Biomimetic-Inspired One-Step Strategy for Improvement of Interfacial Interactions in Cellulose Nanofibers by Modification of the Surface of Nitramine Explosives.

Recently, a burgeoning category of biocompatible botanically derived nanomaterial cellulose nanofibers (CNFs) has captured tremendous attention on account of its entangled nanostructured network, natural abundance, and outstanding mechanical properties. Biomimetically inspired by the superior properties of CNFs, this paper examined them as the coating material to cover cyclotrimethylenetrinitramine (RDX), cyclotetramethylenetetranitramine (HMX), and hexanitrohexaazaisowurtzitane (CL-20) via a facile water suspension method and the ultrasonic technology. The core-shell structure and the composition of energetic crystal@CNF were examined through scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy analyses. The obtained outcomes demonstrated that the dispersibility of the CNF enhanced favorably upon covering the surface of explosive crystals; the interfacial contact ability between CNFs and energetic crystals was also manifested to be increased, which could be ascribed to the interfacial interaction of hydrogen bonds and the electrostatic force of self-assembly. In addition, the stable crystalloid construction of ß-HMX and ε-CL-20 has been preserved positively in the preparation process. In comparison with raw explosives, the thermal stability and sensitivity performances of the core-shell structure composites were outstanding. Accordingly, this work demonstrated the rewarding application of coating CNFs uniformly on the surface of energetic crystals, ulteriorly offering a potential fabrication strategy for the embellishment of high-explosive crystals.

Gold Nanoparticles Grafted with PLL-b-PNIPAM: Interplay on Thermal/pH Dual-Response and Optical Properties.

Narrowly distributed poly(l-lysine-b-N-isopropylacrylamide) (PLL-b-PNIPAM) was prepared through ring-opening polymerization of ε-benzyloxycarbonyl-l-lysine N-carboxy-α-amino anhydride and atom transfer radical polymerization of NIPAM, followed with the removal of ε-benzyloxycarbonyl group. Then gold nanoparticles (AuNPs) grafted with PLL-b-PNIPAM (PNIPAM-PLL-AuNPs) were obtained by the reduction of chloroauric acid with sodium citrate in the presence of PLL-b-PNIPAM. PNIPAM-PLL-AuNPs and its precursors were thoroughly characterized by proton magnetic resonance spectroscope, Fourier transform infrared spectroscope, UV-vis spectroscope, transmission electron microscopy, dynamic light scattering, thermogravimetric analysis, and circular dichroism. The obtained PNIPAM-PLL-AuNPs exhibited high colloid stability even at strong alkaline (pH = 12) and acidic (pH = 2) conditions. The thermal and pH dual-responsive behaviors of the grafting PLL-b-PNIPAM chains was observed to be affected by AuNPs, while not for the secondary structure of PLL chains. Correspondingly, the surface plasmon resonance (SPR) of AuNPs was found to be sensitive to both pH value and temperature. A blue shift in the SPR happened both with increasing pH value and increasing temperature. The stimuli-response was reversible in heating-cooling cycles. The gold nanoparticles with both pH and temperature response may have potential applications in biomedical areas and biosensors.

Ultra-pH-sensitive nanoparticle of gambogenic acid for tumor targeting therapy via anti-vascular strategy plus immunotherapy.

Although the combination of anti-vascular strategy plus immunotherapy has emerged as the optimal first-line treatment of hepatocellular carcinoma, lack of tumor targeting leads to low antitumor efficacy and serious side effect. Here, we report an ultra-pH-sensitive nanoparticle of gambogenic acid (GNA) encapsulated by poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA) for tumor-targeting combined therapy of anti-vascular strategy plus immunotherapy. PEG-PAEMA-GNA nanoparticle was quite stable at pH 7.4 for 30 d. In contrast, it exerted size shrinkage, charge reversal and the release of GNA at pH 6.7 within 24 h. Moreover, PEG-PAEMA-GNA significantly enhanced the anti-vascular activity, membrane-disruptive capability and pro-apoptosis when pH changed from 7.4 to 6.7. Western blot analysis exhibits that PEG-PAEMA and its GNA nanoparticle facilitated the phosphorylation of STING protein. In vivo assays show that PEG-PAEMA-GNA not only displayed much higher tumor inhibition of 92 % than 37 % of free GNA, but also inhibited tumor vasculature, promoted the maturation of dendritic cells and recruited more cytotoxic t-lymphocytes for sufficient anti-vascular therapy and immunotherapy. All these results demonstrate that PEG-PAEMA-GNA displayed tumor-targeting combined treatment of anti-vascular therapy and immunotherapy. This study offers a simple and novel method for the combination of anti-vascular therapy and immunotherapy with high selectivity towards tumor.

Membrane-disruptive homo-polymethacrylate with both hydrophobicity and pH-sensitive protonation for selective cancer therapy.

The membrane-disruptive strategy, which involves host defense peptides and their mimetics, is a revolutionary cancer treatment based on broad-spectrum anticancer activities. However, clinical application is limited by low selectivity towards tumors. In this context, we have established a highly selective anticancer polymer, i.e. poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA), that can mediate the membrane-disruptive activity via a subtle pH change between physiological pH and tumor acidity for selective cancer treatment. Specifically, the resulting PEG-PAEMA can assemble into neutral nanoparticles and silence the membrane-disruptive activity at physiological pH and disassemble into cationic free-chains or smaller nanoparticles with potent membrane-disruptive activity after the protonation of the PAEMA block due to tumor acidity, resulting in high selectivity towards tumors. Dramatically, PEG-PAEMA exhibited a >200-fold amplification in hemolysis and <5% in IC50 against Hepa1-6, SKOV3 and CT-26 cells at pH 6.7 as compared to those at pH 7.4, thanks to the selective membrane-disruptive mechanism. Moreover, mid- and high-dose PEG-PAEMA demonstrated higher anticancer efficacy than an optimal clinical prescription (bevacizumab plus PD-1) and, significantly, had few side effects on major organs in the tumor-bearing mice model, agreeing with the highly selective membrane-disruptive activity in vivo. Collectively, this work showcases the latent anticancer pharmacological activity of the PAEMA block, and also brings new hope for selective cancer therapy.

Temperature-responsive smart nanoreactors: poly(N-isopropylacrylamide)-coated Au@mesoporous-SiO2 hollow nanospheres.

A nanoreactor with temperature-responsive poly(N-isopopylacrylamide) (PNIPAM) coated on the external pore mouth of mesoporous silica hollow spheres and Au nanoparticles at the internal pore mouth were fabricated. Such spatial separation allows both Au nanoparticles and PNIPAM to function without interfering with each other. Transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier transform infrared (FTIR) spectra, and temperature-dependent optical transmittance curves demonstrate successful grafting of PNIPAM. This nanoreactor shows repeated on/off catalytic activity switched by temperature control. It shows excellent catalytic activity toward 4-nitrophenol (4-NP) reduction at 30 °C [below lower critical solution temperature (LCST) of PNIPAM] with a turnover frequency (TOF) of 14.8 h(-1). However, when the temperature was 50 °C (above LCST), the TOF dropped to 2.4 h(-1). Kinetic studies indicated that diffusion into the mesopores of the catalyst was the key factor, and the temperature-responsive behavior of PNIPAM was able to control this diffusion.

Shell-cross-linked micelles from PNIPAM-b-(PLL)2 Y-shaped miktoarm star copolymer as drug carriers.

Well-defined AB2 Y-shaped miktoarm star copolymers of PNIPAM-b-(PZLL)2 and PNIPAM-b-(PLL)2 were synthesized through the combination of atom transfer radical polymerization (ATRP), ring-opening polymerization (ROP), and click chemistry, where PNIPAM, PZLL, and PLL are poly(N-isopropylacrylamide), poly(epsilon-benzyloxy-carbonyl-L-lysine), and poly(L-lysine), respectively. Propargyl amine was employed as ROP initiator for the preparation of alkynyl-terminated PZLL. Diazide-terminated PNIPAM was obtained with an azide-containing ATRP initiator. The subsequent click reaction led to the formation of PNIPAM-b-(PZLL)2. After the removal of the benzyloxycarbonyl group, water-soluble PNIPAM-b-(PLL)2 was obtained. The core-shell micelles of PNIPAM-b-(PLL)2 were formed above lower critical solution temperature of PNIPAM block. At this temperature, the shell cross-linking was performed through the reaction between glutaraldehyde and the primary amine groups of the PLL shell, affording the micelles with the endurance to temperature and pH changes. These shell-cross-linked micelles were used as drug nanocarriers and the release profile was dually controlled by the solution temperature and the cross-linking degree.

A chemistry/physics pathway with nanofibrous scaffolds for gene delivery.

This perspective is to introduce a new pathway for non-viral gene delivery by taking advantage of nanofibrous scaffolds as gene storage devices, gene carriers and homing devices. During gene delivery to the target, the DNA has to be protected in order to pass through a set of barriers before reaching the nucleus. The DNA can form a complex with polycations, and numerous publications exist on how to stabilize the DNA fragments by natural and synthetic materials. Electrospun nanofibrous scaffolds can be used to store the DNA, especially in the form of a more stabilized polyplex, and then to deliver the DNA (polyplex) to cells that are attached to the scaffold. While each essential step has been tested experimentally, the overall yet untested process, especially for in vivo experiments, may lead to a promising specific approach for gene/drug storage and delivery. The pathway described herein is based mainly on our understanding of the physics and chemistry of gene storage and delivery processes, in contrast to using pure biological concepts. Novel biodegradable, biocompatible nanofibrous materials with imbedded DNA (e.g., in the polyplex form) can then be designed to fabricate an intelligent scaffold for gene delivery. To achieve the above goal, the first step is to stabilize the DNA so that it can be incorporated into nanofibrous scaffolds. In this respect, we shall discuss the different methods of DNA/gene condensation and complex formation, and then explain the strategy used to incorporate DNA into electrospun nanofibers. Solvent-induced DNA condensation and then encapsulation were achieved. However, the released naked DNA was not sufficiently protected for gene transfection in cells. The objective of the current perspective is to suggest that, instead of the solvent-induced DNA condensation, one can combine the recently developed polyplex formation by using branched polyethyleneimine (bPEI). More importantly, free bPEI can be incorporated into the nanofibers separately so that during the gene delivery step, the presence of a predesigned amount of free bPEI can greatly increase the gene transfection efficiency, as has been reported recently by Chi Wu and his coworkers. Thus, a physics/chemistry-based pathway that utilizes nanofibrous scaffolds for gene delivery is within reach.

Synthesis of silver @hydroxyapatite nanoparticles based biocomposite and their assessment for viability of Osseointegration for rabbit knee joint anterior cruciate ligament rehabilitation.

In this examination, chitosan-silk fibroin/polyethylene terephthalate (CTS-SF/PET), chitosan-silk fibroin/polyethylene terephthalate/hydroxyapatite (CTS-SF/PET/HAP) and chitosan-silk fibroin/polyethylene terephthalate/Silver @hydroxyapatite (CTS-SF/PET/Ag@HAP) scaffolds were prepared by utilizing the plasma splashing procedure. Field emission scanning electron microscopy (FESEM) results demonstrated that the outside of the PET covered with HAP nanoparticles. The cell viability results demonstrated that the number of Mesenchymal stem cells (MSCs) primarily spread out on CTS-SF/PET/Ag@HAP. RT-PCR results demonstrated that there was an upregulated mRNA articulation of osseous development-related properties in the CTS-SF/PET/Ag@HAP composite. The in vivo rabbit animal assessment scores of the CTS-SF/PET/Ag@HAP composite were significantly better than those of the CTS-SF/PET at 1 to 3 months. Both in-vivo and in-vitro results exhibited in this investigation recommend that the cytocompatibility and osseointegration of CTS-SF/PET/Ag@HAP tendon were fundamentally improved by expanding the multiplication of cells and up-regulating the outflow of tendon development-related properties. In conclusion, the CTS-SF/PET/Ag@HAP tendon is a promising candidate for Anterior Cruciate Ligament (ACL) replacement in the future.

Reduced matrix viscosity in DNA sequencing by CE and microchip electrophoresis using a novel thermo-responsive copolymer.

High viscosity is an inherent problem of sequencing matrices made of hydrophilic polymers. This problem is amplified in separations using microchips where the channels are even smaller. A novel thermal-associating graft copolymer, using linear polyacrylamide (LPA) as the backbone and poly(propylene oxide) (PPO) as the graft side chain was synthesized. The injection problem could be resolved by introducing PPO side chains that can be assembled by using temperature changes but without an obvious detrimental effect on the sieving ability of the LPA. Viscosity measurement showed that these LPA-g-PPO copolymers had a transition temperature of approximately 40 degrees C, above which a significant increase in viscosity was observed. The sequencing performance depended on the thermal association properties of PPO and related parameters. Without optimization, a read length of 1000 bases with a single base resolution of 0.3 was achieved within an hour on an ABI 310 analyzer, using 1.8 wt% LPA-g-PPO (1.8 MDa, PPO, 0.2%). This novel thermal reversible copolymer solution can be a promising candidate as a viable matrix for DNA sequencing in CE, and even more so in microchip electrophoresis.

Reversible thermo-responsive sieving matrix for oligonucleotide separation.

A reversible thermo-responsive gel system, consisting of Pluronic copolymer mixture of F87 and F127, has been used to successfully carry out the separation of oligonucleotides, for the first time, by microchip-based capillary electrophoresis. Pluronic triblock copolymers F87 (E(61)P(40)E(61)) and F127 (E(99)P(69)E(99)), with E, P, and subscript denoting oxyethylene, oxypropylene, and segment length respectively, have a unique temperature dependent viscosity-adjustable property and a dynamic coating ability in aqueous solution, including 1 x TBE buffer. The mixture solution has a reversible thermo-responsive property and its sol-gel transition temperature can be adjusted ranging from about 17 degrees C to 38 degrees C by varying the relative weight ratio of F87 and F127 at an optimized concentration of approximately 30% (w/v) for oligonucleotide separations. Oligonucleotide sizing markers ranging from 8 to 32 base could be successfully separated in a 1.5 cm long separation channel by the mixture solution in its gel-like state. A 30% (w/v) with a F87/F127 weight ratio of 1 ratio 2 which has a "sol-gel" transition point of about 26 degrees C shows the best sieving ability. The sieving ability of the mixture solution was further confirmed in an Agilent Bioanalyzer 2100 system. Fast separation of oligonucleotides has been achieved within 40 s with one base resolution.

Designing polymer matrix for microchip-based double-stranded DNA capillary electrophoresis.

Polyacrylamide (PAM) was used as a model polymer to build up an empirical model that relates polymer molecular weight, polymer concentration and solution viscosity. The desired random copolymers of acrylamide (AM) and N,N-dimethylacrylamide (DMA) used as DNA separation media for different specifications were synthesized under the guidance of the empirical model. The separation performances of rationally designed copolymers were tested in a 1.2 cm long separation channel, simulating microchip-based capillary electrophoresis. pBR322/HaeIII digest was successfully separated with good separation resolution and fast speed. Validation of the sieving ability of our polymers was performed in the Agilent 2,100 Bioanalyzer. The results of the 10 bp (base pair) DNA ladder separation demonstrate the potential of our approach for the sieving matrix in microchip-based electrophoresis.

Bactericidal Dendritic Polycation Cloaked with Stealth Material via Lipase-Sensitive Intersegment Acquires Neutral Surface Charge without Losing Membrane-Disruptive Activity.

Net cationicity of membrane-disruptive antimicrobials is necessary for their activity but may elicit immune attack when administered intravenously. By cloaking a dendritic polycation (G2) with poly(caprolactone-b-ethylene glycol) (PCL-b-PEG), we obtain a nanoparticle antimicrobial, G2-g-(PCL-b-PEG), which exhibits neutral surface charge but kills >99.9% of inoculated bacterial cells at ≤8 µg/mL. The observed activity may be attributed PCL's responsive degradation by bacterial lipase and the consequent exposure of the membrane-disruptive, bactericidal G2 core. Moreover, G2-g-(PCL-b-PEG) exhibits good colloidal stability in the presence of serum and insignificant hemolytic toxicity even at ≥2048 µg/mL. suggesting good blood compatibility required for intravenous administration.

Scale-up development of high-performance polymer matrix for DNA sequencing analysis.

Linear polyacrylamide (LPA) has been widely used as a replaceable separation matrix in CE. An increase in the molecular weight of the separation medium favors the separation of larger DNA fragments. In order to obtain ultrahigh-molecular-weight (UHMW) LPA, a "frozen" method was developed to synthesize the LPA homopolymer. This approach has three major advantages when compared with other existing routes of LPA synthesis: (i) long LPA chains could be obtained easily, with their average molecular weight (MW) being in the high 10 MDa range; (ii) the desired MW could be adjusted over a broad range by controlling the temperature and the concentration of initiators during synthesis; (iii) the product solution contains only a tiny amount of impurity besides the solvent and LPA. Both static and dynamic laser light scattering measurements were carried out to characterize the synthesized LPA in the buffer solution. The DNA sequencing matrix prepared from LPA using this method was studied and the results were compared with the newly developed commercial product POP7 from Applied Biosystems. It should be noted that this approach can be applied to synthesize other water-soluble polymers, resulting in UHMW products because the chain transfer constant is smaller at lower temperatures.

Fast separation of single-stranded oligonucleotides by capillary electrophoresis using OliGreen as fluorescence inducing agent.

The fast separation of oligonucleotide (oligos) sizing marker by CE using OliGreen and including effects due to the concentration of separation medium and urea denaturant is presented. OliGreen dye is found to be more sensitive than ethidium bromide (by a factor of about 6 based on S/N considerations) for the oligos' separations. Higher concentration of F127 in 1xTris-boricacid-EDTA (TBE) up to 30% w/v leads to better resolution of oligos separations. The addition of urea into the separation medium decreases the sensitivity. With an optimized running condition, the oligos sizing marker could be successfully separated with 1-base resolution within 1.3 min by using 30% w/v F127/1xTBE solution as the separation medium at an applied electric field of 800 V/cm in a 3 cm long capillary, the fastest capillary gel electrophoresis separation with high resolution reported to date for oligos in the similar size range.