Multilevel Hollow-Structured Particles through Halogen-Bond Regulated Polymer Assembly under 3D Confinement.

Engineering of hollow particles with tunable internal structures often requires complicated processes and/or invasive cleavage. Halogen-bond driven 3D confined-assembly of block copolymers has shed light on the engineering of polymer organization along with the fabricating of unique nanostructures. Herein, a family of multilevel hollow-structured particles (e.g., fully porous, multi-chamber, multi-shell, and concentric multi-layer architectures) is reported via halogen-bond regulated 3D confined-assembly of amphiphilic polymer networks. To do so, polystyrene-b-poly(2-vinyl pyridine)-b-poly(ethylene oxide) (PS-b-P2VP-b-PEO) amphiphilic triblock copolymer is selected, where P2VP blocks act as halogen acceptor. Meanwhile, poly(3-(2,3,5,6-tetrafluoro-4-iodophenoxy) propyl acrylate) (PTFIPA) is employed as halogen donor. Halogen-bond driven donor-acceptor linking between PTFIPA and P2VP block presented in PS-b-P2VP-b-PEO, can lead to the formation of supramolecular polymeric networks, along with the increased P2VP domain and tunable hydrophobic volume. Therefore, an adjustable packing parameter (p) is thus anticipated, which can enable the morphology transformation sequence until an equilibrium state is reached. Moreover, computer simulations are further utilized as the tool to interpret such morphologies transition and identify the precise distribution of each component. Benefiting from the tunable hollow structure and a substantial surface for transporting purpose, these structurally novel particles open perspectives toward promising applications including encapsulation, nanoreactor, and catalyst support.

Amphiphilic triblock copolymer as the gas chromatographic stationary phase with high-resolution performance towards a wide range of isomers and the components of lemon essential oil.

This work presents the investigation of using the amphiphilic triblock copolymer composed of poly(ethylene oxide)(PEO)-poly(propylene oxide) (PPO)-poly(ethylene oxide) (PEO) (denoted as EPE) as the stationary phase for gas chromatographic (GC) analyses. The EPE capillary column exhibited moderate polarity and column efficiency of 4348 plates/m determined by naphthalene at 120 °C (k = 11.52). Different from the PEG and polysiloxane homopolymers, it showed high-resolution performance towards a wide range of aliphatic and aromatic isomers in terms of polarity and acid-base properties. Particularly, the EPE column displayed distinct advantages for separating the critical isomers of alkanes, anilines and phenols and the components of the lemon essential oil over the commercial PEG and polysiloxane columns. In addition, the EPE column exhibited excellent separation repeatability and reproducibility with the relative standard deviation (RSD) values in the range of 0.03% - 0.08% for run-to-run, 0.14% - 0.61% for day-to-day and 3.1% - 4.0% for column-to-column, respectively. Moreover, the EPE column was investigated in terms of thermal stability, the minimum allowable operating temperature (MiAOT) and sample loadability. Its application to GC-MS analysis of the essential oil demonstrated its feasibility for practical analyses. This work demonstrates the promising future of triblock copolymers as a new class of selective stationary phases for GC analyses, which is barely reported up to date. The findings of this work is of important value for fundamental researches and practical applications.

Surface Modification of Nanofibers by Physical Adsorption of Fiber-Homologous Amphiphilic Copolymers and Nanofiber-Reinforced Hydrogels with Excellent Tissue Adhesion.

Herein, we report a simple approach to modify hydrophobic PCL nanofibers by adsorption of a fiber-homologous amphiphilic triblock copolymer (PCL-b-PEG-b-PCL, PCEC). The modified PCL nanofibers were then utilized to reinforce a physical hydrogel, which was formed by micellar crosslinking of the same PCEC triblock copolymer. Therefore, the copolymer played a dual role in not only dispersing and stabilizing nanofibers but also additionally providing a framework for the hydrogel matrix. The mechanical strength of the hydrogel was significantly enhanced by addition of the modified PCL nanofibers, and the gel modulus can be tuned by varying the concentration of the copolymer and nanofibers. The effect of nanofiber size and content on the mechanical properties of the hydrogel matrices was studied. Different from hydrogel composites that were reinforced by 2D fiber meshes or 3D woven fiber networks, this free fiber-reinforced hydrogel can be readily injected to adapt to the environmental shape and self-heal. The hydrogel composites showed superior tissue adhesion properties compared to the commercially available fibrin glue, especially in muscle adhesion. Due to its injectable and self-healing properties, this nanofiber-reinforced hydrogel may have great potential as a new type of tissue sealant.

Self-powered all weather sensory systems powered by Rhodobacter sphaeroides protein solar cells.

Natural photosynthetic proteins can convert solar energy into electrical energy with close to 100% quantum efficiency, and there is increasing interest in their use for sustainable photoelectrochemical devices. The primary processes of photosynthesis remain operational and efficient down to extremely low temperatures, and natural photosystems exhibit a variety of self-healing mechanisms. Herein we demonstrate the use of an amphiphilic triblock copolymer, Pluronic F127, to fabricate a self-healing photosynthetic protein photoelectrochemical cell that operates optimally at sub-zero temperatures. A concentration of 30% (w/w) Pluronic F127 depressed the freezing point of an electrolyte comprising 50 mM ubiquinone-0 in aqueous buffer such that optimal device solar energy conversion was seen at -12 °C rather than at room temperature. Fabrication of the protein photoelectrochemical cells with flexible electrodes enabled the demonstration of self-healing of damage caused by repeated mechanical deformation. Multiple bending cycles caused a marked deterioration of the photocurrent response to around a third of initial levels due to damage to the gel phase of the electrolyte, but this could be restored to ~95% by simply cooling and rewarming the device. This self-recoverability of the electrolyte extended the operational life of the protein cell through a process that increased its photoelectrochemical output during the repair. Utility of the cells as components of a touch sensor operational across a wide temperature range, including freezing conditions, is demonstrated.

Dynamic covalent linked triblock copolymer micelles for glutathione-mediated intracellular drug delivery.

Redox-responsive linkages dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their niche. In the present work, triblock copolymer PEG-PLA-PEG synthesized and characterized by 1H -NMR and SEC can self-assemble into redox-responsive micelles in aqueous media with nanosized 33nm and 47nm. And the copolymers PEG2000-PLA3000-PEG2000 and PEG2000-PLA5000-PEG2000 present lower CMC with 0.034 and 0.022mg/mL, and higher DLC of 4.28% and 5.14% respectively, compared with that of diblock copolymer. Moreover, drug release from the micelles can be triggered and significantly accelerated in reductive environment. The low cytotoxicity of redox-responsive micelles was confirmed by MTT assay against NIH 3T3 cells. All of these results demonstrated that these polymeric micelles self-assembled from double-disulfide tethered block copolymers are promising carriers for the redox-responsive intracellular delivery of hydrophobic anticancer drugs.

Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices.

Development of highly concentrated formulations of protein and peptide drugs is a major challenge due to increased susceptibility to aggregation and precipitation. Numerous drug delivery systems including implantable and wearable controlled-release devices require thermally stable formulations with high concentrations due to limited device sizes and long-term use. Herein we report a highly concentrated insulin gel formulation (up to 80 mg/mL, corresponding to 2200 IU/mL), stabilized with a non-ionic amphiphilic triblock copolymer (i.e., Pluronic F-127 (PF-127)). Chemical and physical stability of insulin was found to be improved with increasing polymer concentration, as evidenced by reduced insulin fibrillation, formation of degradation products, and preserved secondary structure as measured by HPLC and circular dichroism spectroscopy, respectively. This formulation exhibits excellent insulin stability for up to 30 days in vitro under conditions of continuous shear at 37 °C, attributable to the amphiphilic properties of the copolymer and increased formulation viscosity. The mechanism of stabilizing insulin structure by PF-127 was investigated by coarse-grained molecular dynamics (CG-MD), all-atom MD, and molecular docking simulations. The computation results revealed that PF-127 could reduce fibrillation of insulin by stabilizing the secondary structure of unfolded insulin and forming hydrophobic interaction with native insulin. The gel formulations contained in microfabricated membrane-reservoir devices released insulin at a constant rate dependent on both membrane porosity and copolymer concentration. Subcutaneous implantation of the gel formulation-containing devices into diabetic rats resulted in normal blood glucose levels for the duration of drug release. These findings suggest that the thermally stable gel formulations are suitable for long-term and implantable drug delivery applications.

Increase in transgene expression by pluronic L64-mediated endosomal/lysosomal escape through its membrane-disturbing action.

For efficient transgene delivery and expression, internalized nucleic acids should quickly escape from cellular endosomes and lysosomes to avoid enzymatic destruction and degradation. Here, we report a novel strategy for safe and efficient endosomal/lysosomal escape of transgenes mediated by Pluronic L64, a neutral amphiphilic triblock copolymer. L64 enhanced the permeability of biomembranes by structural disturbance and pore formation in a concentration- and time-dependent manner. When applied at optimal concentration, it rapidly reached the endosome/lysosome compartments, where it facilitated escape of the transfection complex from the compartments and dissociation of the complex. Therefore, when applied properly, L64 not only significantly increased polyethylenimine- and liposome-mediated transgene expression, but also decreased the cytotoxicity occasioned by transfection process. Our studies revealed the function and mechanism of neutral amphiphilic triblock copolymer as potent mediator for safe and efficient gene delivery.

In vitro evaluation of effects of sustained anti-TNF release from MPEG-PCL-MPEG and PCL microspheres on human rheumatoid arthritis synoviocytes.

Anti-tumor necrosis factor α (TNFα) drugs such as etanercept (ETN) have been mostly used in systemic treatment of rheumatoid arthritis. To eliminate the side effects in long-term treatments and to achieve a local sustained anti-inflammatory effect, a controlled drug delivery system is needed for anti-TNFα drugs. This study aims to develop novel injectable microcarriers of ETN that can provide long-term controlled release of this protein drug upon intra-articular application. In this study, poly(ε-caprolactone) (PCL) and its copolymer with poly(ethylene glycol), methoxypoly(ethylene glycol)-poly(ε-caprolactone)-methoxypoly(ethylene glycol) microspheres (MPEG-PCL-MPEG) were compared for their prospective success in rheumatoid arthritis treatment. Microspheres with smooth surface of a mean particle diameter of approximately 5 µm were prepared with both polymers. MPEG-PCL-MPEG microspheres had higher encapsulation efficiency than PCL microspheres. The activity of encapsulated ETN within MPEG-PCL-MPEG microspheres also retained while 90% of the activity of ETN within PCL microspheres could retain during 90-day release. MPEG-PCL-MPEG microspheres showed faster ETN release compared to PCL microspheres in various release media. Cumulative amounts of ETN released from both types of microspheres were significantly lower in cell culture medium and in synovial fluids than in phosphate buffered saline. This was mainly due to protein adsorption onto microspheres. Hydrophilic MPEG segment enhanced ETN release while preventing protein adsorption on microspheres compared to PCL. Sustained ETN release from microspheres resulted with a significant decrease in pro-inflammatory cytokines (TNFα, IFNγ, IL-6, IL-17) and MMP levels (MMP-3, MMP-13), while conserving viability of fibroblast-like synoviocytes compared to the free drug. Results suggest that MPEG-PCL-MPEG is a potential copolymer of PCL that can be used in development of biomedical materials for effective local treatment purposes in chronic inflammatory arthritis owing to enhanced hydrophilicity. Yet, PCL microspheres are also promising systems having good compatibility to synoviocytes and would be especially the choice for treatment approach requiring longer term and slower release.

Bionic design for surface optimization combining hydrophilic and negative charged biological macromolecules.

While polyethersulfone (PES) membrane represents a promising option for blood purification, the blood compatibility must be dramatically enhanced to meet today's ever-increasing demands for many emerging application. In this study, we report a bionic design for optimization and development of a modified PES membrane combining hydrophilic and negative charged biological macromolecules on its surface. The hydrophilic and ionic charged biological macromolecules sulfonated poly(styrene)-b-poly(methyl methacrylate)-b-poly-(styrene) (PSSMSS) and poly(vinyl pyrrolidone)-b-poly(methyl methacrylate)-b-poly-(vinyl pyrrolidone) were synthesized via reversible addition-fragmentation chain transfer polymerization and used together to modify PES membranes by blending method. A hydrophilic membrane surface with negative charged surface coating was obtained, imitating the hydrophilic and negatively charged structure feature of heparin. The modified PES membranes showed suppressed platelet adhesion, and a prolonged blood clotting time, and thereby improved blood compatibility. In addition, the blood clotting time of the modified membranes increased with the blended PSSMSS amounts increment, indicating that both the hydrophilic and negative charged groups play important roles in improving the blood compatibility of PES membranes.

A simple method to prepare modified polyethersulfone membrane with improved hydrophilic surface by one-pot: The effect of hydrophobic segment length and molecular weight of copolymers.

A simple method to prepare modified polyethersulfone (PES) membrane by one-pot is provided, and the method includes three steps: polymerization of vinyl pyrrolidone (VP), copolymerization of methyl methacrylate (MMA) and blending with PES. The effect of the PMMA segment length and molecular weight of the copolymer (PVP-b-PMMA-b-PVP, as an additive) on the structures and properties of the modified membranes was investigated. Activated partial thromboplastin time (APTT) tests indicated that with the increase of the poly(methyl methacrylate) (PMMA) segment length in the chains of the copolymers and with the increase of the molecular weight of the copolymers, the APTTs of the modified membranes increased to some extent, since less of the additives were lost during liquid-liquid phase separation process. Therefore, the copolymer was designed and prepared with appropriate ratio of poly(vinyl pyrrolidone) (PVP) to MMA and with appropriate molecular weight for better membrane performance. When the copolymer was blended in the membrane, the water permeance, protein anti-fouling property and sieving coefficients for PEG-12000 increased obviously. The simple, credible and feasible method had the potential to be used for the modification of membranes with improved blood compatibility, ultrafiltration and antifouling properties of biomaterials and for practical production.

Characteristics and release profiles of MPEG-PCL-MPEG microspheres containing immunoglobulin G.

Polyester-polyether type block copolymers have attracted attention in the area of drug delivery systems with their capability in providing a broad range of amphiphilic characteristics. The aim of the present work was to prepare and characterize immunoglobulin G (IgG) loaded methoxy poly(ethylene glycol)-poly(ɛ-caprolactone)-methoxy poly(ethylene glycol) (MPEG-PCL-MPEG) microspheres as potential carrier for therapeutic monoclonal antibodies used in clinics. MPEG-PCL-MPEG triblock copolymer was synthesized by ring-opening polymerization of ɛ-caprolactone initiated by MPEG and then characterized. Microspheres were prepared by double emulsion-solvent evaporation method and their properties were compared with those of PCL microspheres. Microspheres had spherical shape with a mean particle size around 6 µm. MPEG-PCL-MPEG microspheres had higher encapsulation efficiency than PCL microspheres. After 90 days of release, 30±2% and 57±3% of the bioactivity of IgG released from non-irradiated PCL and MPEG-PCL-MPEG microspheres were protected, respectively. Presence of MPEG in microspheres provided more controlled IgG release rate and protected IgG from denaturation during γ-irradiation (20±3% and 49±2% for PCL and MPEG-PCL-MPEG microspheres, respectively). In vitro cytotoxicity tests revealed that both MPEG-PCL-MPEG and PCL microspheres had no toxic effect on cells. This study showed that MPEG-PCL-MPEG microspheres are promising delivery systems for therapeutic monoclonal antibodies.