starch-based materials can be tailored to specific applications via facile grafting or other chemistries, introducing specific substituents, with starch being effectively the "template" used in all the chemical transformations discussed in this review. A considerable effort has been carried out to obtain specific tailored starch-based grafted polymers, taking advantage of its biocompatibility and biodegradability with appealing sustainability considerations. The aim of this review is to critically explore the latest research that use grafting chemistries on starch for the synthesis of products for biomedical applications. An effort is made in reviewing the literature that proposes synthetic "greener" approaches, the use of enzymes and their immobilized analogues and alternative solvent systems, including water emulsions, ionic liquids and supercritical CO2.

A novel facile one-pot synthesis of photothermally responsive carbon polymer dots as promising drug nanocarriers.

Luminescent and photothermic carbon polymer dots (CPDs-PNM), composed of a carbonized core and cross-linked chains of poly(N-isopropylacrylamide), were synthetized by a novel, simple, solvent- and reagent-free method. The formation of CPDs-PNM was controlled by both temperature and heating time. The CPDs-PNM exhibited LCST behaviour, high photothermal conversion efficiency, curcumin loading capacity and no toxicity to eukaryotic cells. Proof of concept experiments confirmed an excellent thermally induced drug release activity to be used for photothermally controlled drug release.

Conductive graphene coated carboxymethyl cellulose hybrid fibers with polymeric ionic liquids as intermediate.

In this study, a kind of polymeric ionic liquid (PIL) called PIL-Cl was synthesized and modified to obtain conductive graphene coated carboxymethyl cellulose hybrid fibers. Carboxymethyl cellulose (CMC) was formed into fibers by wet spinning assisted with PILCl. Co-precipitation test of CMC and PIL-Cl demonstrated that PIL-Cl could precipitate with CMC through strong electrostatic interaction and molar ratio of CMC and PIL-Cl (calculated in repeating units) would affect the formation of precipitation. Secondly, modified PIL-Cl named PIL-Ac was used as an intermediate connecting CMC fiber and graphene to fabricate conductive CMC/PIL/graphene fibers. A series of tests were performed on CMC/PIL/graphene fibers, including Raman spectroscopy, scanning electron microscopy and conductivity test. The results showed that PIL-Cl could help form CMC fiber, and PIL-Ac could functionalize it and make it conductive.

Surface Coating of Pulmonary siRNA Delivery Vectors Enabling Mucus Penetration, Cell Targeting, and Intracellular Radical Scavenging for Enhanced Acute Lung Injury Therapy.

Pulmonary delivery of anti-inflammatory siRNA presents a promising approach for localized therapy of acute lung injury (ALI), while polycationic vectors can be easily trapped by the negatively charged airway mucin glycoproteins and arbitrarily internalized by epithelial cells with nontargetability for immunological clearance. Herein, we report a material, the dopamine (DA)-grafted hyaluronic acid (HA-DA), coating on an anti-TNF-α vector to address these limitations. HA-DA was simply synthesized and facilely coated on poly(ß-amino ester) (BP)-based siRNA vectors via electrostatic attraction. The resulting HA-DA/BP/siRNA displayed significantly enhanced mucus penetration, attributable to the charge screen effect of HA-DA and the bioadhesive nature of the grafting DA. After transmucosal delivery, the nanosystem could target diseased macrophages via CD44-mediated internalization and rapidly escape from endo/lysosomes through the proton sponge effect, resulting in effective TNF-α regulation. Meanwhile, DA modification endowed the coating material with robust antioxidative capability to scavenge a broad spectrum of reactive oxygen/nitrogen species (RONS), which protected the lung tissue from oxidative damage and synergized with anti-TNF-α to inhibit a cytokine storm. As a result, a remarkable amelioration of ALI was achieved in a lipopolysaccharide (LPS)-stimulated mice model. This study provides a multifunctional coating material to facilitate pulmonary drug delivery for the treatment of lung diseases.

Micro-/Mesoporous Fluorescent Polymers and Devices for Visual Pesticide Detection with Portability, High Sensitivity, and Ultrafast Response.

The residue of pesticides in crops, soil, and water continues to be a widespread concern due to the threat to human health and food safety. With the aim to develop highly sensitive sensing materials and portable detection devices, two dicarbazole-based fluorescent micro-/mesoporous polymers (JYs) with a larger specific surface area and pore sizes ranging from 1.1 to 34.2 nm are synthesized. The Stern-Volmer constants of JY fluorescence quenching for imidacloprid (50,063 M-1) exceed 23-51 times those of the reported porous organic polymers (980-2173 M-1). Of particular interest is the observation that JYs show rapid fluorescence response (2 s) and ultralow detection limit (30 ppb) for imidacloprid in water medium. The pronounced chemsensing property is attributed to the synergistic role of the hierarchical pore structure, large π-conjugation of chromophore groups, and strong inner filter effect between the polymer and imidacloprid molecule. Moreover, the pesticide detection of JYs exhibits good interference resistance in complicated service environments such as the extract liquids of the apple peel and field soil as well as aqueous solutions of various cations and anions. Because of the portability, excellent reusability, and sensitive fluorescence response, the prepared JYs and detection devices have promising applications in the on-site monitoring and early warning of the pesticide residues.

Glycopolymer Engineering of the Cell Surface Changes the Single Cell Migratory Direction and Inhibits the Collective Migration of Cancer Cells.

Cancer cell migration is one of the most important processes in cancer metastasis. Metastasis is the major cause of death from most solid tumors; therefore, suppressing cancer cell migration is an important means of reducing cancer mortality. Cell surface engineering can alter the interactions between cells and their microenvironment, thereby offering an effective method of controlling the migration of the cells. This paper reports that modification of the mouse melanoma (B16) cancer cell surface with glycopolymers affects the migration of the cells. Changes in cell morphology, migratory trajectories, and velocity were investigated by time-lapse cell tracking. The data showed that the migration direction is altered and diffusion slows down for modified B16 cells compared to unmodified B16 cells. When modified and unmodified B16 cells were mixed, wound-healing experiments and particle image velocimetry (PIV) analysis showed that the collective migration of unmodified B16 cells was suppressed because of vortexlike motions induced by the modified cells. The work demonstrates the important role of surface properties/modification in cancer cell migration, thereby providing new insights relative to the treatment of cancer metastasis.

Polymeric nanostructures based on azobenzene and their biomedical applications: synthesis, self-assembly and stimuli-responsiveness.

Amphiphilic polymers can self-assemble to form nanoparticles with different structures under suitable conditions. Polymer nanoparticles functionalized with aromatic azo groups are endowed with photo-responsive properties. In recent years, a variety of photoresponsive polymers and nanoparticles have been developed based on azobenzene, using different molecular design strategies and synthetic routes. This article reviews the progress of this rapidly developing research field, focusing on the structure, synthesis, assembly and response of photo-responsive polymer assemblies. According to the molecular structure, photo-responsive polymers can be divided into linear polymers containing azobenzene in a side chain, linear polymers containing azobenzene in the main chain, linear polymers containing azobenzene in an end group, branched polymers containing azobenzene and supramolecular polymers containing azobenzene. These systems have broad biomedical application prospects in the field of drug delivery and imaging applications.

Systemic delivery of siRNA to the colon using peptide modified PEG-PCL polymer micelles for the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a refractory inflammatory bowel disease that causes inflammation and ulcers in the digestive tract, and significantly reduces the patient's quality of life. While existing UC treatments have many challenges, nanotechnology, and small interfering RNA (siRNA) based formulations are novel and promising for UC treatment. We previously reported that intravenous administration of MPEG-PCL-CH2R4H2C nanomicelles had high inflammatory site accumulation and remarkable therapeutic effects on rheumatoid arthritis by a phenomenon similar to enhanced permeability and retention effect. In this study, we investigated the effects of siRNA delivered using MPEG-PCL-CH2R4H2C nanomicelles through intravenous administration to the inflammation site of dextran sulfate sodium-induced colitis mice. The MPEG-PCL-CH2R4H2C micelles had optimum physical properties and high siRNA compaction ability. Moreover, model-siRNA delivered through MPEG-PCL-CH2R4H2C showed higher accumulation in the inflammatory site than that of the naked siRNA. Furthermore, intravenous administration of MPEG-PCL-CH2R4H2C/siRelA micelles, targeting siRelA, a subunit of NF-κB, significantly decreased the shortening of large intestine, clinical score, and production of inflammatory cytokines compared the 5-ASA and naked siRelA. These results suggest that MPEG-PCL-CH2R4H2C is a useful carrier for the systemic delivery and accumulation of siRNA, thus improving its therapeutic effect.

Development of phenol-grafted polyglucuronic acid and its application to extrusion-based bioprinting inks.

In this present work, we developed a phenol grafted polyglucuronic acid (PGU) and investigated the usefulness in tissue engineering field by using this derivative as a bioink component allowing gelation in extrusion-based 3D bioprinting. The PGU derivative was obtained by conjugating with tyramine, and the aqueous solution of the derivative was curable through a horseradish peroxidase (HRP)-catalyzed reaction. From 2.0 w/v% solution of the derivative containing 5 U/mL HRP, hydrogel constructs were successfully obtained with a good shape fidelity to blueprints. Mouse fibroblasts and human hepatoma cells enclosed in the printed constructs showed about 95% viability the day after printing and survived for 11 days of study without a remarkable decrease in viability. These results demonstrate the great potential of the PGU derivative in tissue engineering field especially as an ink component of extrusion-based 3D bioprinting.

Preparation of LCST regulable DES-lignin-g-PNVCL thermo-responsive polymer by ARGET-ATRP.

To expand the field of high-value utilization of lignin. The degraded deep eutectic solvent lignin-grafted poly (N-Vinyl caprolactam) (DES-lignin-g-PNVCL) was synthesized by modified DES-lignin and NVCL via the combination of activators regenerated by electron transfer-atom transfer radical polymerization (ARGET-ATRP). Fourier transform infrared spectroscopy (FT-IR), 1H NMR, X-ray electron spectroscopy (XPS), dynamic light scattering (DLS), differential scanning calorimeter (DSC) were used to characterize the structure and performance of DES-lignin-g-PNVCL. The results indicated that the PNVCL and DES-lignin-g-PNVCL were successfully prepared by ARGET-ATRP. The lowest critical solution temperature (LCST) of PNVCL was 35.75 °C. Due to different strength of hydrogen bond, different energies were required, so the LCST of the polymer can be regulated. When the molar ratio of phenolic hydroxyl group in degraded DES-lignin to 2-bromoisobutyryl bromide (BiBB) was increased from 1:1 to 1:7, the grafting rate of DES-lignin-Br was increased from 32.87% to 60.84%, and the LCST of DES-lignin-g-PNVCL was decreased from 47.98 °C to 27.88 °C. The LCST of DES-lignin-g-PNVCL was increased from 30.98 °C to 44.64 °C when the addition amount of DES-lignin-Br was increased from 20 mg to 200 mg. The LCST of DES-lignin-g-PNVCL was increased from 27.20 °C to 39.86 °C when the ratio of DMF/water was increased from 1:4 to 4:1. The LCST of DES-lignin-g-PNVCL was decreased from 52.10 °C to 31.02 °C when the concentration of DES-lignin-g-PNVCL was increased from 0.5 mg/mL to 2.5 mg/mL. The equation represented the relationship between LCST and influencing factors was obtained, the good predictability provided a tactics for preparing desired LCST thermo-responsible polymer.

Fluorescent polydopamine based molecularly imprinted sensor for ultrafast and selective detection of p-nitrophenol in drinking water.

A highly effective fluorescent molecularly imprinted sensor (F-PDA-MIS) based on fluorescent polydopamine (F-PDA) was successfully synthesized for selective and ultrafast detection of p-nitrophenol (P-NP) in drinking water. F-PDA with abundant surface functional groups has been artfully modified to firstly serve as both fluorescent monomer and functional monomer in the synthesis of a uniform luminous F-PDA-MIS, which can greatly improve the detection efficiency. As expected, F-PDA-MIS had an obvious emission wavelength of 535 nm with the optimal excitation wavelength at 400 nm. Specially, F-PDA-MIS could detect P-NP in the range 100 to 1100 nM with much lower detection limit of 24.2 nM within 120 s compared with other conventional imprinted fluorescent sensors based on pure quantum dots (QDs) or dyes. This excellent test phenomenon is mainly ascribed to the rapid electron transfer between F-PDA and P-NP. Satisfactory recovery of 98.0-104% for mineral water and 98.6-106% for boiling water were obtained with relative standard deviations (RSDs) of 2.7-3.4% and 2.6-3.5% respectively. The detection reliability of F-PDA-MIS was verified by the comparison with high-performance liquid chromatography (HPLC-UV). Consequently, F-PDA as a fluorescence functional monomer has been shown to be a possible strategy to effectively improve the detection limit and shorten response time of the target determination in water..

Size-Dependent Electroporation of Dye-Loaded Polymer Nanoparticles for Efficient and Safe Intracellular Delivery.

Efficient and safe delivery of nanoparticles (NPs) into the cytosol of living cells constitutes a major methodological challenge in bio-nanotechnology. Electroporation allows direct transfer of NPs into the cytosol by forming transient pores in the cell membrane, but it is criticized for invasiveness, and the applicable particle sizes are not well defined. Here, in order to establish principles for efficient delivery of NPs into the cytosol with minimal cytotoxicity, the influence of the size of NPs on their electroporation and intracellular behavior is investigated. For this study, fluorescent dye-loaded polymer NPs with core sizes between 10 and 40 nm are prepared. Optimizing the electroporation protocol allows minimizing contributions of endocytosis and to study directly the effect of NP size on electroporation. NPs of <20 nm hydrodynamic size are efficiently delivered into the cytosol, whereas this is not the case for NPs of >30 nm. Moreover, only particles of core size <15 nm diffuse freely throughout the cytosol. While electroporation at excessive electric fields induces cytotoxicity, the use of small NPs <20 nm allows efficient delivery at mild electroporation conditions. These results give clear methodological and design guidelines for the safe delivery of NPs for intracellular applications.

Improved Synthesis of a Novel Biodegradable Tunable Micellar Polymer Based on Partially Hydrogenated Poly(ß-malic Acid-co-benzyl Malate).

Poly(benzyl malate) (PBM), together with its derivatives, have been studied as nanocarriers for biomedical applications due to their superior biocompatibility and biodegradability. The acquisition of PBM is primarily from chemical routes, which could offer polymer-controlled molecular weight and a unique controllable morphology. Nowadays, the frequently used synthesis from L-aspartic acid gives an overall yield of 4.5%. In this work, a novel synthesis route with malic acid as the initiator was successfully designed and optimized, increasing the reaction yield up to 31.2%. Furthermore, a crystalline form of PBM (PBM-2) that polymerized from high optical purity benzyl-ß-malolactonate (MLABn) was discovered during the optimization process. X-ray diffraction (XRD) patterns revealed that the crystalline PBM-2 had obvious diffraction peaks, demonstrating that its internal atoms were arranged in a more orderly manner and were different from the amorphous PBM-1 prepared from the racemic MLABn. The differential scanning calorimetry (DSC) curves and thermogravimetric curves elucidated the diverse thermal behaviors between PBM-1 and PBM-2. The degradation curves and scanning electron microscopy (SEM) images further demonstrated the biodegradability of PBM, which have different crystal structures. The hardness of PBM-2 implied the potential application in bone regeneration, while it resulted in the reduction of solubility when compared with PBM-1, which made it difficult to be dissolved and hydrogenated. The solution was therefore heated up to 75 °C to achieve benzyl deprotection, and a series of partially hydrogenated PBM was sequent prepared. Their optimal hydrogenation rates were screened to determine the optimal conditions for the formation of micelles suitable for drug-carrier applications. In summary, the synthesis route from malic acid facilitated the production of PBM for a shorter time and with a higher yield. The biodegradability, biosafety, mechanical properties, and adjustable hydrogenation widen the application of PBM with tunable properties as drug carriers.

Synergic influences of network topologies and associative interactions on the microstructures and bulk performances of hydrogels.

Revealing the relationship between network topologies and mechanical properties of hydrogels is fundamental yet challenging in the design of tough soft materials. Here, we report a series of hydrogels using N-isopropyl acrylamide (NIPAm) and acrylic acid (AAc) as the basic units to form a single network of the copolymer, a semi-interpenetrated network of two homopolymers, and a grafted network with homopolymer chains anchored on another homopolymer network, to investigate the influence of network architectures on the mechanical properties and thermal responses of the gels. We found that the properties of the gels are also significantly influenced by the formation of hydrogen bonds between poly(N-isopropyl acrylamide) (PNIPAm) and poly(acrylic acid) (PAAc) segments. The gels with the single network of poly(NIPAm-co-AAc) are mechanically weak due to the low efficiency for forming robust hydrogen bonds, while micro-segregated domains are formed in the hydrogels with a semi-interpenetrated network structure due to the formation of inter-chain hydrogen bonds that favors energy dissipation and toughening of the gels. On the other hand, dense hydrogen bonds form between the grafted PNIPAm chains and the PAAc network, resulting in nano-segregated domains and excellent mechanical properties of the gels. The hydrogels with the grafted network structure exhibit a more repeatable response to temperature than those with the semi-interpenetrated network structure due to the relatively stable hydrogen-bond network. The comparison of the mechanical properties and thermal stability of the hydrogels with the same composition but different topological networks should be informative for engineering hydrogel properties or functions by tailoring the network structures.

Expanding the spectrum of polydopamine antioxidant activity by nitroxide conjugation.

Polydopamine (PDA) materials are important due to their unique physicochemical properties and their potential as chemopreventive agents for diseases connected with oxidative stress. Although PDA has been suggested to display antioxidant activity, its efficacy is controversial and its mechanism of action is still unclear. Herein, we report that accurately purified PDA nanoparticles in water at pH 7.4 are unable to quench alkylperoxyls (ROO˙), which are the radicals responsible for the propagation of lipid peroxidation, despite PDA reacting with the model DPPH˙ and ABTS˙+ radicals. PDA nanoparticles prepared by copolymerization of dopamine with the dialkyl nitroxide 4-NH2TEMPO show instead good antioxidant activity, thanks to the ROO˙ trapping ability of the nitroxide. Theoretical calculations performed on a quinone-catechol dimer, reproducing the structural motive of PDA, indicate a reactivity with ROO˙ similar to catechol. These results suggest that PDA nanoparticles have an "onion-like" structure, with a catechol-rich core, which can be reached only by DPPH˙ and ABTS˙+, and a surface mainly represented by quinones. The importance of assessing the antioxidant activity by inhibited autoxidation studies is also discussed.

Chemical and Mechanical Characterization of Licorice Root and Palm Leaf Waste Incorporated into Poly(urethane-acrylate) (PUA).

A poly(urethane-acrylate) polymer (PUA) was synthesized, and a sufficiently high molecular weight starting from urethane-acrylate oligomer (UAO) was obtained. PUA was then loaded with two types of powdered ligno-cellulosic waste, namely from licorice root and palm leaf, in amounts of 1, 5 and 10%, and the obtained composites were chemically and mechanically characterized. FTIR analysis of final PUA synthesized used for the composite production confirmed the new bonds formed during the polymerization process. The degradation temperatures of the two types of waste used were in line with what observed in most common natural fibers with an onset at 270 °C for licorice waste, and at 290 °C for palm leaf one. The former was more abundant in cellulose (44% vs. 12% lignin), whilst the latter was richer in lignin (30% vs. 26% cellulose). In the composites, only a limited reduction of degradation temperature was observed for palm leaf waste addition and some dispersion issues are observed for licorice root, leading to fluctuating results. Tensile performance of the composites indicates some reduction with respect to the pure polymer in terms of tensile strength, though stabilizing between data with 5 and 10% filler. In contrast, Shore A hardness of both composites slightly increases with higher filler content, while in stiffness-driven applications licorice-based composites showed potential due to an increase up to 50% compared to neat PUA. In general terms, the fracture surfaces tend to become rougher with filler introduction, which indicates the need for optimizing interfacial adhesion.

Nanotechnology for Topical Drug Delivery to the Anterior Segment of the Eye.

Topical drug delivery is one of the most challenging aspects of eye therapy. Eye drops are the most prevalent drug form, especially for widely distributed anterior segment eye diseases (cataracts, glaucoma, dry eye syndrome, inflammatory diseases, etc.), because they are convenient and easy to apply by patients. However, conventional drug formulations are usually characterized by short retention time in the tear film, insufficient contact with epithelium, fast elimination, and difficulties in overcoming ocular tissue barriers. Not more than 5% of the total drug dose administered in eye drops reaches the interior ocular tissues. To overcome the ocular drug delivery barriers and improve drug bioavailability, various conventional and novel drug delivery systems have been developed. Among these, nanosize carriers are the most attractive. The review is focused on the different drug carriers, such as synthetic and natural polymers, as well as inorganic carriers, with special attention to nanoparticles and nanomicelles. Studies in vitro and in vivo have demonstrated that new formulations could help to improve the bioavailability of the drugs, provide sustained drug release, enhance and prolong their therapeutic action. Promising results were obtained with drug-loaded nanoparticles included in in situ gel.