Nano-induced endothelial leakiness-reversing nanoparticles for targeting, penetration and restoration of endothelial cell barrier.

Nano-induced endothelial leakiness (NanoEL) can improve the ability of nanoparticles (NPs) to enter the tumor environment, nevertheless, it can inadvertently trigger adverse effects such as tumor metastasis. To overcome these concerns, it becomes important to develop a NPs design strategy that capitalizes on the NanoEL effect while averting unwanted side effects during the drug delivery process. Herein, we introduce the PLGA-ICG-PEI-Ang1@M NP which has a core comprising poly (lactic-co-glycolic acid) (PLGA) and the inner shell with a highly positively charged polyethyleneimine (PEI) and the anti-permeability growth factor Angiopoietin 1 (Ang1), while the outer shell is camouflaged with a Jurkat cell membrane. During the drug delivery process, our NPs exhibit their capability to selectively target and penetrate endothelial cell layers. Once the NPs penetrate the endothelial layer, the proton sponge effect triggered by PEI in the acidic environment surrounding the tumor site can rupture the cell membrane on the NPs' surface. This rupture, in turn, enables the positively charged Ang1 to be released due to the electrostatic repulsion from PEI and the disrupted endothelial layer can be restored. Consequently, the designed NPs can penetrate endothelial layers, promote the cell layer recovery, restrict the tumor metastasis, and facilitate efficient cancer therapy. STATEMENT OF SIGNIFICANCE.

Thermo-sensitive amylase-starch double-layer polymer nanoparticles with self-polishing and protein corona-free property for drug delivery applications.

Protein corona formation can lead to obstructive screening of targeting groups of nanoparticles (NPs). Also, the targeting groups are subjected to physiochemical interactions when exposed to solvents. Here, these two factors can influence NP targeting efficiency. Therefore, it is necessary to prepare a general method of preparing an anti-fouling NPs with protected targeting groups. Here, we designed α-amylase-starch double-layer coated poly (methyl methacrylate-co-acrylic acid) NPs (α-ams-SCMMA NPs), functionalized with aptamer targeting groups and doped with Tetrakis(para-hydraoxylphenyl) porphyrin (TPPOH) as a payload drug. Natural polysaccharide starch and enzyme α-amylase were applied here for thermo-sensitive activation of starch hydrolyzation in order to render the NPs' self-polishing from protein corona effects. During incubation with serum media, the protein corona was formed at the exterior shell of NPs, while the self-polishing process was activated to remove the "protein fouling" when the incubation temperature increased to 37 °C (body temperature). Mechanistically, the starch layer of α-ams-SCMMA NPs was readily hydrolysed by α-amylase, whereby the adsorbed protein corona could be efficiently eliminated and the targeting groups were then presented. With this unique self-polishing NP design, we believe our method can be applied for potential NP applications in cancer therepy due to excellent antifouling property and protected targeting groups.

Phosphorylation of covalent organic framework nanospheres for inhibition of amyloid-ß peptide fibrillation.

The development and exploration of new nanostructural inhibitors against Alzheimer's disease (AD)-associated amyloid-ß (Aß) fibrillation have attracted extensive attention and become a new frontier in nanomedicine. However, focusing on finding an effective nanostructure is one of the most challenging parts of the therapeutics task. Herein, nanoscale spherical covalent organic frameworks (COFs) via post-synthetic functionalization with sodium phosphate (SP) groups on the channel networks were found to efficiently inhibit Aß fibrillation. The as-prepared uniform SP-COF nanospheres with high surface area, good crystallinity, and chemical stability were characterized by multifarious microscopic and spectroscopic techniques. Moreover, molecular dynamics simulation together with fibrillation kinetics and cytotoxicity assay experiments shows that there were restricted-access adsorption channels in the SP-COFs which were formed by the cavities with size and functional groups accommodated to the Aß peptide sequence and significantly affected the fibrillation and cytotoxicity of Aß. Transmission electron microscopy (TEM), dynamic light scattering (DLS) monitoring, isothermal titration calorimetry (ITC), Fourier transform infrared (FT-IR) and circular dichroism (CD) spectra measurements, and confocal imaging observation were performed to understand the inhibition mechanism and influencing factors of the SP-COFs. To our knowledge, our strategy is the first exploration of COF-based anti-amyloidogenic nanomaterials with high affinity and specific targeting, which are crucial for the inhibition of Aß fibrillation for AD prevention and treatment.

Aspartic Acid-Assisted Size-Controllable Synthesis of Nanoscale Spherical Covalent Organic Frameworks with Chiral Interfaces for Inhibiting Amyloid-ß Fibrillation.

Covalent organic framework nanospheres (COF NSs) have garnered special attention due to their uniform sphere morphology, adjustable particle size, and mesoporous microenvironment. However, methods to control an optimal particle size scale while achieving solution dispersibility and specific surface properties remain underdeveloped, which precludes many of the biomedical applications. Here, we propose and develop a general strategy to access simultaneous size control and surface functionalization of uniform spherical COF NSs in a single step using aspartic acid (d-/l-Asp) that plays center roles in an acid catalyst, hydrophilicity, size-controllable synthesis, and chiral enantiomer. In this study, for the first time, we have employed a surface chemistry engineering study to create a variety of nanoscale spherical COFs and subsequently measure parameters to evaluate the effectiveness of Asp in the regulation of the particle size. Moreover, the potential utilization of the d/l-enantiomeric Asp-COF NSs in preventing ß-amyloid (Aß) aggregation is investigated by analyzing their interactions with Aß amyloids using a multitechnique experimental approach. To our knowledge, our strategy is the first synthesis of hydrophilic COF NSs with an optimal length scale and a chiral-selective targeting surface, which are crucial for the inhibition of Aß fibrillation for Alzheimer's disease prevention.

Quantitative Analysis of Protein Corona on Precoated Protein Nanoparticles and Determined Nanoparticles with Ultralow Protein Corona and Efficient Targeting in Vivo.

The protein corona on nanoparticles (NPs) is a critical problem that often screens the targeting molecules and becomes one of the key reasons for the lack of practical application in nanotherapy. It is critical to fully understand the mechanism of the nanoparticle-biological interactions to design the nanoparticle-based therapeutic agents. Some types of proteins can be precoated on the nanoparticles to avoid unwanted protein attachment; however, the ultralow level of protein corona is hard to achieve, and the relationship of the antifouling property of the precoated protein nanoparticles with protein conformation and protein-nanoparticle interaction energy has never been investigated. In this work, we provided the quantitative protein corona composition analysis on different precoated protein nanoparticles, and on the basis of the molecular simulation process, we found their antifouling property strongly depended on the interaction energy of the precoated protein-serum protein pair and the number of hydrogen bonds formed between them. Furthermore, it also depended on the nanoparticle-serum protein pair interaction energy and the protein conformation on the nanoparticle. The casein coated nanoparticle with the antifouling property was determined, and after aptamer conjugation and drug loading, they exhibited superior targeting and internalization behavior for photodynamic and photothermal therapy in vitro and in vivo. Our work adds to the understanding of the protein corona behavior of precoated protein nanoparticles, and the determined antifouling NP can potentially be used as a highly efficient nanodrug carrier.

Stealthy nanoparticles protect endothelial barrier from leakiness by resisting the absorption of VE-cadherin.

Nanomaterial induced endothelial cell leakiness (NanoEL) is caused because nanomaterials enter the interstitial space of the endothelial cells and disrupt the endothelial cell-cell interactions by interacting with vascular endothelial cadherin (VE-cad). Whereas the NanoEL effect could cause controllable leakiness in cancer therapy, the gaps created by the NanoEL effect can make the cancer cells cross the endothelial barrier and produce side effects induced by using nanomedicine. In this paper, a series of ultralow protein corona nanoparticle is reported that can penetrate the endothelial cell junction without obviously interacting with the VE-cad and phosphorylating the tyrosine 658 (Y658) and tyrosine 731 (Y731) residues on VE-cad, thus preventing the VE-cad from being activated by Src kinase, and this avoids inducing of the NanoEL effect and cancer cell migration, regardless of particle material, density and surface charge. These findings provide a new idea for the design of novel nanoparticles without side effects and can maximize their cancer-killing effect.

The combined impact of protein corona-free property of starch coated poly (methyl methacrylate) nanoparticles: Amylose content and surface charge.

The protein corona on nano drug carriers is an important well-known biological issue that often induce biological incompatibility and screens the targeting molecules on the surfaces of carriers, therefore, the design of NPs with good protein corona-free property is highly desired and challenged. The natural polysaccharide has been demonstrated as one types of stealth materials after the functional group modification process, but the types and structures of their chains has never been considered. Here, we have designed five types of core-shell starch-coated poly (methyl methacrylate) nanoparticles and we found the starch coated NPs with low amylose content (<15%) could exhibit the excellent protein corona-free property without any modification and the starch with high amylose content coated NPs can also exhibit protein corona-free property after etherifying the surface of NPs to positive surface charge. Therefore, the combined impact of both low amylose content and positive surface charges by etherification modification of the starch can provide the excellent protein corona-free property for starch coated polymer NPs, that is very promising for highly efficient nano drug carries and marine coatings.

Amphoteric natural starch-coated polymer nanoparticles with excellent protein corona-free and targeting properties.

The protein corona on nano drug carriers is an important well-known biological issue that often induces biological incompatibility and screens the targeting molecules on the surfaces of carriers, thus causing a loss of targeting specificity. Although polyethylene glycol (PEG) and zwitterionic polymers have been widely used as anti-fouling materials, there still remain critical challenges for their use as protein-corona agents for drug delivery and targeting. Here, we have designed novel amphoteric natural starch-stabilized core-shell colloidal nanoparticles with more efficient protein corona-free properties, under long term circulation, at different protein concentrations and in different protein charge environments, compared to typical anti-fouling materials such as PEG and zwitterionic polymers. More importantly, the starch-coated polymer nanoparticles can be further functionalized by antibodies to achieve additional excellent targeting and cell internalization capabilities for their use in photodynamic therapy. Our findings demonstrate a novel protein-free or anti-fouling natural material that is very promising for use as highly efficient nano drug carriers and marine coatings.

Highly elastic and flexible transparent conductive films derived from latex copolymerization: P(SSNa-BA-St)/PEDOT/graphene.

We reported an innovative transparent, elastic and flexible conductive composite materials P(SSNa-BA-St)/PEDOT/graphene which were prepared by using P(SSNa-BA-St) latex as template for PEDOT polymerization and graphene doping. This P(SSNa-BA-St)/PEDOT/graphene film exhibited highly transparent, good water resistance, low moisture adsorption, highly elastic and highly conductive properties, which can serve as a practical approach to fabricate the flexible, conductive and transparent films for wearable and implantable electronic devices, and photovoltaic cells.

Energy-Saving Synthesis of MOF-Derived Hierarchical and Hollow Co(VO3)2-Co(OH)2 Composite Leaf Arrays for Supercapacitor Electrode Materials.

A one-step and energy-saving method was proposed to synthesize hierarchical and hollow Co(VO3)2-Co(OH)2 composite leaf arrays on carbon cloth, which expressed high capacitance (522 mF cm-2 or 803 F g-1 at the current density of 0.5 mA cm-2), good rate capability (79.5% capacitance retention after a 30-fold increase of the current density) and excellent cycling stability (90% capacitance retention after 15 000 charge-discharge cycles) when tested as a supercapacitor electrode.

A novel sensor made of Antimony Doped Tin Oxide-silica composite sol on a glassy carbon electrode modified by single-walled carbon nanotubes for detection of norepinephrine.

In this study, we designed a novel molecularly imprinted polymer (MIP), Antimony Doped Tin Oxide (ATO)-silica composite sol, which was made using a sol-gel method. Then a sensitive and selective imprinted electrochemical sensor was constructed with the ATO-silica composite sol on a glassy carbon electrode modified by single-walled carbon nanotubes (SWNTs). The introduction of SWNTs increased the sensitivity of the MIP sensor. The surface morphology of the MIP and MIP/SWNTs were characterized by scanning electron microscopy (SEM), and the optimal conditions for detection were determined. The oxidative peak current increased linearly with the concentration of norepinephrine in the range of 9.99×10-8M to 1.50×10-5M, as detected by cyclic voltammetry (CV), the detection limit was 3.33×10-8M (S/N=3). In addition, the proposed electrochemical sensors were successfully applied to detect the norepinephrine concentration in human blood serum samples. The recoveries of the sensors varied from 99.67% to 104.17%, indicating that the sensor has potential for the determination of norepinephrine in clinical tests. Moreover, the imprinted electrochemical sensor was used to selectively detect norepinephrine. The analytical application was conducted successfully and yielded accurate and precise results.

Application of Gemini quaternary ammonium with ester groups in cationic P(St-co-BA) nanolatex and study on its antibacterial properties.

Novel Gemini quaternary ammonium salts (GQASs) with ester groups were synthesized. Cationic poly(styrene-co-butyl acrylate) (P(St-co-BA)) nanolatex was synthesized in the presence of GQASs as emulsifier. The structures of GQASs were characterized with Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy; the property of P(St-co-BA) nanolatex was characterized with dynamic light scattering. The results indicated that GQASs and P(St-co-BA) nanolatex with GQASs were successfully synthesized. GQASs, nanolatex, and the polymer films exhibited excellent antibacterial activities against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. The GQASs performed even better than the corresponding single-stranded quaternary ammoniums. The antibacterial mechanism was also preliminarily studied, and longer, softer hydrophobic chains of GQAS had stronger antibacterial activity. The work provided a novel, simple approach for developing high-efficiency antibacterial polymer material with a low cost, which has broad biomaterial applications.

Stable poly(St-co-BA) nanoemulsion polymerization for high performance antibacterial coatings in the presence of dioctyldimethylammonium chloride.

In this study, a stable antibacterial poly(styrene-co-butyl acrylate) (poly(St-co-BA)) nano-latex was prepared in the presence of a dioctyldimethylammonium chloride (D821)-CTAB mixed surfactant and a novel bis-unsaturated Gemini comonomer (i.e., α,ω-hexanediyl bis(dimethyl methacrylamidopropyl ammonium bromide) (GMAP-6-MAP)) using a feasible and mild semicontinuous technology. The effects of the emulsifiers and GMAP-6-MAP on the properties and antibacterial activities of poly(St-co-BA) coatings were systematically investigated. The results indicate that an optimal monodispersed stable nanoemulsion was obtained with Dw=58.24nm and PDI=0.026, the emulsifier amount was 3.75% (D821/CTAB=4:1), and the GMAP-6-MAP amount was 1.5%. CTAB improved the stabilities and antibacterial activities of the poly(St-co-BA) nanoemulsions. The incorporation of GMAP-6-MAP into poly(St-co-BA) can enhance the antibacterial activity, improve the thermal stability of latex films, as well as the consistency among the chain segments, and decrease the roughness of latex films. This nanoemulsion exhibits effective antibacterial activity with MBCs of 2µg·mL(-1) against Staphylococcus aureus and 16µg·mL(-1) against Escherichia coli. The sterilization rates of the optimized latex film reached 100% against S. aureus and 98.74% against E. coli, which indicated that this latex film could be utilized as an outstanding antibacterial coating.

A novel, molecularly imprinted polymer sensor made using an oligomeric methyl silsesquioxane-TiO2 composite sol on a glassy carbon electrode for the detection of procainamide hydrochloride.

In this study, we designed a novel molecularly imprinted polymer (MIP), oligomeric methyl silsesquioxane (O-MSSQ)-TiO2 composite sol, which was made using a sol-gel reaction. This polymer has structural rigidity and high surface area of O-MSSQ, as well as high bio-compatibility and relatively good conductivity of the TiO2. Next, a sensitive and selective imprinted electrochemical sensor was successfully constructed for the direct detection of procainamide hydrochloride by molecularly imprinting a film onto the surface of a glassy carbon electrode. Adding TiO2 resulted in a noticeable enhancement in the sensitivity of the MIP sensor. The performance of the O-MSSQ-TiO2 film was discussed, and the optimal conditions for detection were determined. The oxidative peak current increased linearly with the concentration of procainamide hydrochloride in the range of 4.00 × 10(-9)-4.97 × 10(-5) M using differential pulse voltammetry, and the detection limit was 1.30 × 10(-9) M with S/N = 3. Furthermore, the sensor was applied to determine the procainamide hydrochloride content in a human blood serum sample. The recoveries of the sensors varied from 96.77% to 101.35%, indicating that the prepared sensor might be promising for the determination of procainamide hydrochloride in clinical tests. Moreover, the imprinted electrochemical sensor was used to selectively detect procainamide hydrochloride. The analytical application was conducted successfully and yielded accurate and precise results.

Resonance light scattering method for the determination of DNA with cationic methacrylate based polymer nanoparticle probes.

Narrowly distributed cationic poly (methyl methacrylate-co-diacetone acrylamide) (P(MMA-DAAM)) nanoparticles were successfully prepared by microemulsion polymerization. Photon correlation spectrometer (PCS) measurement and transmission electron microscope (TEM) observation revealed that z-average particle size of P(MMA-DAAM) is ∼27.5 nm. It was found that these cationic nanoparticles interact with DNA through electrostatic interaction to form P(MMA-DAAM)-DNA complex, which significantly enhances the resonance light scattering (RLS) signal. Therefore, a novel method using this polymer nanoparticle as a new probe for the detection of DNA by RLS technique is developed in this paper. The results showed this method is very convenient, sensitive, and reproducible.

Detection of DNA using cationic polyhedral oligomeric silsesquioxane nanoparticles as the probe by resonance light scattering technique.

A novel cationic polyhedral oligomeric silsesquioxane nanoparticle (cationic POSS) was synthesized and successfully used as a new probe for the detection of DNA by resonance light scattering technique (RLS). It was found that the electrostatic interaction of cationic POSS and DNA could obviously enhance the RLS signal, the enhanced RLS intensity at 360 nm was proportional to the concentration of nucleic acids within the range of 0.35-42.82 microg ml-1 for calf thymus DNA, the determination limit (3sigma) was 0.32 ng ml-1. The results showed this method was very sensitive, convenient, rapid and reproducible.

Investigation of thermodynamic properties of poly(methyl methacrylate-co-n-butylacrylate-co-cyclopentyl styryl-polyhedral oligomeric silsesquioxane) by inverse gas chromatography.

The thermodynamic properties of poly(methyl methacrylate-co-butyl acrylate-co-cyclo -pentylstyryl polyhedral oligomeric silsesquioxane) (poly(MMA-co-BA-co-styryl-POSS)) were investigated by means of inverse gas chromatography (IGC) using 20 different kinds of solvents as the probes. Some thermodynamic parameters, such as molar heats of sorption, weight fraction activity coefficient, Flory-Huggins interaction parameter, partial molar heats of mixing and solubility parameter were obtained to judge the interactions between POSS-contained polymers and solvents and the solubility of the polymers in these solvents. It was found that acetates, aromatic hydrocarbons and hydrocarbon halides were good solvents, n-hexane, ethanol, n-propanol, n-butanol and n-pentanol were moderate solvents, while n-heptane, n-octane, n-nonane, n-decane and methanol were poor solvents for all POSS-contained polymers within the experimental temperature range. Incorporation of POSS in polymer increased the solubility of polymers in solvents, and the more the POSS in polymer was, the better the solubility was and stronger the hydrogen bonding interaction was, but the POSS content in polymers seemed to have no obvious influence on the solubility parameter of polymers.

Surface characterization of poly(methyl methacrylate-co-n-butyl acrylate-co-cyclopentylstyryl-polyhedral oligomeric silsesquioxane) by inverse gas chromatography.

The surface properties of poly(methyl methacrylate-co-n-butyl acrylate-co-cyclopentylstyryl polyhedral oligomeric silsesquioxane) (poly(MMA-co-BA-co-styryl-POSS)) were studied by means of inverse gas chromatography (IGC) using 10 non-polar and polar solvents as the probes. Thermodynamic parameters of adsorption, e.g., specific retention volume, the dispersive component of the surface free energy, the specific interaction contribution to the free energy of adsorption and the acid/base constants were obtained to investigate the interactions between the surfaces of the copolymers and different solvents. It was found that incorporation of styryl-POSS into polymer resulted in increasing interactions between polymers and solvents, dispersive component of surface free energy of polymer and acidity of the surfaces of the polymers. The more the styryl-POSS were embedded, the stronger the interaction between the polymer surface and solvent, the dispersive component of the surface free energy and the acidity of the polymer surface were.

Electrochemical behavior of epinephrine at l-cysteine self-assembled monolayers modified gold electrode.

The electrochemical behaviors of epinephrine (EP) at the l-cysteine self-assembled monolayers modified gold electrode have been studied. The modified electrode shows an excellent electrocatalytic activity for the oxidation of EP and accelerates electron transfer rate. The diffusion coefficient (D) is 1.48x10(-7) cm(2) s(-1). FTIR has shown that cysteine can bind onto the gold surface through the strong sulfur-gold interaction. The electrocatalytic mechanism to EP has been studied. The catalytic current of EP nu s its concentration has a good linear relation in the range of 1.0x10(-7)-2.0x10(-6) mol l(-1), with the correlation coefficient of 0.9989 by differential pulse voltametric (DPV) response. Detection limit is down to 1.0x10(-8) mol l(-1). At a high EP concentration, the relationship between the catalytic current and its concentration exhibits a Michaelis-Menten kinetic mechanism for the electrocatalytic process and the constant K(m) is about 0.155 mmol l(-1). The highest catalytic current I(m) is 2.72 muA. The modified electrode can be used for the determination of EP in practical injection. The method is simple, quick, sensitive and accurate.

[Analysis of confined crystalline behaviors of poly(styrene)-poly(ethyleneoxide)-poly(styrene) triblock copolymers by inverse gas chromatography].

The confined crystalline behaviors of the triblock copolymers, poly(styrene)-poly(ethyleneoxide)-poly(styrene) (PS-PEO-PS), were studied by using inverse gas chromatography(IGC) probe technique, including phase-transformation of melting crystalline, crystallinity (Xc), melting temperature(Tm) and melting range of temperature. The effects of the molecule-chain length of linear alkane probes on the results are discussed. Results showed that micro-phase separation of PS-PEO-PS had a greater influence on crystallization of PEO molecule-chain. Crystalline-structure of PS-PEO-PS had interphase formed by some kinds of imperfect PEO crystal and amorphous PS. The molecule-chain length of linear alkane probes had no effect on the determination of melting temperature and melting range of temperature of PS-PEO-PS, but had a greater influence on the determination of crystallinity of PS-PEO-PS and investigation phase-transformation of melting crystalline. Crystallinity of PS-PEO-PS determined by IGC was decreased with the increase of molecule-chain length of linear alkane probes. By suitable shorter molecule-chain length of linear alkane probes, it was truer to reflect the existence of interphase of PS-PEO-PS and multi-phase-transformation of melting crystalline presenting in interphase.